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Sun ZG, Chen SX, Sun BL, Zhang DK, Sun HL, Chen H, Hu YW, Zhang TY, Han ZH, Wu WX, Hou ZY, Yao L, Jie JZ. Important role of lymphovascular and perineural invasion in prognosis of colorectal cancer patients with N1c disease. World J Gastroenterol 2025; 31:102210. [PMID: 39926214 PMCID: PMC11718613 DOI: 10.3748/wjg.v31.i5.102210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/04/2024] [Accepted: 12/16/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with decreased survival in colorectal cancer (CRC), but its significance in N1c stage remains to be clearly defined. AIM To evaluate LVI and PNI as potential prognostic indicators in N1c CRC. METHODS We retrospectively identified 107 consecutive patients who had CRC with N1c disease radically resected at our hospital. Tumors were reviewed for LVI and PNI by one pathologist blinded to the patients' outcomes. Disease-free survival (DFS), overall survival (OS) and cancer-specific survival (CSS) were determined using the Kaplan-Meier method, with LVI and PNI prognosis differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using log-rank test. The receiver operating characteristic (ROC) curve was used to evaluate the prognostic predictive ability. RESULTS The median follow-up time was 63.17 (45.33-81.37) months for DFS, with 33.64% (36/107) of patients experiencing recurrence; 21.5% of tumors were found to be LVI positive and 44.9% PNI positive. The 5-year DFS rate was greater for patients with LVI-negative tumors compared with LVI-positive tumors (74.0% vs 35.6%), and PNI was similar (82.5% vs 45.1%). On multivariate analysis, LVI [hazard ratio (HR) = 3.368, 95% confidence interval (CI): 1.628-6.966, P = 0.001] and PNI (HR = 3.055, 95%CI: 1.478-6.313, P = 0.002) were independent prognostic factors for DFS. All patients could be divided into three groups of patients with different prognosis according to LVI and PNI. The 5-year ROC curve for LVI, PNI and their combination prediction of DFS was 0.646, 0.709 and 0.759, respectively. Similar results were seen for OS and CSS. CONCLUSION LVI and PNI could serve as independent prognostic factors of outcomes in N1c CRC patients. Patients with LVI or PNI should be given more attention during treatment.
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Affiliation(s)
- Zhi-Gang Sun
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shao-Xuan Chen
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bai-Long Sun
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Da-Kui Zhang
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hong-Liang Sun
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Huang Chen
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yu-Wan Hu
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Tong-Yin Zhang
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Zi-Han Han
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wen-Xiao Wu
- Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhi-Yong Hou
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Li Yao
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jian-Zheng Jie
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
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Wu Y, Shang J, Zhang X, Li N. Advances in molecular imaging and targeted therapeutics for lymph node metastasis in cancer: a comprehensive review. J Nanobiotechnology 2024; 22:783. [PMID: 39702277 PMCID: PMC11657939 DOI: 10.1186/s12951-024-02940-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 10/19/2024] [Indexed: 12/21/2024] Open
Abstract
Lymph node metastasis is a critical indicator of cancer progression, profoundly affecting diagnosis, staging, and treatment decisions. This review article delves into the recent advancements in molecular imaging techniques for lymph nodes, which are pivotal for the early detection and staging of cancer. It provides detailed insights into how these techniques are used to visualize and quantify metastatic cancer cells, resident immune cells, and other molecular markers within lymph nodes. Furthermore, the review highlights the development of innovative, lymph node-targeted therapeutic strategies, which represent a significant shift towards more precise and effective cancer treatments. By examining cutting-edge research and emerging technologies, this review offers a comprehensive overview of the current and potential impact of lymph node-centric approaches on cancer diagnosis, staging, and therapy. Through its exploration of these topics, the review aims to illuminate the increasingly sophisticated landscape of cancer management strategies focused on lymph node assessment and intervention.
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Affiliation(s)
- Yunhao Wu
- Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Jin Shang
- Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xinyue Zhang
- The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
| | - Nu Li
- The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
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Zhu L, Bai Y, Li A, Wan J, Sun M, Lou X, Duan X, Sheng Y, Lei N, Qin Z. IFN-γ-responsiveness of lymphatic endothelial cells inhibits melanoma lymphatic dissemination via AMPK-mediated metabolic control. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167314. [PMID: 38936516 DOI: 10.1016/j.bbadis.2024.167314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 05/28/2024] [Accepted: 06/13/2024] [Indexed: 06/29/2024]
Abstract
The integrity of the lymphatic system is critical for preventing the dissemination of tumor cells, such as melanoma, to distant parts of the body. IFN-γ is well studied as a negative regulator for lymphangiogenesis, which is strongly associated with cancer metastasis. However, the exact mechanisms underlying this process remain unclear. In the present study, we investigated whether IFN-γ signaling in lymphatic endothelial cells (LECs) affects tumor cell dissemination by regulating the barrier function of tumor-associated lymphatic vessels. Using LEC-specific IFN-γ receptor (IFN-γR) knockout mice, we found that the loss of IFN-γR in LECs increased the dissemination of melanoma cells into the draining lymph nodes. Notably, IFN-γ signaling in LECs inhibited trans-lymphatic endothelial cell migration of melanoma cells, indicating its regulation of lymphatic barrier function. Further investigations revealed that IFN-γ upregulated the expression of the tight junction protein Claudin-3 in LECs, while knockdown of Claudin-3 in LECs abolished IFN-γ-induced inhibition of trans-lymphatic endothelial migration activity. Mechanistically, IFN-γ inhibits AMPK signaling activation, which is involved in the regulation of fatty acid metabolism. Modulating fatty acid metabolism and AMPK activation in LECs also affected the lymphatic dissemination of melanoma cells, further confirming that this process is involved in IFN-γ-induced regulation of lymphatic barrier function. These results provide novel insights into how IFN-γ modulates tight junctions in LECs, inhibiting the dissemination of melanoma cells via the lymphatic vessels.
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Affiliation(s)
- Linyu Zhu
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Yueyue Bai
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Anqi Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Jiajia Wan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Mengyao Sun
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaohan Lou
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Xixi Duan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuqiao Sheng
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Ningjing Lei
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China; Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
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Shi L, Lu S, Han X, Ye F, Li X, Zhang Z, Jiang Q, Yan B. Lymphatic-specific methyltransferase-like 3-mediated m 6A modification drives vascular patterning through prostaglandin metabolism reprogramming. MedComm (Beijing) 2024; 5:e728. [PMID: 39372388 PMCID: PMC11450254 DOI: 10.1002/mco2.728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/11/2024] [Accepted: 08/18/2024] [Indexed: 10/08/2024] Open
Abstract
Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N 6-methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase-like 3 (METTL3)-mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures-induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin-endoperoxide synthase 2 expression through an m6A-YTHDF2-dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic-specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis-related diseases.
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Affiliation(s)
- Lianjun Shi
- Department of Ophthalmology and OptometryThe Affiliated Eye Hospital, Nanjing Medical UniversityChina
- The Fourth School of Clinical MedicineNanjing Medical UniversityNanjingChina
| | - Shuting Lu
- The Fourth School of Clinical MedicineNanjing Medical UniversityNanjingChina
| | - Xue Han
- The Fourth School of Clinical MedicineNanjing Medical UniversityNanjingChina
| | - Fan Ye
- The Fourth School of Clinical MedicineNanjing Medical UniversityNanjingChina
| | - Xiumiao Li
- Department of Ophthalmology and OptometryThe Affiliated Eye Hospital, Nanjing Medical UniversityChina
| | - Ziran Zhang
- The Fourth School of Clinical MedicineNanjing Medical UniversityNanjingChina
| | - Qin Jiang
- Department of Ophthalmology and OptometryThe Affiliated Eye Hospital, Nanjing Medical UniversityChina
- The Fourth School of Clinical MedicineNanjing Medical UniversityNanjingChina
| | - Biao Yan
- Department of OphthalmologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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Shen G, Jia X, Qi T, Hu Z, Xiao A, Liu Q, He K, Guo W, Zhang D, Li W, Cao G, Li G, Tian J, Huang X, Hu Y. Data-Driven Design of Triple-Targeted Protein Nanoprobes for Multiplexed Imaging of Cancer Lymphatic Metastasis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2405877. [PMID: 38889909 DOI: 10.1002/adma.202405877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/06/2024] [Indexed: 06/20/2024]
Abstract
Targeted imaging of cancer lymphatic metastasis remains challenging due to its highly heterogeneous molecular and phenotypic diversity. Herein, triple-targeted protein nanoprobes capable of specifically binding to three targets for imaging cancer lymphatic metastasis, through a data-driven design approach combined with a synthetic biology-based assembly strategy, are introduced. Specifically, to address the diversity of metastatic lymph nodes (LNs), a combination of three targets, including C-X-C motif chemokine receptor 4 (CXCR4), transferrin receptor protein 1 (TfR1), and vascular endothelial growth factor receptor 3 (VEGFR3) is identified, leveraging machine leaning-based bioinformatics analysis and examination of LN tissues from patients with gastric cancer. Using this identified target combination, ferritin nanocage-based nanoprobes capable of specifically binding to all three targets are designed through the self-assembly of genetically engineered ferritin subunits using a synthetic biology approach. Using these nanoprobes, multiplexed imaging of heterogeneous metastatic LNs is successfully achieved in a polyclonal lymphatic metastasis animal model. In 19 freshly resected human gastric specimens, the signal from the triple-targeted nanoprobes significantly differentiates metastatic LNs from benign LNs. This study not only provides an effective nanoprobe for imaging highly heterogeneous lymphatic metastasis but also proposes a potential strategy for guiding the design of targeted nanomedicines for cancer lymphatic metastasis.
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Affiliation(s)
- Guodong Shen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaohua Jia
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Department of Ultrasound, Shuozhou Grand Hospital of Shanxi Medical University, Shuozhou, 036000, China
| | - Tianyi Qi
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhenhua Hu
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Anqi Xiao
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Qiqi Liu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Keyu He
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Weihong Guo
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Dan Zhang
- Center of Biomedical Analysis, Tsinghua University, Beijing, 100084, China
| | - Wanjun Li
- Department of Pathology, Affiliated 3201 Hospital of Xi'an Jiaotong University, Hanzhong, 723000, China
| | - Genmao Cao
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Guoxin Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jie Tian
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing, 100191, China
| | - Xinglu Huang
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yanfeng Hu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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Li JJ, Mao JX, Zhong HX, Zhao YY, Teng F, Lu XY, Zhu LY, Gao Y, Fu H, Guo WY. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review. World J Hepatol 2024; 16:537-549. [PMID: 38689749 PMCID: PMC11056903 DOI: 10.4254/wjh.v16.i4.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/24/2024] Open
Abstract
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Affiliation(s)
- Jing-Jing Li
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia-Xi Mao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Han-Xiang Zhong
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Yu Zhao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xin-Yi Lu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Ye Zhu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yang Gao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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Mei X, Xiong J, Liu J, Huang A, Zhu D, Huang Y, Wang H. DHCR7 promotes lymph node metastasis in cervical cancer through cholesterol reprogramming-mediated activation of the KANK4/PI3K/AKT axis and VEGF-C secretion. Cancer Lett 2024; 584:216609. [PMID: 38211648 DOI: 10.1016/j.canlet.2024.216609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/13/2023] [Accepted: 12/28/2023] [Indexed: 01/13/2024]
Abstract
Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. However, the molecular mechanism of LNM in CC is unclear, and there is no effective clinical treatment. Here, we found that 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the last step of cholesterol synthesis, was upregulated in CC and closely related to LNM. Gain-of-function and loss-of-function experiments proved that DHCR7 promoted the invasion ability of CC cells and lymphangiogenesis in vitro and induced LNM in vivo. The LNM-promoting effect of DHCR7 was partly mediated by upregulating KN motif and ankyrin repeat domains 4 (KANK4) expression and subsequently activating the PI3K/AKT signaling pathway. Alternatively, DHCR7 promoted the secretion of vascular endothelial growth factor-C (VEGF-C), and thereby lymphangiogenesis. Interestingly, cholesterol reprogramming was needed for the DHCR7-mediated promotion of activation of the KANK4/PI3K/AKT axis, VEGF-C secretion, and subsequent LNM. Importantly, treatment with the DHCR7 inhibitors AY9944 and tamoxifen (TAM) significantly inhibited LNM of CC, suggesting the clinical application potential of DHCR7 inhibitors in CC. Collectively, our results uncover a novel molecular mechanism of LNM in CC and identify DHCR7 as a new potential therapeutic target.
