|
1
|
Qiu YJ, Cao JY, Liao JH, Duan Y, Chen S, Cheng R, Huang YL, Lu XY, Cheng J, Wang WP, Duan YR, Dong Y. CXCR4-targeted ultrasound microbubbles for imaging and enhanced chemotherapy/Immunotherapy in liver cancer. Acta Biomater 2025:S1742-7061(25)00191-6. [PMID: 40089129 DOI: 10.1016/j.actbio.2025.03.018] [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: 11/26/2024] [Revised: 03/09/2025] [Accepted: 03/12/2025] [Indexed: 03/17/2025]
Abstract
Ultrasound molecular imaging is an innovative imaging modality that combines ultrasound with molecular probes to observe live biological processes at the cellular and molecular levels. C-X-C chemokine receptor type 4 (CXCR4) is a specific target in liver tumors and plays a crucial role in promoting tumor growth, invasion, metastasis, and angiogenesis. This study pioneered the use of CXCR4-targeted ultrasound molecular imaging for visualized antitumor therapy and investigated the potential of CXCR4-targeted microbubbles (MBs) in sensitizing liver tumor treatment. CXCR4-targeted MBs demonstrated high ligands conjugation efficiency to vascular endothelial cells (99.77 ± 0.15 %) and significantly inhibited the migration and invasion of Hepa1-6 cells. Molecular CEUS imaging results indicated that the MBs carrying LFC131 peptides facilitated site-specific recognition in BALB/c mice bearing Hep G2 tumors. After the 2-week of chemotherapy, ultrasound molecular imaging signals were significantly reduced in liver cancer when using CXCR4-targeted MBs compared to the SonoVue group which were corroborated by quantitative immunohistochemical grading of CXCR4 expression. In liver cancer immunotherapy, the anti-PD-L1 mAb + CXCR4-targeted MBs group yielded a remarkable tumor inhibition rate (94.6 %) with increased CD8+ T-cell infiltration and decreased FOXP3+ regulatory T cells. Bulk RNA-seq analysis and animal experiment confirmed that anti-PD-L1 mAb combined with CXCR4-targeted MBs effectively induced a robust immune response in liver cancer. These findings establish a solid foundation for future molecular CEUS imaging applications and the development of sensitization strategies for liver cancer therapy. STATEMENT OF SIGNIFICANCE: Ultrasound molecular imaging plays a pivotal role in advancing precision medicine by optimizing tumor diagnosis and treatment. This study pioneers ultrasound molecular imaging in liver tumor therapy using CXCR4-targeted microbubbles (MBs) conjugated with LFC131 peptides. Achieving 99.77 % ligand binding efficiency, the CXCR4-targeted MBs group suppressed tumor migration and enabled precise molecular imaging validated by immunohistochemistry. Moreover, the integration of CXCR4-targeted MBs with anti-PD-L1 immunotherapy resulted in a remarkable tumor inhibition rate of 94.6 %, accompanied by increased CD8+ T cells and decreased FOXP3+ regulatory T cells. These findings underscore the dual role of CXCR4-targeted MBs in both imaging and enhancing chemotherapy/immunotherapy, establishing a foundational framework for the future advancement of molecular imaging-guided liver cancer treatment.
Collapse
Affiliation(s)
- Yi-Jie Qiu
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Jia-Ying Cao
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Jing-Han Liao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China
| | - Yi Duan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China
| | - Sheng Chen
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Rui Cheng
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Yun-Lin Huang
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Xiu-Yun Lu
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Juan Cheng
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China
| | - Wen-Ping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
| | - You-Rong Duan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China.
| | - Yi Dong
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China.