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Affiliation(s)
- Xinyu Mei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Jinfeng Xiong
- Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Jian Liu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Anni Huang
- Department of Medical, Guangxi Hospital, The First Affiliated Hospital, Sun Yat-sen University, Nanning, Guangxi, 530022, China
| | - Da Zhu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Yafei Huang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, And State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Hui Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
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Sáinz-Jaspeado M, Ring S, Proulx ST, Richards M, Martinsson P, Li X, Claesson-Welsh L, Ulvmar MH, Jin Y. VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis. Life Sci Alliance 2024; 7:e202302168. [PMID: 38148112 PMCID: PMC10751244 DOI: 10.26508/lsa.202302168] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 12/28/2023] Open
Abstract
The endothelial junction component vascular endothelial (VE)-cadherin governs junctional dynamics in the blood and lymphatic vasculature. Here, we explored how lymphatic junction stability is modulated by elevated VEGFA signaling to facilitate metastasis to sentinel lymph nodes. Zippering of VE-cadherin junctions was established in dermal initial lymphatic vessels after VEGFA injection and in tumor-proximal lymphatics in mice. Shape analysis of pan-cellular VE-cadherin fragments revealed that junctional zippering was accompanied by accumulation of small round-shaped VE-cadherin fragments in the lymphatic endothelium. In mice expressing a mutant VEGFR2 lacking the Y949 phosphosite (Vegfr2 Y949F/Y949F ) required for activation of Src family kinases, zippering of lymphatic junctions persisted, whereas accumulation of small VE-cadherin fragments was suppressed. Moreover, tumor cell entry into initial lymphatic vessels and subsequent metastatic spread to lymph nodes was reduced in mutant mice compared with WT, after challenge with B16F10 melanoma or EO771 breast cancer. We conclude that VEGFA mediates zippering of VE-cadherin junctions in initial lymphatics. Zippering is accompanied by increased VE-cadherin fragmentation through VEGFA-induced Src kinase activation, correlating with tumor dissemination to sentinel lymph nodes.
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Affiliation(s)
- Miguel Sáinz-Jaspeado
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Sarah Ring
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Steven T Proulx
- ETH Zürich, Institute of Pharmaceutical Sciences, Zürich, Switzerland
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Mark Richards
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Pernilla Martinsson
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Xiujuan Li
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Lena Claesson-Welsh
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Maria H Ulvmar
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Yi Jin
- Beijer and Science for Life Laboratories, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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Miao D, Shi J, Lv Q, Tan D, Zhao C, Xiong Z, Zhang X. NAT10-mediated ac 4C-modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear-cell renal cell carcinoma by attenuating YWHAE-driven cytoplasmic retention of YAP1. Cancer Commun (Lond) 2024; 44:361-383. [PMID: 38407929 PMCID: PMC10962679 DOI: 10.1002/cac2.12523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/30/2024] [Accepted: 02/03/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma (ccRCC). N-acetyltransferase 10 (NAT10) is known to catalyze N4-acetylcytidine (ac4C) modification of mRNA and participate in many cellular processes. However, its role in the lymphangiogenic process of ccRCC has not been reported. This study aimed to elucidate the role of NAT10 in ccRCC lymphangiogenesis, providing valuable insights into potential therapeutic targets for intervention. METHODS ac4C modification and NAT10 expression levels in ccRCC were assessed using public databases and clinical samples. Functional investigations involved manipulating NAT10 expression in cellular and mouse models to study its role in ccRCC. Mechanistic insights were gained through a combination of RNA sequencing, mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, and site-specific mutation analyses. RESULTS We found that ac4C modification and NAT10 expression levels increased in ccRCC. NAT10 promoted tumor progression and lymphangiogenesis of ccRCC by enhancing the nuclear import of Yes1-associated transcriptional regulator (YAP1). Subsequently, we identified ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1 (ANKZF1) as the functional target of NAT10, and its upregulation in ccRCC was caused by NAT10-mediated ac4C modification. Mechanistic analyses demonstrated that ANKZF1 interacted with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) to competitively inhibit cytoplasmic retention of YAP1, leading to transcriptional activation of pro-lymphangiogenic factors. CONCLUSIONS These results suggested a pro-cancer role of NAT10-mediated acetylation in ccRCC and identified the NAT10/ANKZF1/YAP1 axis as an under-reported pathway involving tumor progression and lymphangiogenesis in ccRCC.
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Affiliation(s)
- Daojia Miao
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Jian Shi
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Qingyang Lv
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Diaoyi Tan
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Chuanyi Zhao
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Zhiyong Xiong
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Xiaoping Zhang
- Department of UrologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP. R. China
- Institute of UrologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
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10
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Fan S, Qi M, Qi Q, Miao Q, Deng L, Pan J, Qiu S, He J, Huang M, Li X, Huang J, Lin J, Lyu W, Deng W, He Y, Liu X, Gao L, Zhang D, Ye W, Chen M. Targeting FAP α-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis. Acta Pharm Sin B 2024; 14:682-697. [PMID: 38322324 PMCID: PMC10840431 DOI: 10.1016/j.apsb.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/18/2023] [Accepted: 10/24/2023] [Indexed: 02/08/2024] Open
Abstract
Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
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Affiliation(s)
- Shuran Fan
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Ming Qi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Qi Qi
- School of Medicine, Jinan University, Guangzhou 510632, China
| | - Qun Miao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Lijuan Deng
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China
| | - Jinghua Pan
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Shenghui Qiu
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Jiashuai He
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Maohua Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaobo Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jie Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jiapeng Lin
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Wenyu Lyu
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Weiqing Deng
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yingyin He
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xuesong Liu
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Lvfen Gao
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Dongmei Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Wencai Ye
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Minfeng Chen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
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11
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Du R, Li K, Guo K, Chen Z, Zhao X, Han L, Bian H. Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target. Front Oncol 2024; 14:1309687. [PMID: 38347836 PMCID: PMC10859502 DOI: 10.3389/fonc.2024.1309687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/12/2024] [Indexed: 02/15/2024] Open
Abstract
Transducin beta-like 1X-related protein 1 (TBL1XR1) was discovered two decades ago and was implicated as part of the nuclear transcription corepressor complex. Over the past 20 years, the emerging oncogenic function of TBL1XR1 in cancer development has been discovered. Recent studies have highlighted that the genetic aberrations of TBL1XR1 in cancers, especially in hematologic tumors, are closely associated with tumorigenesis. In solid tumors, TBL1XR1 is proposed to be a promising prognostic biomarker due to the correlation between abnormal expression and clinicopathological parameters. Post-transcriptional and post-translational modification are responsible for the expression and function of TBL1XR1 in cancer. TBL1XR1 exerts its functional role in various processes that involves cell cycle and apoptosis, cell proliferation, resistance to chemotherapy and radiotherapy, cell migration and invasion, stemness and angiogenesis. Multitude of cancer-related signaling cascades like Wnt-β-catenin, PI3K/AKT, ERK, VEGF, NF-κB, STAT3 and gonadal hormone signaling pathways are tightly modulated by TBL1XR1. This review provided a comprehensive overview of TBL1XR1 in tumorigenesis, shedding new light on TBL1XR1 as a promising diagnostic biomarker and druggable target in cancer.
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Affiliation(s)
- Ruijuan Du
- Zhang Zhongjing School of Chinese Medicine, Nanyang Institute of Technology, Nanyang, Henan, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, Henan, China
| | - Kai Li
- Zhang Zhongjing School of Chinese Medicine, Nanyang Institute of Technology, Nanyang, Henan, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, Henan, China
| | - KeLei Guo
- Zhang Zhongjing School of Chinese Medicine, Nanyang Institute of Technology, Nanyang, Henan, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, Henan, China
| | - Zhiguo Chen
- Zhang Zhongjing School of Chinese Medicine, Nanyang Institute of Technology, Nanyang, Henan, China
| | - Xulin Zhao
- Oncology Department, Nanyang First People’s Hospital, Nan Yang, Henan, China
| | - Li Han
- Zhang Zhongjing School of Chinese Medicine, Nanyang Institute of Technology, Nanyang, Henan, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, Henan, China
| | - Hua Bian
- Zhang Zhongjing School of Chinese Medicine, Nanyang Institute of Technology, Nanyang, Henan, China
- Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang, Henan, China
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12
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Lim WJ, Chan PF, Hamid RA. A 1, 4-benzoquinone derivative isolated from Ardisia crispa (Thunb.) A. DC. root suppresses angiogenesis via its angiogenic signaling cascades. Saudi Pharm J 2024; 32:101891. [PMID: 38111673 PMCID: PMC10727947 DOI: 10.1016/j.jsps.2023.101891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 11/30/2023] [Indexed: 12/20/2023] Open
Abstract
The root hexane extract of Ardisia crispa (ACRH), which belongs to the Primulaceae family, has been reported to possess anti-inflammatory, chemopreventive, anti-arthritic, and antiangiogenic activities. In this study, we isolated a p-benzoquinone derivative, 2-methoxy-6-undecyl-1,4-benzoquinone (AC2), from ACRH and investigated its potential antiangiogenic activity in human umbilical vein endothelial cells (HUVECs) and zebrafish embryo models. Prior to this study, AC2 was characterized using 1H NMR spectroscopy and MS. AC2 significantly suppressed HUVEC proliferation in a time-independent manner, with an IC50 value of 1.35 ± 0.05, 1.15 ± 0.02, and 1.00 ± 0.01 µg/mL at 24, 48, and 72 h, respectively. AC2 also induced apoptosis in HUVECs and significantly suppressed their migration, invasion, and tube formation in a concentration-dependent manner. Additionally, AC2 significantly attenuated most of the analyzed protein markers, including pro-MMP-2, VEGF-C, VEGF-D, angiopoietin-2, endothelin-1, fibroblast growth factor (FGF)-1, FGF-2, follistatin, heparin-binding epidermal growth factor-like growth factor (HB-EGF), and hepatocyte growth factor (HGF) at all tested concentrations. Furthermore, AC2 significantly inhibited zebrafish embryo intersegmental vessels (ISVs), confirming its antiangiogenic role. In conclusion, AC2 exhibits a potential anti-angiogenic effect by suppressing several proangiogenic and growth factors. Further studies are needed to investigate their effects on other excessive angiogenic diseases.
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Affiliation(s)
- Wen Jun Lim
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Pit Foong Chan
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Roslida Abd Hamid
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
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13
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Bou Malham V, Benzoubir N, Vaquero J, Desterke C, Agnetti J, Song PX, Gonzalez-Sanchez E, Arbelaiz A, Jacques S, Di Valentin E, Rahmouni S, Tan TZ, Samuel D, Thiery JP, Sebagh M, Fouassier L, Gassama-Diagne A. Intrinsic cancer cell phosphoinositide 3-kinase δ regulates fibrosis and vascular development in cholangiocarcinoma. Liver Int 2023; 43:2776-2793. [PMID: 37804055 DOI: 10.1111/liv.15751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/06/2023] [Accepted: 09/16/2023] [Indexed: 10/08/2023]
Abstract
BACKGROUND & AIMS The class I- phosphatidylinositol-3 kinases (PI3Ks) signalling is dysregulated in almost all human cancers whereas the isoform-specific roles remain poorly investigated. We reported that the isoform δ (PI3Kδ) regulated epithelial cell polarity and plasticity and recent developments have heightened its role in hepatocellular carcinoma (HCC) and solid tumour progression. However, its role in cholangiocarcinoma (CCA) still lacks investigation. APPROACH & RESULTS Immunohistochemical analyses of CCA samples reveal a high expression of PI3Kδ in the less differentiated CCA. The RT-qPCR and immunoblot analyses performed on CCA cells stably overexpressing PI3Kδ using lentiviral construction reveal an increase of mesenchymal and stem cell markers and the pluripotency transcription factors. CCA cells stably overexpressing PI3Kδ cultured in 3D culture display a thick layer of ECM at the basement membrane and a wide single lumen compared to control cells. Similar data are observed in vivo, in xenografted tumours established with PI3Kδ-overexpressing CCA cells in immunodeficient mice. The expression of mesenchymal and stemness genes also increases and tumour tissue displays necrosis and fibrosis, along with a prominent angiogenesis and lymphangiogenesis, as in mice liver of AAV8-based-PI3Kδ overexpression. These PI3Kδ-mediated cell morphogenesis and stroma remodelling were dependent on TGFβ/Src/Notch signalling. Whole transcriptome analysis of PI3Kδ using the cancer cell line encyclopedia allows the classification of CCA cells according to cancer progression. CONCLUSIONS Overall, our results support the critical role of PI3Kδ in the progression and aggressiveness of CCA via TGFβ/src/Notch-dependent mechanisms and open new directions for the classification and treatment of CCA patients.
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Affiliation(s)
- Vanessa Bou Malham
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
| | - Nassima Benzoubir
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
| | - Javier Vaquero
- Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France
- Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
| | | | - Jean Agnetti
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
| | - Pei Xuan Song
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
| | - Ester Gonzalez-Sanchez
- Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Inovarion, Paris, France
| | - Ander Arbelaiz
- Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France
| | - Sophie Jacques
- Laboratory of Animal Genomics, GIGA-Medical Genomics, GIGA-Institute, University of Liège, Liège, Belgium
| | - Emanuel Di Valentin
- Plateforme des vecteurs viraux, Université de Liège, GIGA B34, Liège, Belgium
| | - Souad Rahmouni
- Laboratory of Animal Genomics, GIGA-Medical Genomics, GIGA-Institute, University of Liège, Liège, Belgium
| | - Tuan Zea Tan
- Genomics and Data Analytics Core (GeDaC), Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Didier Samuel
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
- Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Villejuif, France
| | - Jean Paul Thiery
- Guangzhou Laboratory, International Biological Island Guangzhou, Guangzhou, China
| | - Mylène Sebagh
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
- Laboratoire d'Anatomopathologie, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Laura Fouassier
- Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, INSERM, Paris, France
| | - Ama Gassama-Diagne
- INSERM, Unité 1193, Villejuif, France
- Université Paris-Saclay, UMR-S 1193, Villejuif, France
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14
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Hong M, Talluri S, Chen YY. Advances in promoting chimeric antigen receptor T cell trafficking and infiltration of solid tumors. Curr Opin Biotechnol 2023; 84:103020. [PMID: 37976958 DOI: 10.1016/j.copbio.2023.103020] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 09/05/2023] [Accepted: 10/23/2023] [Indexed: 11/19/2023]
Abstract
T cells engineered to express chimeric antigen receptors (CARs) have demonstrated robust response rates in treating hematological malignancies. However, solid tumors present multiple challenges that hinder the antitumor efficacy of CAR-T cells, including antigen heterogeneity, off-tumor and systemic toxicities, and the immunosuppressive milieu of the tumor microenvironment (TME). Notably, the TME of solid tumors is characterized by chemokine dysregulation and a dense architecture consisting of tumor stroma, extracellular matrix, and aberrant vasculature that impede migration of CAR-T cells to the tumor site as well as infiltration into the solid-tumor mass. In this review, we highlight recent advances to improve CAR-T-cell trafficking to and infiltration of solid tumors to promote effective antigen recognition by CAR-T cells.
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Affiliation(s)
- Mihe Hong
- Department of Chemical and Biomolecular Engineering, University of California-Los Angeles, Los Angeles, CA 90095, USA
| | - Sohan Talluri
- Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90095, USA
| | - Yvonne Y Chen
- Department of Chemical and Biomolecular Engineering, University of California-Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA 90095, USA.
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15
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Matsui K, Torii S, Hara S, Maruyama K, Arai T, Imanaka-Yoshida K. Tenascin-C in Tissue Repair after Myocardial Infarction in Humans. Int J Mol Sci 2023; 24:10184. [PMID: 37373332 DOI: 10.3390/ijms241210184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 06/09/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Adverse ventricular remodeling after myocardial infarction (MI) is progressive ventricular dilatation associated with heart failure for weeks or months and is currently regarded as the most critical sequela of MI. It is explained by inadequate tissue repair due to dysregulated inflammation during the acute stage; however, its pathophysiology remains unclear. Tenascin-C (TNC), an original member of the matricellular protein family, is highly up-regulated in the acute stage after MI, and a high peak in its serum level predicts an increased risk of adverse ventricular remodeling in the chronic stage. Experimental TNC-deficient or -overexpressing mouse models have suggested the diverse functions of TNC, particularly its pro-inflammatory effects on macrophages. The present study investigated the roles of TNC during human myocardial repair. We initially categorized the healing process into four phases: inflammatory, granulation, fibrogenic, and scar phases. We then immunohistochemically examined human autopsy samples at the different stages after MI and performed detailed mapping of TNC in human myocardial repair with a focus on lymphangiogenesis, the role of which has recently been attracting increasing attention as a mechanism to resolve inflammation. The direct effects of TNC on human lymphatic endothelial cells were also assessed by RNA sequencing. The results obtained support the potential roles of TNC in the regulation of macrophages, sprouting angiogenesis, the recruitment of myofibroblasts, and the early formation of collagen fibrils during the inflammatory phase to the early granulation phase of human MI. Lymphangiogenesis was observed after the expression of TNC was down-regulated. In vitro results revealed that TNC modestly down-regulated genes related to nuclear division, cell division, and cell migration in lymphatic endothelial cells, suggesting its inhibitory effects on lymphatic endothelial cells. The present results indicate that TNC induces prolonged over-inflammation by suppressing lymphangiogenesis, which may be one of the mechanisms underlying adverse post-infarct remodeling.
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Affiliation(s)
- Kenta Matsui
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu 514-8507, Japan
| | - Sota Torii
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu 514-8507, Japan
| | - Shigeru Hara
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu 514-8507, Japan
| | - Kazuaki Maruyama
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu 514-8507, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 3-52 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan
| | - Kyoko Imanaka-Yoshida
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu 514-8507, Japan
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16
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Qiu W, Zhong X, Jiang J, Huang L, Li J, Zheng R, Cai Z, Yuan Y. Prognostic significance of cervical radiologic carotid artery invasion by lymph node on magnetic resonance imaging in nasopharyngeal carcinoma. Cancer Imaging 2023; 23:26. [PMID: 36915156 PMCID: PMC10009921 DOI: 10.1186/s40644-023-00544-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 03/07/2023] [Indexed: 03/16/2023] Open
Abstract
PURPOSE Carotid artery invasion (CAI) has been demonstrated to be an important prognosticator in some head and neck cancers. This study aimed to examine the prognostic value of radiologic CAI (rCAI) by cervical lymphadenopathy in nasopharyngeal carcinoma (NPC). METHODS NPC patients treated between January 2013 and December 2016 were included. Pre-treatment MRIs were reviewed for cervical rCAI according to the radiologic criteria. Univariate and multivariate models were constructed to assess the association between cervical rCAI and clinical outcomes. A new N classification system was proposed and compared to the 8th AJCC system. RESULTS The percentage of patients with MRI-positive lymph nodes was 84.7% (494/583), of whom cervical rCAI cases accounted for 42.3% (209/494). Cervical rCAI was associated with significantly poorer OS, DFS, DFFS and RFFS compared to non-rCAI (P < 0.05). Multivariate analyses confirmed that cervical rCAI was an independent prognosticator for DFS and DFFS, surpassing other nodal features, such as laterality, size, cervical node necrosis (CNN) and radiologic extranodal extension (rENE), while location of positive LNs remained independently associated with OS, DFS and DFFS. We propose a refined N classification: New_N1: upper neck LNs only without cervical rCAI; New_N2: upper neck LNs only with cervical rCAI; New_N3: upper and lower LNs. The proposed classification broadened the differences in OS, DFS and DFFS between N1 and N2 disease, and achieved a higher c-index for DFS and DFFS. CONCLUSIONS Cervical rCAI was an independent unfavorable indicator of NPC. Compared to the AJCC system, the proposed N category showed satisfactory stratification between N1 and N2 disease, and better prediction of distant metastasis and disease failure.
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Affiliation(s)
- Wenze Qiu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Xi Zhong
- Department of Radiology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Jiali Jiang
- Health Ward, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Laiji Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Jiansheng Li
- Department of Radiology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Ronghui Zheng
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China.
| | - Zhuochen Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, China. .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China.
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17
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Zhang X, Liu J, Yang X, Jiao W, Shen C, Zhao X, Wang Y. High expression of COL6A1 predicts poor prognosis and response to immunotherapy in bladder cancer. Cell Cycle 2023; 22:610-618. [PMID: 36474424 PMCID: PMC9928451 DOI: 10.1080/15384101.2022.2154551] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Extracellular matrix (ECM), as an important framework for tumor microenvironment, plays important roles in many critical processes, including tumor growth, invasion, immune suppression, and drug resistance. However, few biomarkers of ECM-related genes (ERGs) have been developed for prognosis prediction and clinical treatment of bladder cancer (BC) patients. Bioinformatics analysis and LC-MS/MS analysis were used to screen differentially expressed ERGs in BC. Multivariate Cox regression analysis and Lasso regression analysis were used to construct and validate an ERGs-based prognostic prediction model for BC. Immunohistochemistry was used to detect the protein expression of hub gene-COL6A1 in BC patients. Using bioinformatics analysis from The Cancer Genome Atlas (TCGA) database and proteomic analysis from our BC cohort, we constructed and validated an effective prognostic prediction model for BC patients based on four differentially expressed ERGs (MAP1B, FBN1, COL6A1, and MFAP5). Moreover, we identified human collagen VI-COL6A1 was a hub gene in this prognostic prediction model and found that COL6A1 was closely related to malignancy progression, prognosis, and response to PD-1 inhibitor immunotherapy in BC. Our findings highlight the satisfactory predictive value of ECM-related prognostic models in BC and suggested that COL6A1 may be a potential biomarker in predicting malignant progression, prognosis, and efficacy of immunotherapy in BC.
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Affiliation(s)
- Xuezhou Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jing Liu
- Department of Research Management and International Cooperation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xuecheng Yang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Wei Jiao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Chengquan Shen
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xinzhao Zhao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yonghua Wang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China,CONTACT Yonghua Wang Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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Li A, Zhu L, Lei N, Wan J, Duan X, Liu S, Cheng Y, Wang M, Gu Z, Zhang H, Bai Y, Zhang L, Wang F, Ni C, Qin Z. S100A4-dependent glycolysis promotes lymphatic vessel sprouting in tumor. Angiogenesis 2023; 26:19-36. [PMID: 35829860 DOI: 10.1007/s10456-022-09845-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/20/2022] [Indexed: 01/12/2023]
Abstract
Tumor-induced lymphangiogenesis promotes the formation of new lymphatic vessels, contributing to lymph nodes (LNs) metastasis of tumor cells in both mice and humans. Vessel sprouting appears to be a critical step in this process. However, how lymphatic vessels sprout during tumor lymphangiogenesis is not well-established. Here, we report that S100A4 expressed in lymphatic endothelial cells (LECs) promotes lymphatic vessel sprouting in a growing tumor by regulating glycolysis. In mice, the loss of S100A4 in a whole body (S100A4-/-), or specifically in LECs (S100A4ΔLYVE1) leads to impaired tumor lymphangiogenesis and disrupted metastasis of tumor cells to sentinel LNs. Using a 3D spheroid sprouting assay, we found that S100A4 in LECs was required for the lymphatic vessel sprouting. Further investigations revealed that S100A4 was essential for the position and motility of tip cells, where it activated AMPK-dependent glycolysis during lymphatic sprouting. In addition, the expression of S100A4 in LECs was upregulated under hypoxic conditions. These results suggest that S100A4 is a novel regulator of tumor-induced lymphangiogenesis. Targeting S100A4 in LECs may be a potential therapeutic strategy for lymphatic tumor metastasis.