| |
Collapse
|
|
2
|
Teuter M, Hu Y, Ross TL, Lolatte K, Ott M, Bengel FM, Balakrishnan A, Bankstahl JP. Longitudinal multi-tracer imaging of hepatocellular carcinoma identifies novel stage- and oncogene-specific changes. Nucl Med Biol 2025; 144-145:109000. [PMID: 39970776 DOI: 10.1016/j.nucmedbio.2025.109000] [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: 11/18/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, globally. There is a need for novel biomarkers for early detection and novel, effective targeted therapies. Molecular imaging can faithfully visualize, characterize and quantify specific relevant biological processes. BASIC PROCEDURE We performed longitudinal dedicated small-animal positron emission tomography-computed tomography (PET/CT) imaging to analyze changes in glucose metabolism using [18F]fluorodeoxyglucose ([18F]FDG), amino acid turnover with [18F]fluoroethyltyrosine ([18F]FET), and chemokine receptor expression using [68Ga]pentixafor targeting CXCR4, during stages of early tumor development, overt HCC and regression. We used two conditional transgenic mouse models of HCC, driven by clinically relevant oncogenes c-MYC (LT2/MYC) or HRASV12 (LT2/RAS). Conditional doxycycline-regulated mouse models, enable liver-specific oncogene activation or inhibition, leading to liver tumor development and regression, respectively. Correlation of our PET/CT findings with our gene expression and metabolomics data and with histological analyses followed. MAIN FINDINGS We show PET/CT identifies HCC stage-specific and oncogene-specific molecular changes that may serve as potential novel biomarkers and therapeutic targets. Glucose metabolism and CXCR4 chemokine expression are differentially deregulated during HCC development in an oncogene-specific manner. Our [18F]FDG results correlated with glucose transporter GLUT1 gene expression and with our metabolomics data. Increased expression of CXCR4 and CD68 inflammatory markers mirrored [68Ga]pentixafor results in LT2/MYC mice. FET-based measurement of amino acid turnover are insensitive to stages of HCC-development, in our studies. Concurrently, no significant changes in expression of tyrosine metabolism genes were observed. PRINCIPAL CONCLUSIONS Our study highlights that identified changes in targeted molecular imaging can facilitate a better understanding of underlying biological processes and may help guide novel oncogene-specific targeted anti-tumor therapies in HCC, with promising translational potential.
Collapse
Affiliation(s)
- Mari Teuter
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Yuhai Hu
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany
| | - Tobias L Ross
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Kelsey Lolatte
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Michael Ott
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany
| | - Frank M Bengel
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany.
| | - Jens P Bankstahl
- Department of Nuclear Medicine, Hannover Medical School, Germany.
| |
Collapse
|
|
3
|
Yen JH, Chang CC, Hsu HJ, Yang CH, Mani H, Liou JW. C-X-C motif chemokine ligand 12-C-X-C chemokine receptor type 4 signaling axis in cancer and the development of chemotherapeutic molecules. Tzu Chi Med J 2024; 36:231-239. [PMID: 38993827 PMCID: PMC11236080 DOI: 10.4103/tcmj.tcmj_52_24] [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: 02/26/2024] [Revised: 03/14/2024] [Accepted: 04/18/2024] [Indexed: 07/13/2024] Open
Abstract
Chemokines are small, secreted cytokines crucial in the regulation of a variety of cell functions. The binding of chemokine C-X-C motif chemokine ligand 12 (CXCL12) (stromal cell-derived factor 1) to a G-protein-coupled receptor C-X-C chemokine receptor type 4 (CXCR4) triggers downstream signaling pathways with effects on cell survival, proliferation, chemotaxis, migration, and gene expression. Intensive and extensive investigations have provided evidence suggesting that the CXCL12-CXCR4 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, as well as in creating tumor microenvironment, thus implying that this axis is a potential target for the development of cancer therapies. The structures of CXCL12 and CXCR4 have been resolved with experimental methods such as X-ray crystallography, NMR, or cryo-EM. Therefore, it is possible to apply structure-based computational approaches to discover, design, and modify therapeutic molecules for cancer treatments. Here, we summarize the current understanding of the roles played by the CXCL12-CXCR4 signaling axis in cellular functions linking to cancer progression and metastasis. This review also provides an introduction to protein structures of CXCL12 and CXCR4 and the application of computer simulation and analysis in understanding CXCR4 activation and antagonist binding. Furthermore, examples of strategies and current progress in CXCL12-CXCR4 axis-targeted development of therapeutic anticancer inhibitors are discussed.
Collapse
Affiliation(s)
- Jui-Hung Yen
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
| | - Chun-Chun Chang
- Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan
| | - Hao-Jen Hsu
- Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien, Taiwan
| | - Chin-Hao Yang
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hemalatha Mani
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Je-Wen Liou
- Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan
- Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien, Taiwan
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| |
Collapse
|
|
4
|
Yoshida S, Kawai H, Soe Y, Eain HS, Sanou S, Takabatake K, Takeshita Y, Hisatomi M, Nagatsuka H, Asaumi J, Yanagi Y. Efficacy of Cisplatin-CXCR4 Antagonist Combination Therapy in Oral Cancer. Cancers (Basel) 2024; 16:2326. [PMID: 39001388 PMCID: PMC11240506 DOI: 10.3390/cancers16132326] [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: 05/03/2024] [Revised: 06/13/2024] [Accepted: 06/20/2024] [Indexed: 07/16/2024] Open
Abstract
Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin-AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.