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Affiliation(s)
- Anqi Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
| | - Linyu Zhu
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
| | - Ningjing Lei
- School of Basic Medical Sciences, The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
| | - Jiajia Wan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Xixi Duan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuangqing Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yanru Cheng
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Ming Wang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhuoyu Gu
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Huilei Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yueyue Bai
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Li Zhang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Fazhan Wang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Ni
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
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Dharavath B, Butle A, Pal A, Desai S, Upadhyay P, Rane A, Khandelwal R, Manavalan S, Thorat R, Sonawane K, Vaish R, Gera P, Bal M, D'Cruz AK, Nair S, Dutt A. Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer. Commun Biol 2023; 6:57. [PMID: 36650344 PMCID: PMC9845355 DOI: 10.1038/s42003-023-04437-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023] Open
Abstract
Occult lymph-node metastasis is a crucial predictor of tongue cancer mortality, with an unmet need to understand the underlying mechanism. Our immunohistochemical and real-time PCR analysis of 208 tongue tumors show overexpression of Matrix Metalloproteinase, MMP10, in 86% of node-positive tongue tumors (n = 79; p < 0.00001). Additionally, global profiling for non-coding RNAs associated with node-positive tumors reveals that of the 11 significantly de-regulated miRNAs, miR-944 negatively regulates MMP10 by targeting its 3'-UTR. We demonstrate that proliferation, migration, and invasion of tongue cancer cells are suppressed by MMP10 knockdown or miR-944 overexpression. Further, we show that depletion of MMP10 prevents nodal metastases using an orthotopic tongue cancer mice model. In contrast, overexpression of MMP10 leads to opposite effects upregulating epithelial-mesenchymal-transition, mediated by a tyrosine kinase gene, AXL, to promote nodal and distant metastasis in vivo. Strikingly, AXL expression is essential and sufficient to mediate the functional consequence of MMP10 overexpression. Consistent with our findings, TCGA-HNSC data suggests overexpression of MMP10 or AXL positively correlates with poor survival of the patients. In conclusion, our results establish that the miR-944/MMP10/AXL- axis underlies lymph node metastases with potential therapeutic intervention and prediction of nodal metastases in tongue cancer patients.
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Affiliation(s)
- Bhasker Dharavath
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India
| | - Ashwin Butle
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Ankita Pal
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Sanket Desai
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India
| | - Pawan Upadhyay
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India
| | - Aishwarya Rane
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Risha Khandelwal
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Sujith Manavalan
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Rahul Thorat
- Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Kavita Sonawane
- Division of Head and Neck Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, 400012, India
| | - Richa Vaish
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India
- Division of Head and Neck Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, 400012, India
| | - Poonam Gera
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India
- Tissue Biorepository, Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Munita Bal
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, 400012, India
| | - Anil K D'Cruz
- Division of Head and Neck Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, 400012, India
- Apollo Cancer Center, Apollo Hospitals, CBD Belapur, Navi Mumbai, 400614, India
| | - Sudhir Nair
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India.
- Division of Head and Neck Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Parel, Mumbai, 400012, India.
| | - Amit Dutt
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, 410210, India.
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, 400094, India.
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Chen SM, Zhao CK, Yao LC, Wang LX, Ma YN, Meng L, Cai SQ, Liu CY, Qu LK, Jia YX, Shou CC. Aiphanol, a multi-targeting stilbenolignan, potently suppresses mouse lymphangiogenesis and lymphatic metastasis. Acta Pharmacol Sin 2023; 44:189-200. [PMID: 35778489 PMCID: PMC9813257 DOI: 10.1038/s41401-022-00940-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/07/2022] [Indexed: 01/18/2023]
Abstract
The high incidence of lymphatic metastasis is closely related to poor prognosis and mortality in cancers. Potent inhibitors to prevent pathological lymphangiogenesis and lymphatic spread are urgently needed. The VEGF-C-VEGFR3 pathway plays a vital role in driving lymphangiogenesis and lymph node metastasis. In addition, COX2 in tumor cells and tumor-associated macrophages (TAMs) facilitates lymphangiogenesis. We recently reported that aiphanol, a natural stilbenolignan, attenuates tumor angiogenesis by repressing VEGFR2 and COX2. In this study, we evaluated the antilymphangiogenic and antimetastatic potency of aiphanol using in vitro, ex vivo and in vivo systems. We first demonstrated that aiphanol directly bound to VEGFR3 and blocked its kinase activity with an half-maximal inhibitory concentration (IC50) value of 0.29 μM in an in vitro ADP-GloTM kinase assay. Furthermore, we showed that aiphanol (7.5-30 μM) dose-dependently counteracted VEGF-C-induced proliferation, migration and tubular formation of lymphatic endothelial cells (LECs), which was further verified in vivo. VEGFR3 knockdown markedly mitigated the inhibitory potency of aiphanol on lymphangiogenesis. In 4T1-luc breast tumor-bearing mice, oral administration of aiphanol (5 and 30 mg· kg-1 ·d-1) dose-dependently decreased lymphatic metastasis and prolonged survival time, which was associated with impaired lymphangiogenesis, angiogenesis and, interestingly, macrophage infiltration. In addition, we found that aiphanol decreased the COX2-dependent secretion of PGE2 and VEGF-C from tumor cells and macrophages. These results demonstrate that aiphanol is an appealing agent for preventing lymphangiogenesis and lymphatic dissemination by synergistically targeting VEGFR3 and inhibiting the COX2-PGE2-VEGF-C signaling axis.
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Affiliation(s)
- Shan-Mei Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Chuan-Ke Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Li-Cheng Yao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Li-Xin Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yu-Nan Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lin Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Shao-Qing Cai
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Cai-Yun Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Li-Ke Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Yan-Xing Jia
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Cheng-Chao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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Lampejo AO, Ghavimi SAA, Hägerling R, Agarwal S, Murfee WL. Lymphatic/blood vessel plasticity: motivation for a future research area based on present and past observations. Am J Physiol Heart Circ Physiol 2023; 324:H109-H121. [PMID: 36459445 PMCID: PMC9829479 DOI: 10.1152/ajpheart.00612.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 12/04/2022]
Abstract
The lymphatic system plays a significant role in homeostasis and drainage of excess fluid back into venous circulation. Lymphatics are also associated with a number of diseases including lymphedema, tumor metastasis, and various lymphatic malformations. Emerging evidence suggests that lymphatics might have a bigger connection to the blood vascular system than originally presumed. As these two systems are often studied in isolation, several knowledge gaps exist surrounding what constitutes lymphatic vascular plasticity, under what conditions it arises, and where structures characteristic of plasticity can form. The objective of this review is to overview current structural, cell lineage-based, and cell identity-based evidence for lymphatic plasticity. These examples of plasticity will then be considered in the context of potential clinical and surgical implications of this evolving research area. This review details our current understanding of lymphatic plasticity, highlights key unanswered questions in the field, and motivates future research aimed at clarifying the role and therapeutic potential of lymphatic plasticity in disease.
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Affiliation(s)
- Arinola O Lampejo
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | | | - René Hägerling
- Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
- Clinician Scientist Program, Berlin Institute of Health Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Shailesh Agarwal
- Division of Plastic and Reconstructive Surgery, Brigham and Women's Hospital, Boston, Massachusetts
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
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22
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Tandon A, Sandhya K, Singh NN, Kumar A. Prognostic Relevance of Lymphatic Vessel Density in Squamous Cell Carcinomas of the Oral Cavity: A Systematic Review and Meta-Analysis. Head Neck Pathol 2022; 16:1185-1194. [PMID: 35904748 PMCID: PMC9729525 DOI: 10.1007/s12105-022-01474-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/01/2022] [Accepted: 07/01/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Oral Squamous Cell Carcinoma (OSCC), a major debilitating illness demands focus in recent times due to a constant upsurge in cases and poor prognostic implications. An urgent mandate upon finding evidence of relevant prognostic markers is the need of the hour. This systematic review and meta-analysis, therefore, elect an objective assessment of Lymphatic Vessel Density (LVD) as a pertinent parameter governing OSCC prognosis. METHODS The study protocol was registered at the International Prospective Register Of Systematic Reviews (PROSPERO). Databases were searched using the MeSH keywords for all study types following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The exposure under consideration was the evaluation of LVD in patients of OSCC. The outcome was measured as pooled Hazard/Odd's/Risk ratios in survived versus non-survived OSCC population. The risk of bias assessment was performed using the QUIPS tool. Heterogeneity was assessed by Chi-square and I2 statistics whereas publication bias was investigated using Egger's test of significance. All the statistical analysis was conducted using STATA version 13.0. RESULTS The initial search of 226 records were screened and filtered through the inclusion and exclusion criteria to achieve an outcome of 15 studies for qualitative synthesis out of which seven studies were eligible for meta-analysis. Pooled Hazard of enhanced Lymphatic Vessel Density was not found to be statistically significant (HR = 1.98, p = 0.553); contrary to the pooled Odd's/Risk for patient survival which was statistically significant (RR = 1.33, p = 0.046). The I2 test of heterogeneity was also significant (58.8%, p = 0.046). CONCLUSIONS This meta-analysis helps to generate pathfinding evidence for a noteworthy role of Lymphatic Vessel Density evaluation in suggesting OSCC prognosis.
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Affiliation(s)
- Ankita Tandon
- Department of Oral Pathology, Microbiology, and Forensic Odontology, Dental Institute, RIMS, Ranchi, India
| | | | - Narendra Nath Singh
- Department of Oral Pathology, Microbiology, and Forensic Odontology, Dental Institute, RIMS, Ranchi, India
| | - Amit Kumar
- Department of Lab Medicine, RIMS, Ranchi, India
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Long noncoding RNA CLAN promotes lymphangiogenesis in the colorectal carcinoma. Virchows Arch 2022; 481:847-852. [PMID: 36301367 DOI: 10.1007/s00428-022-03439-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 12/14/2022]
Abstract
Metastasis is the main cause of colorectal cancer (CRC)-related death and lymph node plays a vital role in this process. Long noncoding RNAs (lncRNAs) are emerging as an important factor of biological progress in cancers. However, lncRNAs related to CRC metastasis was rarely reported.CLAN expression data of tumor tissues and normal tissues were obtained from GEPIA database and 23 paired tumor and normal samples of patients. CLAN expression of 85 patients was carried out with RNA extracted from FFPE samples and quantified with qRT-PCR. Patients' clinical features were collected from department of Pathology of the Affiliated Hospital of Southwest Medical University. Immunohistochemistry staining was used to detect the metastasis-related proteins.CLAN was highly expressed in tumor tissues. And the expression level was not correlated with age, gender, differentiation, and location of CRC patients. Also, CLAN expression did not correlated with budding, LVI, and TILs. However, CLAN expression was strongly associated with lymph node metastasis and higher TNM stage. CLAN changed the lymphatic vessel density by promoting lymphangiogenesis but CLAN did not affect the blood vessel density.CLAN was a unique lncRNA that promoted lymphangiogenesis to accelerate CRC metastasis. CLAN might play a unique role in tumor early dissemination through lymphatic vessel.
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24
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Benyahia Z, Gaudy-Marqueste C, Berenguer-Daizé C, Chabane N, Dussault N, Cayol M, Vellutini C, Djemli A, Nanni I, Beaufils N, Mabrouk K, Grob JJ, Ouafik L. Adrenomedullin Secreted by Melanoma Cells Promotes Melanoma Tumor Growth through Angiogenesis and Lymphangiogenesis. Cancers (Basel) 2022; 14:cancers14235909. [PMID: 36497391 PMCID: PMC9738606 DOI: 10.3390/cancers14235909] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Metastatic melanoma is an aggressive tumor and can constitute a real therapeutic challenge despite the significant progress achieved with targeted therapies and immunotherapies, thus highlighting the need for the identification of new therapeutic targets. Adrenomedullin (AM) is a peptide with significant expression in multiple types of tumors and is multifunctional. AM impacts angiogenesis and tumor growth and binds to calcitonin receptor-like receptor/receptor activity-modifying protein 2 or 3 (CLR/RAMP2; CLR/RAMP3). METHODS In vitro and in vivo studies were performed to determine the functional role of AM in melanoma growth and tumor-associated angiogenesis and lymphangiogenesis. RESULTS In this study, AM and AM receptors were immunohistochemically localized in the tumoral compartment of melanoma tissue, suggesting that the AM system plays a role in melanoma growth. We used A375, SK-MEL-28, and MeWo cells, for which we demonstrate an expression of AM and its receptors; hypoxia induces the expression of AM in melanoma cells. The proliferation of A375 and SK-MEL-28 cells is decreased by anti-AM antibody (αAM) and anti-AMR antibodies (αAMR), supporting the fact that AM may function as a potent autocrine/paracrine growth factor for melanoma cells. Furthermore, migration and invasion of melanoma cells increased after treatment with AM and decreased after treatment with αAMR, thus indicating that melanoma cells are regulated by AM. Systemic administration of αAMR reduced neovascularization of in vivo Matrigel plugs containing melanoma cells, as demonstrated by reduced numbers of vessel structures, which suggests that AM is one of the melanoma cells-derived factors responsible for endothelial cell-like and pericyte recruitment in the construction of neovascularization. In vivo, αAMR therapy blocked angiogenesis and lymphangiogenesis and decreased proliferation in MeWo xenografts, thereby resulting in tumor regression. Histological examination of αAMR-treated tumors showed evidence of the disruption of tumor vascularity, with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. CONCLUSIONS The expression of AM by melanoma cells promotes tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.
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Affiliation(s)
- Zohra Benyahia
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Caroline Gaudy-Marqueste
- Aix Marseille Univ, APHM, CHU Timone, Service de Dermatologie et de Cancérologie Cutanée, 13005 Marseille, France
| | | | - Norhimane Chabane
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Nadège Dussault
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Mylène Cayol
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Christine Vellutini
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
| | - Amina Djemli
- Aix Marseille Univ, APHM, CHU Nord, Service D’anatomopathologie, 13015 Marseille, France
| | - Isabelle Nanni
- Aix Marseille Univ, APHM, CHU Nord, Service D’Onco-Biologie, 13015 Marseille, France
| | - Nathalie Beaufils
- Aix Marseille Univ, APHM, CHU Nord, Service D’Onco-Biologie, 13015 Marseille, France
| | - Kamel Mabrouk
- Aix Marseille Univ, CNRS, ICR, Institut de Chimie Radicalaire, 13013 Marseille, France
| | - Jean-Jacques Grob
- Aix Marseille Univ, APHM, CHU Timone, Service de Dermatologie et de Cancérologie Cutanée, 13005 Marseille, France
| | - L’Houcine Ouafik
- Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France
- Aix Marseille Univ, APHM, CHU Nord, Service D’Onco-Biologie, 13015 Marseille, France
- Correspondence: ; Tel.: +33-491324447
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Choi KH, Song JH, Hong JH, Lee YS, Kang JH, Sun DI, Kim MS, Kim YS. Importance of lymph node ratio in HPV-related oropharyngeal cancer patients treated with surgery and adjuvant treatment. PLoS One 2022; 17:e0273059. [PMID: 35960785 PMCID: PMC9374241 DOI: 10.1371/journal.pone.0273059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 08/01/2022] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVES The pathologic nodal stage of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) patients is classified according to the number of lymph nodes (LNs), as revised in 2018. Previous studies showed that the LN ratio (LNR) could be also a significant prognostic factor in head and neck cancer, but there are few studies on the LNR in HPV-related [HPV(+)] OPC. The aim of the present study was to analyze the predictive value of the LNR for survival and recurrence in HPV(+) OPC patients. MATERIALS AND METHODS HPV(+) OPC patients treated with surgery with or without postoperative radiotherapy from January 2000 to March 2019 were evaluated. The patients were divided into two sets of three groups, according to LN numbers based on pathologic nodal stages, and LNRs by a cutoff value of 0.05. The medical records were reviewed, and the overall survival (OS), disease-free survival, locoregional recurrence, and distant metastasis incidence were analyzed. RESULTS Ninty patients were included and the median follow-up period was 38.2 months. There were no significant differences in OS in the LN number groups. However, there was a significant difference in OS in the LNR groups (P = 0.010). The incidence of distant metastasis in the LNR groups was significantly different (P = 0.005). CONCLUSION The LNR in HPV(+) OPC patients may be a more useful tool to predict survival and distant metastasis than the LN number. Additional research and consensus on surgical pathology are needed before applying the LNR to adjuvant treatment decisions and pathologic nodal staging.
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Affiliation(s)
- Kyu Hye Choi
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jin Ho Song
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Hyun Hong
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Youn Soo Lee
- Department of Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jin Hyoung Kang
- Department of Medical Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dong-Il Sun
- Department of Otolaryngology–Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Min-Sik Kim
- Department of Otolaryngology–Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yeon-Sil Kim
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Mehta V, Suman P, Chander H. High levels of unfolded protein response component CHAC1 associates with cancer progression signatures in malignant breast cancer tissues. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2351-2365. [PMID: 35930144 DOI: 10.1007/s12094-022-02889-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/07/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues. METHODS Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan-Meier plotter. RESULTS Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts. CONCLUSION As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients' survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer.
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Affiliation(s)
- Vikrant Mehta
- Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | - Prabhat Suman
- Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | - Harish Chander
- Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India. .,Biotherapeutics Division, National Institute of Biologicals, Noida, 201309, India.
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Chen G, Chang Y, Xiong Y, Hao J, Liu L, Liu Z, Li H, Qiang P, Han Y, Xian Y, Shimosawa T, Wang X, Yang F, Xu Q. Eplerenone inhibits UUO-induced lymphangiogenesis and cardiac fibrosis by attenuating inflammatory injury. Int Immunopharmacol 2022; 108:108759. [DOI: 10.1016/j.intimp.2022.108759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 04/01/2022] [Accepted: 04/02/2022] [Indexed: 12/30/2022]
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Cadamuro M, Romanzi A, Guido M, Sarcognato S, Cillo U, Gringeri E, Zanus G, Strazzabosco M, Simioni P, Villa E, Fabris L. Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma. J Pers Med 2022; 12:jpm12071086. [PMID: 35887583 PMCID: PMC9324584 DOI: 10.3390/jpm12071086] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/23/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022] Open
Abstract
The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments.
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Affiliation(s)
| | - Adriana Romanzi
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia and Modena University-Hospital, 41124 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (M.G.); (S.S.)
- Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy;
| | - Samantha Sarcognato
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (M.G.); (S.S.)
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35122 Padua, Italy; (U.C.); (E.G.); (G.Z.)
| | - Enrico Gringeri
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35122 Padua, Italy; (U.C.); (E.G.); (G.Z.)
| | - Giacomo Zanus
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35122 Padua, Italy; (U.C.); (E.G.); (G.Z.)
| | - Mario Strazzabosco
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale University, New Haven, CT 208056, USA;
| | - Paolo Simioni
- Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy;
- General Internal Medicine Unit, Padua University-Hospital, 35122 Padua, Italy
| | - Erica Villa
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia and Modena University-Hospital, 41124 Modena, Italy;
- Correspondence: (E.V.); (L.F.); Tel.: +39-059-422-5308 (E.V.); +39-049-821-3131 (L.F.); Fax: +39-059-422-4424 (E.V.); +39-049-827-2355 (L.F.)
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, 35122 Padua, Italy;
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale University, New Haven, CT 208056, USA;
- General Internal Medicine Unit, Padua University-Hospital, 35122 Padua, Italy
- Correspondence: (E.V.); (L.F.); Tel.: +39-059-422-5308 (E.V.); +39-049-821-3131 (L.F.); Fax: +39-059-422-4424 (E.V.); +39-049-827-2355 (L.F.)
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Li J, Yan Z, Ma J, Chu Z, Li H, Guo J, Zhang Q, Zhao H, Li Y, Wang T. ZKSCAN5 Activates VEGFC Expression by Recruiting SETD7 to Promote the Lymphangiogenesis, Tumour Growth, and Metastasis of Breast Cancer. Front Oncol 2022; 12:875033. [PMID: 35600335 PMCID: PMC9117617 DOI: 10.3389/fonc.2022.875033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/15/2022] [Indexed: 12/28/2022] Open
Abstract
The growth of lymphatic vessels (lymphangiogenesis) plays a pivotal role in breast cancer progression and metastasis and the immune response. Vascular endothelial growth factor C (VEGFC) has been demonstrated to accelerate cancer metastasis and modulate the immune system by enhancing lymphangiogenesis. However, it remains largely unclear how transcription factors physically regulate VEGFC expression by interacting with histone-modifying enzymes. Like many histone-modifying enzymes, SETD7 plays a key role in cell proliferation and inhibits tumour cell differentiation. In this study, we identified the role of the transcription factor zinc finger with KRAB and SCAN domains 5 (ZKSCAN5) in interacting with histone methyltransferase SETD7 and mediating VEGFC transcription and tumour lymphangiogenesis. ZKSCAN5 interacts with and recruits SETD7 to the VEGFC promoter. By regulating breast cancer-secreted VEGFC, ZKSCAN5 could induce the tube formation of lymph endothelial cells, which promotes tumour proliferation, migration, and metastasis. Clinically, the expression of ZKSCAN5 was frequently upregulated in patients with breast cancer and positively correlated with the expression of VEGFC and the number of lymphatic microvessels. ZKSCAN5 is a poor prognostic factor for patients with breast cancer. Our results characterise the role of ZKSCAN5 in regulating VEGFC transcription and predict ZKSCAN5 as a breast cancer therapeutic target.
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Affiliation(s)
- Jingtong Li
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhifeng Yan
- Department of Obstetrics and Gynecology, Seventh Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Jianli Ma
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhong Chu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Huizi Li
- Department of Nutrition, People’s Liberation Army (PLA) Rocket Force Characteristic Medical Center, Beijing, China
| | - Jingjing Guo
- Department of Oncology, Fourth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Qingyuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
| | - Hui Zhao
- Department of Oncology, Fourth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
| | - Ying Li
- Department of Oncology, Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
| | - Tao Wang
- Department of Oncology, Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Qingyuan Zhang, ; Hui Zhao, ; Ying Li, ; Tao Wang,
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Masood F, Bhattaram R, Rosenblatt MI, Kazlauskas A, Chang JH, Azar DT. Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression. Front Physiol 2022; 13:846936. [PMID: 35392370 PMCID: PMC8980686 DOI: 10.3389/fphys.2022.846936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/25/2022] [Indexed: 02/03/2023] Open
Abstract
Aberrant lymphatic system function has been increasingly implicated in pathologies such as lymphedema, organ transplant rejection, cardiovascular disease, obesity, and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. While some pathologies are exacerbated by lymphatic vessel regression and dysfunction, induced lymphatic regression could be therapeutically beneficial in others. Despite its importance, our understanding of lymphatic vessel regression is far behind that of blood vessel regression. Herein, we review the current understanding of blood vessel regression to identify several hallmarks of this phenomenon that can be extended to further our understanding of lymphatic vessel regression. We also summarize current research on lymphatic vessel regression and an array of research tools and models that can be utilized to advance this field. Additionally, we discuss the roles of lymphatic vessel regression and dysfunction in select pathologies, highlighting how an improved understanding of lymphatic vessel regression may yield therapeutic insights for these disease states.