Collapse
Affiliation(s)
- Saori Yoshida
- Preliminary Examination Room, Okayama University Hospital, Okayama 700-8558, Japan; (S.Y.); (Y.Y.)
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.S.); (H.S.E.); (H.N.)
| | - Yamin Soe
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.S.); (H.S.E.); (H.N.)
| | - Htoo Shwe Eain
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.S.); (H.S.E.); (H.N.)
| | - Sho Sanou
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan;
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.S.); (H.S.E.); (H.N.)
| | - Yohei Takeshita
- Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.T.); (J.A.)
| | - Miki Hisatomi
- Department of Oral and Maxillofacial Radiology, Okayama University Hospital, Okayama 700-8558, Japan;
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.S.); (H.S.E.); (H.N.)
| | - Junichi Asaumi
- Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; (Y.T.); (J.A.)
| | - Yoshinobu Yanagi
- Preliminary Examination Room, Okayama University Hospital, Okayama 700-8558, Japan; (S.Y.); (Y.Y.)
- Department of Dental Informatics, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| |
Collapse
|
|
5
|
Lu X, Wang X, Cheng H, Wang X, Liu C, Tan X. Anti-triple-negative breast cancer metastasis efficacy and molecular mechanism of the STING agonist for innate immune pathway. Ann Med 2023; 55:2210845. [PMID: 37162544 PMCID: PMC10173802 DOI: 10.1080/07853890.2023.2210845] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND With high recurrence and metastatic rates, triple-negative breast cancer (TNBC) has few therapy choices. The innate immune stimulator of interferon genes protein (STING) pathway has emerged as a critical foundation for improving anticancer immunotherapy. Although 2',3'-cGAMP has been shown to have therapeutic potential as a STING agonist in subcutaneous solid tumour treatments in mice, the effect of cGAMP in metastatic malignancies has received less attention. METHODS Bioluminescence imaging technology was applied to monitor TNBC tumour cell metastasis in living mice. Serum biochemical test and blood routine examination of mice were used to demonstrate cGAMP administration had no toxicity. The activation of DCs and CD8+ T cells was demonstrated by flow cytometry. The pharmacological mechanism of cGAMP for suppressing breast tumour metastasis was also explored. RESULTS cGAMP treatment substantially suppressed tumour development and metastasis without adverse effects. cGAMP activated the cGAS-STING-IRF3 pathway, which modified the tumour immune milieu to reverse the Epithelial-Mesenchymal Transition (EMT) and PI3K/AKT pathways and prevent tumour metastasis. It was postulated and proven that cGAMP had a pharmacological mechanism for reducing breast tumour metastasis. CONCLUSION The findings suggest that cGAMP could be useful in the immunotherapy of immune-insensitive metastatic breast cancer.
Collapse
Affiliation(s)
- Xing Lu
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiang Wang
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hao Cheng
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaoqing Wang
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chang Liu
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiangshi Tan
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| |
Collapse
|
|
6
|
Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathol Res Pract 2023; 248:154616. [PMID: 37379710 DOI: 10.1016/j.prp.2023.154616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
Colorectal cancer (CRC) is comprised of transformed cells and non-malignant cells including cancer-associated fibroblasts (CAF), endothelial vasculature cells, and tumor-infiltrating cells. These nonmalignant cells, as well as soluble factors (e.g., cytokines), and the extracellular matrix (ECM), form the tumor microenvironment (TME). In general, the cancer cells and their surrounding TME can crosstalk by direct cell-to-cell contact and via soluble factors, such as cytokines (e.g., chemokines). TME not only promotes cancer progression through growth-promoting cytokines but also provides resistance to chemotherapy. Understanding the mechanisms of tumor growth and progression and the roles of chemokines in CRC will likely suggest new therapeutic targets. In this line, a plethora of reports has evidenced the critical role of chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis in CRC pathogenesis. In the current review, we take a glimpse into the role of the CXCR4/CXCL12 axis in CRC growth, metastasis, angiogenesis, drug resistance, and immune escape. Also, a summary of recent reports concerning targeting CXCR4/CXCL12 axis for CRC management and therapy has been delivered.