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31
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Bekisz S, Baudin L, Buntinx F, Noël A, Geris L. In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies. Cancers (Basel) 2022; 14:1525. [PMID: 35326676 PMCID: PMC8946816 DOI: 10.3390/cancers14061525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/24/2022] [Accepted: 03/08/2022] [Indexed: 12/04/2022] Open
Abstract
Lymphangiogenesis (LA) is the formation of new lymphatic vessels by lymphatic endothelial cells (LECs) sprouting from pre-existing lymphatic vessels. It is increasingly recognized as being involved in many diseases, such as in cancer and secondary lymphedema, which most often results from cancer treatments. For some cancers, excessive LA is associated with cancer progression and metastatic dissemination to the lymph nodes (LNs) through lymphatic vessels. The study of LA through in vitro, in vivo, and, more recently, in silico models is of paramount importance in providing novel insights and identifying the key molecular actors in the biological dysregulation of this process under pathological conditions. In this review, the different biological (in vitro and in vivo) models of LA, especially in a cancer context, are explained and discussed, highlighting their principal modeled features as well as their advantages and drawbacks. Imaging techniques of the lymphatics, complementary or even essential to in vivo models, are also clarified and allow the establishment of the link with computational approaches. In silico models are introduced, theoretically described, and illustrated with examples specific to the lymphatic system and the LA. Together, these models constitute a toolbox allowing the LA research to be brought to the next level.
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Affiliation(s)
- Sophie Bekisz
- Biomechanics Research Unit, GIGA In silico Medicine, ULiège, 4000 Liège, Belgium;
| | - Louis Baudin
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Florence Buntinx
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Agnès Noël
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Liesbet Geris
- Biomechanics Research Unit, GIGA In silico Medicine, ULiège, 4000 Liège, Belgium;
- Biomechanics Section, KU Leuven, 3000 Leuven, Belgium
- Skeletal Biology and Engineering Research Center, KU Leuven, 3000 Leuven, Belgium
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32
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Winarno AS, Fehm TN, Hampl M. Vulvar cancer during pregnancy and/or breastfeeding: a report of five cases from a single center study at the University Hospital of Düsseldorf. BMC Pregnancy Childbirth 2022; 22:207. [PMID: 35291960 PMCID: PMC8922737 DOI: 10.1186/s12884-022-04448-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/02/2022] [Indexed: 11/10/2022] Open
Abstract
Background The incidence of vulvar cancer (VC) in pregnancy is unknown due to its rarity; between 1955 and 2014 only 36 case reports were reported worldwide. Underreporting may also be a contributing factor to the unknown incidence of VC in pregnancy. The aim of this study was to analyze the diagnosis, treatment and outcome of vulvar cancer cases diagnosed during pregnancy and/or breastfeeding. Case presentation Patient 1 was diagnosed at 18 weeks’ gestation (WG) with Grade 2 VC (pT1a, pN0, 0/4 sentinel lymph nodes biopsy (SLNB) involved) and was treated by having the tumor resected (R0). She is currently recurrence-free at 4 years post-diagnosis. Patient 2 was diagnosed at 7 WG with Grade 2 VC (pT1b, pN1a, 1/17 SLNB, R0) and was treated during the first trimester and during the second trimester with SLNB. She is currently recurrence-free at 5 years post-diagnosis. Patient 3 was diagnosed at 30 WG with Grade 2 VC (pT1b, pN0, 0/5 SLNB, R0). She subsequently experienced a number of local recurrences postpartum that were managed by resection and is currently recurrence-free at 3 years post-diagnosis. Patient 4 was diagnosed a VL later, at 14 months during breastfeeding, that was diagnosed as Grade 3 VC (pT1b, pN1a, 1/14 SLNB, R0). The patient is currently recurrence-free at 9 years post-diagnosis. Patient 5 was not diagnosed during pregnancy, but was diagnosed with G3 VC (pT2, pN2c, 2/17 SLNB, R0) 8 months postpartum. The patient due to the extent of tumor involvement and lymph node metastasis, underwent chemoradiation therapy post-surgery. Despite adjuvant therapy, the patient progressed and developed bone metastases. Analysis of the tumour tissue revealed increased expression of PD-L1 (programmed cell death protein 1) indicating that the patient may have benefited from treatment with nivolumab to block the PD-L1 interaction; unfortunately the patient passed away at 24 months post-diagnosis before immunotherapy treatment could commence. Conclusion Surgical resection and simultaneous SLNB in VC cases are considered safe during pregnancy, with comparable outcomes to non-pregnant women. Prompt diagnostic workup and treatment should never be delayed during pregnancy as delayed diagnosis could lead to tumour progression with fatal consequences.
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Affiliation(s)
- Andreas Suhartoyo Winarno
- Department of Obstetrics and Gynecology, The Heinrich Heine University Hospital of Duesseldorf, Moorenstraße 5, 40225, Duesseldorf, Nordrhein-Westfalen, Germany.
| | - Tanja Natascha Fehm
- Department of Obstetrics and Gynecology, The Heinrich Heine University Hospital of Duesseldorf, Moorenstraße 5, 40225, Duesseldorf, Nordrhein-Westfalen, Germany
| | - Monika Hampl
- Department of Obstetrics and Gynecology, The Heinrich Heine University Hospital of Duesseldorf, Moorenstraße 5, 40225, Duesseldorf, Nordrhein-Westfalen, Germany
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Zhu G, Cheng Z, Wang Q, Lin C, Lin P, He R, Chen H, Hoffman RM, Ye J. TRAF6 regulates the signaling pathway influencing colorectal cancer function by ubiquitination mechanisms. Cancer Sci 2022; 113:1393-1405. [PMID: 35179811 PMCID: PMC8990288 DOI: 10.1111/cas.15302] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 12/24/2022] Open
Abstract
Tumor necrosis factor receptor‐associated factor‐6 (TRAF6) is a ubiquitin E3 ligase. TRAF6 plays an important role in tumor invasion and metastasis. However, the specific mechanism by which TRAF6 promotes colorectal cancer (CRC) metastasis is incompletely understood. This study aimed to determine whether TRAF6 affects the LPS‐NF‐κB‐VEGF‐C signaling pathway through ubiquitination, which plays a role in colorectal cancer metastasis. Here, our results showed that TRAF6 affected lymphangiogenesis through the LPS‐NF‐κB‐VEGF‐C signaling pathway. Using ubiquitination experiments, we found that TRAF6 was mainly ubiquitinated with the K63‐linked chains, and LPS promoted ubiquitination of TRAF6 and K63‐linked chains. More importantly, TRAF6 124mut is the main ubiquitination site of TRAF6 interacting with K63‐linked chains. TRAF6 affected the migration, invasion, and lymphatic metastasis of colorectal cancer through its ubiquitination. In subcutaneous xenograft models, TRAF6 124mut inhibited tumor growth. In conclusion, our results provide new insight for studying the mechanism of lymphangiogenesis in colorectal cancer to promote cancer metastasis, which may provide new ideas for tumor immunotherapy.
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Affiliation(s)
- Guangwei Zhu
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China
| | - Zhibin Cheng
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China
| | - Qin Wang
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China
| | - Chunlin Lin
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Penghang Lin
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Ruofan He
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Hui Chen
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350000, China
| | - Robert M Hoffman
- AntiCancer, Inc, San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Jianxin Ye
- Department of Gastrointestinal Surgery, Section, Institute of Abdominal Surgery, Key Laboratory of accurate diagnosis and treatment of cancer, The First Hospital Affiliated to Fujian Medical University, Fuzhou, 350005, China
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Poghosyan S, Frenkel N, Lentzas A, Laoukili J, Rinkes IB, Kranenburg O, Hagendoorn J. Loss of Neuropilin-2 in Murine Mesenchymal-like Colon Cancer Organoids Causes Mesenchymal-to-Epithelial Transition and an Acquired Dependency on Insulin-Receptor Signaling and Autophagy. Cancers (Basel) 2022; 14:cancers14030671. [PMID: 35158941 PMCID: PMC8833430 DOI: 10.3390/cancers14030671] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Many cancer types are reported to have high lymphangiogenic receptor Neuropilin-2 (Nrp2) expression, including colorectal cancer (CRC). Nrp2 is shown to be associated with tumor progression in vivo and poor prognosis in CRC patients. Although the role of Nrp2 is well established in lymphangiogenesis, the tumor cell-intrinsic role of Nrp2 remains elusive. Here, we employed murine CRC tumor-derived mesenchymal-like organoids to induce Nrp2 depletion. We demonstrate that Nrp2 deletion in CRC organoids results in a drastically altered phenotype that is characterized by mesenchymal-to-epithelial transition (MET), and an acquired dependency on IR signaling and autophagy. This phenotype is preserved in subcutaneous tumors generated by CRC organoids. We conclude that there is a complex interaction between Nrp2 and alternative pro-survival mechanisms in aggressive CRC, which could be therapeutically exploited. Abstract Neuropilin-2 (Nrp2), an important regulator of lymphangiogenesis and lymphatic metastasis, has been associated with progression in colorectal cancer (CRC). However, the tumor cell-intrinsic role of Nrp2 in cancer progression is incompletely understood. To address this question, we employed CRISPR-Cas9 technology to generate Nrp2-knockout organoids derived from murine CRC tumors with a mesenchymal phenotype. Transcriptome profiling and tumor tissue analysis showed that Nrp2 loss resulted in mesenchymal-to-epithelial transition (MET), which was accompanied with restored polarity and tight junction stabilization. Signaling pathway analysis revealed that Nrp2-knockout organoids acquire de novo dependency on insulin receptor (IR) signaling and autophagy as alternative survival mechanisms. Combined inhibition of IR signaling and autophagy prevented the stabilization of cell-cell junctions, reduced metabolic activity, and caused profound cell death in Nrp2-knockout organoids. Collectively, the data demonstrate a key role for Nrp2 in maintaining the aggressive phenotype and survival of tumor-derived CRC organoids. The identified connection between Nrp2, insulin receptor signaling and autophagy may guide the development of novel combination-treatment strategies for aggressive CRC.
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Kinami S, Saito H, Takamura H. Significance of Lymph Node Metastasis in the Treatment of Gastric Cancer and Current Challenges in Determining the Extent of Metastasis. Front Oncol 2022; 11:806162. [PMID: 35071010 PMCID: PMC8777129 DOI: 10.3389/fonc.2021.806162] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 12/13/2021] [Indexed: 12/16/2022] Open
Abstract
The stomach exhibits abundant lymphatic flow, and metastasis to lymph nodes is common. In the case of gastric cancer, there is a regularity to the spread of lymph node metastasis, and it does not easily metastasize outside the regional nodes. Furthermore, when its extent is limited, nodal metastasis of gastric cancer can be cured by appropriate lymph node dissection. Therefore, identifying and determining the extent of lymph node metastasis is important for ensuring accurate diagnosis and appropriate surgical treatment in patients with gastric cancer. However, precise detection of lymph node metastasis remains difficult. Most nodal metastases in gastric cancer are microscopic metastases, which often occur in small-sized lymph nodes, and are thus difficult to diagnose both preoperatively and intraoperatively. Preoperative nodal diagnoses are mainly made using computed tomography, although the specificity of this method is low because it is mainly based on the size of the lymph node. Furthermore, peripheral nodal metastases cannot be palpated intraoperatively, nodal harvesting of resected specimens remains difficult, and the number of lymph nodes detected vary greatly depending on the skill of the technician. Based on these findings, gastrectomy with prophylactic lymph node dissection is considered the standard surgical procedure for gastric cancer. In contrast, several groups have examined the value of sentinel node biopsy for accurately evaluating nodal metastasis in patients with early gastric cancer, reporting high sensitivity and accuracy. Sentinel node biopsy is also important for individualizing and optimizing the extent of uniform prophylactic lymph node dissection and determining whether patients are indicated for function-preserving curative gastrectomy, which is superior in preventing post-gastrectomy symptoms and maintaining dietary habits. Notably, advancements in surgical treatment for early gastric cancer are expected to result in individualized surgical strategies with sentinel node biopsy. Chemotherapy for advanced gastric cancer has also progressed, and conversion gastrectomy can now be performed after downstaging, even in cases previously regarded as inoperable. In this review, we discuss the importance of determining lymph node metastasis in the treatment of gastric cancer, the associated difficulties, and the need to investigate strategies that can improve the diagnosis of lymph node metastasis.
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Affiliation(s)
- Shinichi Kinami
- Department of Surgical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Japan
- Department of General and Gastroenterologic Surgery, Kanazawa Medical University Himi Municipal Hospital, Himi City, Japan
| | - Hitoshi Saito
- Department of General and Gastroenterologic Surgery, Kanazawa Medical University Himi Municipal Hospital, Himi City, Japan
| | - Hiroyuki Takamura
- Department of Surgical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Japan
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Chen JM, Luo B, Ma R, Luo XX, Chen YS, Li Y. Lymphatic Endothelial Markers and Tumor Lymphangiogenesis Assessment in Human Breast Cancer. Diagnostics (Basel) 2021; 12:diagnostics12010004. [PMID: 35054174 PMCID: PMC8774380 DOI: 10.3390/diagnostics12010004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 12/11/2022] Open
Abstract
Metastasis via lymphatic vessels or blood vessels is the leading cause of death for breast cancer, and lymphangiogenesis and angiogenesis are critical prerequisites for the tumor invasion–metastasis cascade. The research progress for tumor lymphangiogenesis has tended to lag behind that for angiogenesis due to the lack of specific markers. With the discovery of lymphatic endothelial cell (LEC) markers, growing evidence demonstrates that the LEC plays an active role in lymphatic formation and remodeling, tumor cell growth, invasion and intravasation, tumor–microenvironment remodeling, and antitumor immunity. However, some studies have drawn controversial conclusions due to the variation in the LEC markers and lymphangiogenesis assessments used. In this study, we review recent findings on tumor lymphangiogenesis, the most commonly used LEC markers, and parameters for lymphangiogenesis assessments, such as the lymphatic vessel density and lymphatic vessel invasion in human breast cancer. An in-depth understanding of tumor lymphangiogenesis and LEC markers can help to illustrate the mechanisms and distinct roles of lymphangiogenesis in breast cancer progression, which will help in exploring novel potential predictive biomarkers and therapeutic targets for breast cancer.
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Affiliation(s)
- Jia-Mei Chen
- Center of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (J.-M.C.); (X.-X.L.)
| | - Bo Luo
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China;
| | - Ru Ma
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China;
| | - Xi-Xi Luo
- Center of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (J.-M.C.); (X.-X.L.)
| | - Yong-Shun Chen
- Center of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (J.-M.C.); (X.-X.L.)
- Correspondence: (Y.-S.C.); (Y.L.); Tel.: +86-027-88048911 (Y.-S.C.); +86-010-63926525 (Y.L.)
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China;
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Correspondence: (Y.-S.C.); (Y.L.); Tel.: +86-027-88048911 (Y.-S.C.); +86-010-63926525 (Y.L.)
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Pankova MN, Lobov GI. Lymphangiogenesis and Features of Lymphatic Drainage in Different Organs: the Significance for Allograft Fate. J EVOL BIOCHEM PHYS+ 2021. [DOI: 10.1134/s0022093021050100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Lugo-Cintrón KM, Ayuso JM, Humayun M, Gong MM, Kerr SC, Ponik SM, Harari PM, Virumbrales-Muñoz M, Beebe DJ. Primary head and neck tumour-derived fibroblasts promote lymphangiogenesis in a lymphatic organotypic co-culture model. EBioMedicine 2021; 73:103634. [PMID: 34673450 PMCID: PMC8528684 DOI: 10.1016/j.ebiom.2021.103634] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/05/2021] [Accepted: 10/05/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In head and neck cancer, intratumour lymphatic density and tumour lymphangiogenesis have been correlated with lymphatic metastasis, making lymphangiogenesis a promising therapeutic target. However, inter-patient tumour heterogeneity makes it challenging to predict tumour progression and lymph node metastasis. Understanding the lymphangiogenic-promoting factors leading to metastasis (e.g., tumour-derived fibroblasts or TDF), would help develop strategies to improve patient outcomes. METHODS A microfluidic in vitro model of a tubular lymphatic vessel was co-cultured with primary TDF from head and neck cancer patients to evaluate the effect of TDF on lymphangiogenesis. We assessed the length and number of lymphangiogenic sprouts and vessel permeability via microscopy and image analysis. Finally, we characterised lymphatic vessel conditioning by TDF via RT-qPCR. FINDINGS Lymphatic vessels were conditioned by the TDF in a patient-specific manner. Specifically, the presence of TDF induced sprouting, altered vessel permeability, and increased the expression of pro-lymphangiogenic genes. Gene expression and functional responses in the fibroblast-conditioned lymphatic vessels were consistent with the patient tumour stage and lymph node status. IGF-1, upregulated among patients, was targeted to validate our personalised medicine approach. Interestingly, IGF-1 blockade was not effective across different patients. INTERPRETATION The use of lymphatic organotypic models incorporating head and neck TDF provides insight into the pathways leading to lymphangiogenesis in each patient. This model provided a platform to test anti-angiogenic therapeutics and inform of their effectiveness for individual patients. FUNDING NIH R33CA225281. Wisconsin Head and Neck SPORE NIH P50DE026787. NIH R01AI34749.
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Affiliation(s)
- Karina M Lugo-Cintrón
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - José M Ayuso
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI, USA
| | - Mouhita Humayun
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Max M Gong
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Biomedical Engineering, Trine University, Angola, IN, USA
| | - Sheena C Kerr
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Suzanne M Ponik
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - María Virumbrales-Muñoz
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
| | - David J Beebe
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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Ribera J, Portolés I, Córdoba-Jover B, Rodríguez-Vita J, Casals G, González-de la Presa B, Graupera M, Solsona-Vilarrasa E, Garcia-Ruiz C, Fernández-Checa JC, Soria G, Tudela R, Esteve-Codina A, Espadas G, Sabidó E, Jiménez W, Sessa WC, Morales-Ruiz M. The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice. Commun Biol 2021; 4:1192. [PMID: 34654883 PMCID: PMC8519955 DOI: 10.1038/s42003-021-02722-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 09/24/2021] [Indexed: 01/29/2023] Open
Abstract
DHX15 is a downstream substrate for Akt1, which is involved in key cellular processes affecting vascular biology. Here, we explored the vascular regulatory function of DHX15. Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development. DHX15+/- mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and proteome analysis of DHX15 silenced endothelial cells revealed differential expression of genes involved in the metabolism of ATP biosynthesis. The validation of these results demonstrated a lower activity of the Complex I in the mitochondrial membrane of endothelial cells, resulting in lower intracellular ATP production and lower oxygen consumption. After injection of syngeneic LLC1 tumor cells, DHX15+/- mice showed partially inhibited primary tumor growth and reduced lung metastasis. Our results revealed an important role of DHX15 in vascular physiology and pave a new way to explore its potential use as a therapeutical target for metastasis treatment.
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Affiliation(s)
- Jordi Ribera
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Irene Portolés
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Bernat Córdoba-Jover
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Juan Rodríguez-Vita
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- German Cancer Research Center, Heidelberg, Germany
| | - Gregori Casals
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Bernardino González-de la Presa
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Mariona Graupera
- Vascular Signalling Laboratory, Program Against Cancer Therapeutic Resistance (ProCURE), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). CIBERonc, Barcelona, Spain
| | - Estel Solsona-Vilarrasa
- Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC), Liver Unit, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, 08036, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Carmen Garcia-Ruiz
- Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC), Liver Unit, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, 08036, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain
- USC Research Center for ALPD, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - José C Fernández-Checa
- Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC), Liver Unit, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, 08036, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain
- USC Research Center for ALPD, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Guadalupe Soria
- Experimental 7T-MRI Unit, IDIBAPS, Barcelona, Spain
- CIBERbbn, University of Barcelona, Barcelona, Spain
| | - Raúl Tudela
- Experimental 7T-MRI Unit, IDIBAPS, Barcelona, Spain
- CIBERbbn, University of Barcelona, Barcelona, Spain
| | - Anna Esteve-Codina
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Guadalupe Espadas
- Proteomics Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Universitat Pompeu Fabra, Barcelona, Spain
| | - Eduard Sabidó
- Proteomics Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Universitat Pompeu Fabra, Barcelona, Spain
| | - Wladimiro Jiménez
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Department of Biomedicine-Biochemistry Unit, School of Medicine University of Barcelona, Barcelona, Spain
| | - William C Sessa
- Department of Pharmacology, Department of Cardiology, Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
| | - Manuel Morales-Ruiz
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
- Department of Biomedicine-Biochemistry Unit, School of Medicine University of Barcelona, Barcelona, Spain.
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Li DK, Chen XR, Wang LN, Wang JH, Wen YT, Zhou ZY, Li JK, Liu JX, Cai LB, Zhong SS, Lyu XM, Damola FO, Li MY, Zhang JJ, Zeng YM, Wang QL, Zhang QB, Lyu H, Fu XY, Wang W, Li X, Huang ZX, Yao KT. Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma. Mol Cancer Res 2021; 20:161-175. [PMID: 34654722 DOI: 10.1158/1541-7786.mcr-21-0164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/21/2021] [Accepted: 09/30/2021] [Indexed: 11/16/2022]
Abstract
Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.
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Affiliation(s)
- Deng-Ke Li
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Xing-Rui Chen
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Li-Na Wang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China.,Guangzhou First People's Hospital, School of Medicine, Southern China University of Technology, Guangzhou, P.R. China
| | - Jia-Hong Wang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Yue-Ting Wen
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Zi-Ying Zhou
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Ji-Ke Li
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Jing-Xian Liu
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Lin-Bo Cai
- Guangdong Sanjiu Brain Hospital, Guangzhou, P.R. China
| | | | - Xiao-Ming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Faleti Oluwasijibomi Damola
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Min-Ying Li
- Department of Radiotherapy, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, P.R. China
| | - Jing-Jing Zhang
- Department of Radiotherapy, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, P.R. China
| | - Yu-Mei Zeng
- Department of Pathology, Tumor Hospital of Zhongshan People's Hospital, Zhongshan, P.R. China
| | - Qian-Li Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, P.R. China
| | - Qian-Bing Zhang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Hao Lyu
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China
| | - Xiao-Yan Fu
- Department of Otorhinolaryngology Head and Neck Surgery, General Hospital of Southern Theater Command, People's Liberation Army of China, Guangzhou, P.R. China
| | - Wei Wang
- Department of Pathology, General Hospital of Southern Theater Command, People's Liberation Army of China, Guangzhou, P.R. China
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, P.R. China.
| | - Zhong-Xi Huang
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China.
| | - Kai-Tai Yao
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P.R. China.
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Aqueous outflow channels and its lymphatic association: A review. Surv Ophthalmol 2021; 67:659-674. [PMID: 34656556 PMCID: PMC9008077 DOI: 10.1016/j.survophthal.2021.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 10/07/2021] [Accepted: 10/11/2021] [Indexed: 11/24/2022]
Abstract
The human eye has a unique immune architecture and behavior. While the conjunctiva is known to have a well-defined lymphatic drainage system, the cornea, sclera, and uveal tissues were historically considered "alymphatic" and thought to be immune privileged. The very fact that the aqueous outflow channels carry a clear fluid (aqueous humor) along the outflow pathway makes it hard to ignore its lymphatic-like characteristics. The development of novel lymphatic lineage markers and expression of these markers in aqueous outflow channels and improved imaging capabilities has sparked a renewed interest in the study of ocular lymphatics. Ophthalmic lymphatic research has had a directional shift over the last decade, offering an exciting new physiological platform that needs further in-depth understanding. The evidence of a presence of distinct lymphatic channels in the human ciliary body is gaining significant traction. The uveolymphatic pathway is an alternative new route for aqueous outflow and adds a new dimension to pathophysiology and management of glaucoma. Developing novel animal models, markers, and non-invasive imaging tools to delineate the core anatomical structure and physiological functions may help pave some crucial pathways to understand disease pathophysiology and help develop novel targeted therapeutic approaches for glaucoma.