Collapse
Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Rabia Noor
- Amna Inayat Medical College, Lahore, Pakistan
| | - Ali Alsalamy
- College of Medical Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 75471, Aljouf, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of Research & Innovation, Uttaranchal University, Dehradun 248007, India
| |
Collapse
|
|
7
|
Weich A, Serfling SE, Schlötelburg W, Higuchi T, Hartrampf PE, Schirbel A, Heinrich M, Buck AK, Rowe SP, Kosmala A, Werner RA. Impact of CXCR4-Directed PET/CT on Staging and Proposed Oncologic Management in Patients With Digestive System Tumors. Clin Nucl Med 2023; 48:586-593. [PMID: 37167408 DOI: 10.1097/rlu.0000000000004674] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
PURPOSE To elucidate the influence of CXC motif chemokine receptor 4 (CXCR4)-directed imaging on staging and proposed oncologic management in patients with digestive system tumors compared with guideline-appropriate imaging (GAI). METHODS From our PET/CT database, we retrospectively identified 37 patients with advanced digestive system tumors, which had been scheduled for CXCR4-targeted [ 68 Ga]Ga-pentixafor PET/CT for potential theranostic considerations. In all subjects, concurrent GAI was also available. Patients were afflicted with gastroenteropancreatic neuroendocrine neoplasms (21/37 [56.8%]), pancreatic duct adenocarcinoma (6/37 [16.2%]), cholangiocarcinoma (5/37 [13.5%]), hepatocellular carcinoma (4/37 [10.8%]), and colorectal carcinoma (1/37 [2.7%]). Staging results and impact on proposed oncologic management by a board-certified gastroenterologist were compared between GAI and [ 68 Ga]Ga-pentixafor PET/CT. RESULTS Relative to GAI, CXCR4-directed PET/CT resulted in staging changes in 14 of 37 patients (37.8%). Upstaging was seen in 1 of 14 patients (7.1%), whereas downstaging was recorded in the remaining 13 of 14 patients (92.9%). Among those, staging changes would not have triggered any changes in oncological management in 4 of 14 (28.6%). For the remaining 10 of 14 patients (71.4%), however, findings on [ 68 Ga]Ga-pentixafor PET/CT would have impacted subsequent clinical algorithm, including the necessity for further diagnostic steps or failure to initiate antitumor therapy. CONCLUSION [ 68 Ga]Ga-pentixafor PET/CT missed tumor lesions in 13 patients with digestive system tumors, which would have led to inappropriate downstaging and clinical treatment of 10 patients. As such, our results do not support a more widespread use of [ 68 Ga]Ga-pentixafor PET/CT for clinical staging in those tumor entities.
Collapse
Affiliation(s)
| | | | - Wiebke Schlötelburg
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | | | - Philipp E Hartrampf
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Andreas Schirbel
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | | | - Andreas K Buck
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Steven P Rowe
- Johns Hopkins School of Medicine, The Russell H Morgan Department of Radiology and Radiological Sciences, Baltimore, MD
| | - Aleksander Kosmala
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | | |
Collapse
|
|
8
|
Afshar-Khamseh R, Javeri A, Taha MF. MiR-146a suppresses the expression of CXCR4 and alters survival, proliferation and migration rate in colorectal cancer cells. Tissue Cell 2021; 73:101654. [PMID: 34601384 DOI: 10.1016/j.tice.2021.101654] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 12/14/2022]
Abstract
CXCR4 plays an important role in colorectal cancer (CRC) development and metastasis. Some previous studies have indicated CXCR4 as a therapeutic target in cancer. CXCR4 is known as a direct target of miR-146a. The present study aimed to investigate how exogenous induction of miR-146a affects CXCR4 gene and protein expression and also proliferation, apoptosis and migration of CRC cells. Transfection of Caco-2 and SW480 cells by a synthetic miR-146a mimic led to downregulation of CXCR4 expression at both gene and protein levels. It also downregulated expression of several miR-146a targets, including GSK3B, IRAK1, TRAF6, AKT2, SMAD4, EGFR and NFKB1, mostly in SW480 cells. Overexpression of miR-146a resulted in a partial cell cycle arrest in the both cell lines, while the apoptotic rate was also decreased. In regards to epithelial-mesenchymal transition factors, VIM was downregulated in the both cell lines, but SNAI1 was upregulated in Caco-2 cells. The wound closure assay showed a reduction in cell migration in SW480 cells, but an opposite effect was detected in Caco-2 cells following transfection with miR-146a mimic. Therefore, our results are indicating that overexpression of miR-146a, despite downregulation of oncogenic CXCR4, may not lead to a universal tumor suppressive effect in all CRC cells, and this is possibly due to differences in miR-146a effects on signaling pathways in each cell type. Selection of miR-146a for tumor suppression requires enough details regarding the signaling profile of cancer cells otherwise it may produce unexpected outcome.