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Chen C, Shen N, Chen Y, Jiang P, Sun W, Wang Q, Wang Z, Jiang Y, Cheng W, Fu S, Wang S. LncCCLM inhibits lymphatic metastasis of cervical cancer by promoting STAU1-mediated IGF-1 mRNA degradation. Cancer Lett 2021; 518:169-179. [PMID: 34273467 DOI: 10.1016/j.canlet.2021.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 11/25/2022]
Abstract
Cervical cancer (CC) patients with lymph node (LN) metastasis often have an extremely poor prognosis. However, the precise molecular mechanisms involved in LN metastasis of CC remain largely unknown. Herein, through RNA screening, we identified a novel long noncoding RNA (lncRNA), LncCCLM, that was downregulated in cervical cancer tissues and closely associated with lymphatic metastasis in cervical cancer patients. Gain-of-function and loss-of-function studies in CC cells demonstrated that LncCCLM inhibited cervical cancer-associated lymphangiogenesis, and CC cell migration and invasion in vitro and suppressed LN metastasis in vivo, but did not affect the growth of CC cells. Mechanistically, LncCCLM localized in the cytoplasm and interacted with staufen double-stranded RNA binding protein 1 (STAU1), promoting the binding of the STAU1 protein to the 3' untranslated region (3'UTR) of insulin-like growth factor 1 (IGF-1) mRNA, which accelerated the degradation of IGF-1 mRNA and decreased the IGF-1 protein level, ultimately reducing lymphangiogenesis and lymphatic metastasis in cervical cancer. Collectively, our findings suggest that LncCCLM acts as a tumor suppressor and may be used as a prognostic biomarker and therapeutic target for clinical intervention in LN-metastatic cervical cancer.
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Affiliation(s)
- Chen Chen
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Ningmei Shen
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Yali Chen
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Pinping Jiang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Wei Sun
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Zhangding Wang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Yi Jiang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Wenjun Cheng
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China.
| | - Shilong Fu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China.
| | - Shouyu Wang
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
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Lu J, Cao LL, Xu Y, Huang XY, Cho SJ, Ashktorab H, Smoot DT, Li P, Zheng CH, Kim JW, Ryeom SW, Yoon SS, Yoon C, Huang CM. WITHDRAWN: FOXC1 modulates stem-like cell properties and chemoresistance through hedgehog and EMT signaling in gastric adenocarcinoma. Mol Ther 2021:S1525-0016(21)00464-0. [PMID: 34534693 DOI: 10.1016/j.ymthe.2021.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/30/2021] [Accepted: 09/07/2021] [Indexed: 11/21/2022] Open
Abstract
This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- Jun Lu
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10013, USA
| | - Long-Long Cao
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Yu Xu
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical, 35001 University, Fuzhou 35001, Fujian Province, China
| | - Xiao-Yan Huang
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Soo-Jeong Cho
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul 100-000, South Korea
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC 20541, USA
| | - Duane T Smoot
- Department of Medicine, Howard University, Washington, DC 20541, USA
| | - Ping Li
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Ji-Won Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi-do 100-000, South Korea
| | - Sandra W Ryeom
- Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19019, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032
| | - Sam S Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10013, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032
| | - Changhwan Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10013, USA; Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032.
| | - Chang-Ming Huang
- Department of Gastric Surgery, Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China.
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Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke. Int J Mol Sci 2021; 22:ijms22179486. [PMID: 34502395 PMCID: PMC8431165 DOI: 10.3390/ijms22179486] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/26/2021] [Accepted: 08/28/2021] [Indexed: 12/21/2022] Open
Abstract
Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.
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45
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Wang Q, Liang T, Wu J, Li Z, Liu Z. Dye-Sensitized Rare Earth-Doped Nanoparticles with Boosted NIR-IIb Emission for Dynamic Imaging of Vascular Network-Related Disorders. ACS APPLIED MATERIALS & INTERFACES 2021; 13:29303-29312. [PMID: 34133138 DOI: 10.1021/acsami.1c04612] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Real-time dynamic vascular network imaging can provide accurate hemodynamic and anatomical information, facilitating the diagnosis of blood circulatory system-related diseases and achieving precise evaluation of therapeutic effects. In vivo luminescence imaging in the NIR-IIb biological window (1500-1700 nm) has developed into a next generation of optical imaging method with significantly improved temporal-spatial resolution and penetration depth. Unfortunately, an imaging contrast agent capable of emitting NIR-IIb luminescence with sufficient brightness in this region is lacking. Herein, we designed and proposed a type of dye-sensitized rare earth-doped nanoparticle (RENPs@Alk-pi) with obviously boosted NIR-IIb emission and high biocompatibility, which can be used to realize the real-time NIR-IIb luminescence imaging with high temporal-spatial resolution and contrast. The dye sensitization process provides a 40-fold enhanced brightness of the NIR-IIb emission at 1525 nm of Er3+. Consequently, the RENPs@Alk-pi was not only able to depict a vascular network but also applicable in noninvasively monitoring the dynamic vascular processes and changes in the vascular anatomy of two blood circulatory system-related disorders, including hindlimbs ischemia and atherosclerosis. Our research provides a powerful tool for evaluating vascular network-related dysfunction and physiological processes.
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Affiliation(s)
- Qirong Wang
- College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
| | - Tao Liang
- Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, College of Chemistry and Materials Science, South-Central University for Nationalities, Wuhan 430074, China
| | - Junjie Wu
- College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
| | - Zhen Li
- College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
| | - Zhihong Liu
- College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
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46
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Ma SN, Mao ZX, Wu Y, Liang MX, Wang DD, Chen X, Chang PA, Zhang W, Tang JH. The anti-cancer properties of heparin and its derivatives: a review and prospect. Cell Adh Migr 2021; 14:118-128. [PMID: 32538273 PMCID: PMC7513850 DOI: 10.1080/19336918.2020.1767489] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Heparin, including unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and heparin derivatives, are commonly used in venous thromboembolism treatment and reportedly have beneficial effects on cancer survival. Heparin can affect the proliferation, adhesion, angiogenesis, migration and invasion of cancer cells via multiple mechanisms. The main mechanisms involve inhibition of heparanase, P-/L-selectin, angiogenesis, and interference with the CXCL12-CXCR4 axis. Here we summarize the current experimental evidence regarding the anti-cancer role of heparin and its derivatives, and conclude that there is evidence to support heparin’s role in inhibiting cancer progression, making it a promising anti-cancer agent.
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Affiliation(s)
- Sai-Nan Ma
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China.,Department of Oncology, The Affiliated Suqian Hospital of Xuzhou Medical University , Suqian, P.R.China
| | - Zhi-Xiang Mao
- Department of Oncology, Affiliated Hospital of Xuzhou Medical University , Xuzhou, P.R. China
| | - Yang Wu
- Core Facility, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Ming-Xing Liang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Dan-Dan Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Xiu Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Ping-An Chang
- Urinary Surgery, Dongtai People's Hospital , Dongtai, P.R. China
| | - Wei Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
| | - Jin-Hai Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, P.R. China
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47
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Güç E, Pollard JW. Redefining macrophage and neutrophil biology in the metastatic cascade. Immunity 2021; 54:885-902. [PMID: 33979586 DOI: 10.1016/j.immuni.2021.03.022] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/08/2020] [Accepted: 03/26/2021] [Indexed: 02/07/2023]
Abstract
Tumor cells metastasize to distant organs through a complex series of events that are driven by tumor intrinsic and extrinsic factors. In particular, non-malignant stromal cells, including immune cells, modify tumor metastatic behavior. Of these cells, tumor-associated innate immune cells, particularly macrophages and neutrophils, suppress the cytotoxic activity of innate and adaptive killer cells and interact with tumor cells to promote their growth and malignancy. These findings in mouse cancer models suggest that targeting these sub-populations of immune cells holds therapeutic promise in treating metastatic disease. In this review, we describe the origin and role of the macrophages, neutrophils, and their progenitors in the metastatic cascade and suggest strategies that might enhance cancer therapy.
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Affiliation(s)
- Esra Güç
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Jeffrey W Pollard
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
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48
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He M, He Q, Cai X, Chen Z, Lao S, Deng H, Liu X, Zheng Y, Liu X, Liu J, Xie Z, Yao M, Liang W, He J. Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances. Transl Lung Cancer Res 2021; 10:2252-2277. [PMID: 34164274 PMCID: PMC8182726 DOI: 10.21037/tlcr-21-40] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. Methods To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. Results In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. Conclusions LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.
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Affiliation(s)
- Miao He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qihua He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiuyu Cai
- Department of VIP Region, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zisheng Chen
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China
| | - Shen Lao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hongsheng Deng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiwen Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongmei Zheng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jun Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Maojin Yao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenhua Liang
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,The First People Hospital of Zhaoqing, Zhaoqing, China
| | - Jianxing He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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PEDF inhibits lymphatic metastasis of nasopharyngeal carcinoma as a new lymphangiogenesis inhibitor. Cell Death Dis 2021; 12:295. [PMID: 33731707 PMCID: PMC7969934 DOI: 10.1038/s41419-021-03583-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/24/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most malignant tumors in southern China and Asia, and lymph node metastasis is an important cause for treatment failure. Lymphangiogenesis is a crucial step in lymphatic metastasis of NPC, while little is known about lymphangiogenesis in NPC. Similar to angiogenesis, lymphangitic neovascularization is a process of balance between pro-lymphangiogenesis and anti-lymphangiogenesis factors, but there are few studies on endogenous lymphangiogenesis inhibitors. Pigment epithelium-derived factor (PEDF) is a well-known effective endogenous angiogenesis inhibitor. However, the relationship between PEDF and lymphangiogenesis remains unknown. Our present study reveals that PEDF is lowly expressed in human NPC tissues with poor prognosis and is negatively correlated with lymphatic vessel density (LVD). Consistently, PEDF inhibits lymphangiogenesis and lymphatic metastasis of NPC in vivo experiments. Mechanistically, PEDF inhibits the proliferation, migration, and tube formation of lymphatic endothelial cells and promotes cell apoptosis. On the other hand, PEDF reduces the expression and secretion of vascular endothelial growth factor C (VEGF-C) of NPC cells through the nuclear factor-κB (NF-κB) signaling pathway. Our findings indicate that PEDF plays a vital role in lymphatic metastasis by targeting both lymphatic endothelial cells and NPC cells, and PEDF may represent a novel therapeutic target for NPC.
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50
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Polyglutamic acid-based crosslinked doxorubicin nanogels as an anti-metastatic treatment for triple negative breast cancer. J Control Release 2021; 332:10-20. [PMID: 33587988 DOI: 10.1016/j.jconrel.2021.02.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 01/12/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023]
Abstract
Treatment of triple negative breast cancer (TNBC)-associated metastasis represents an unmet clinical need, and we lack effective therapeutics for a disease that exhibits high relapse rates and associates with poor patient outcomes. Advanced nanosized drug delivery systems may enhance the efficacy of first-line chemotherapeutics by altering drug pharmacokinetics and enhancing tumor/metastasis targeting to significantly improve efficacy and safety. Herein, we propose the application of injectable poly-amino acid-based nanogels (NGs) as a versatile hydrophilic drug delivery platform for the treatment of TNBC lung metastasis. We prepared biocompatible and biodegradable cross-linked NGs from polyglutamic acid (PGA) loaded with the chemotherapeutic agent doxorubicin (DOX). Our optimized synthetic procedures generated NGs of ~100 nm in size and 25 wt% drug loading content that became rapidly internalized in TNBC cell lines and displayed IC50 values comparable to the free form of DOX. Importantly, PGA-DOX NGs significantly inhibited lung metastases and almost completely suppressed lymph node metastases in a spontaneously metastatic orthotopic mouse TNBC model. Overall, our newly developed PGA-DOX NGs represent a potentially effective therapeutic strategy for the treatment of TNBC metastases.
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