Collapse
Affiliation(s)
- Reyhaneh Afshar-Khamseh
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran
| | - Arash Javeri
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran.
| | - Masoumeh Fakhr Taha
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran.
| |
Collapse
|
|
9
|
Fujimoto N, Dieterich LC. Mechanisms and Clinical Significance of Tumor Lymphatic Invasion. Cells 2021; 10:cells10102585. [PMID: 34685565 PMCID: PMC8533989 DOI: 10.3390/cells10102585] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/20/2021] [Accepted: 09/25/2021] [Indexed: 12/17/2022] Open
Abstract
Tumor-associated lymphatic vessels play an important role in tumor progression, mediating lymphatic dissemination of malignant cells to tumor-draining lymph nodes and regulating tumor immunity. An early, necessary step in the lymphatic metastasis cascade is the invasion of lymphatic vessels by tumor cell clusters or single tumor cells. In this review, we discuss our current understanding of the underlying cellular and molecular mechanisms, which include tumor-specific as well as normal, developmental and immunological processes “hijacked” by tumor cells to gain access to the lymphatic system. Furthermore, we summarize the prognostic value of lymphatic invasion, discuss its relationship with local recurrence, lymph node and distant metastasis, and highlight potential therapeutic options and challenges.
Collapse
Affiliation(s)
- Noriki Fujimoto
- Department of Dermatology, Shiga University of Medical Science, Otsu 520-2192, Japan;
| | - Lothar C. Dieterich
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland
- Correspondence:
| |
Collapse
|
|
10
|
Olmeda D, Cerezo-Wallis D, Castellano-Sanz E, García-Silva S, Peinado H, Soengas MS. Physiological models for in vivo imaging and targeting the lymphatic system: Nanoparticles and extracellular vesicles. Adv Drug Deliv Rev 2021; 175:113833. [PMID: 34147531 DOI: 10.1016/j.addr.2021.113833] [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: 02/01/2021] [Revised: 05/24/2021] [Accepted: 06/11/2021] [Indexed: 02/06/2023]
Abstract
Imaging of the lymphatic vasculature has gained great attention in various fields, not only because lymphatic vessels act as a key draining system in the body, but also for their implication in autoimmune diseases, organ transplant, inflammation and cancer. Thus, neolymphangiogenesis, or the generation of new lymphatics, is typically an early event in the development of multiple tumor types, particularly in aggressive ones such as malignant melanoma. Still, the understanding of how lymphatic endothelial cells get activated at distal (pre)metastatic niches and their impact on therapy is still unclear. Addressing these questions is of particular interest in the case of immune modulators, because endothelial cells may favor or halt inflammatory processes depending on the cellular context. Therefore, there is great interest in visualizing the lymphatic vasculature in vivo. Here, we review imaging tools and mouse models used to analyze the lymphatic vasculature during tumor progression. We also discuss therapeutic approaches based on nanomedicines to target the lymphatic system and the potential use of extracellular vesicles to track and target sentinel lymph nodes. Finally, we summarize main pre-clinical models developed to visualize the lymphatic vasculature in vivo, discussing their applications with a particular focus in metastatic melanoma.
Collapse
Affiliation(s)
- David Olmeda
- Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Daniela Cerezo-Wallis
- Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain; Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, 28029, Spain
| | - Elena Castellano-Sanz
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
| | - María S Soengas
- Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
| |
Collapse
|
|
11
|
Clinical association of CXCR4 in primary tumor of papillary thyroid cancer and response to iodine-131 treatment. Nucl Med Commun 2021; 42:396-401. [PMID: 33306632 DOI: 10.1097/mnm.0000000000001340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECT Papillary thyroid cancer (PTC) has an excellent prognosis. However, patients with such, if refract to radioiodine treatment, increase recurrent and mortality rates. Tumor aggressiveness in primary tumor of PTC expresses CXCR4 chemokine receptor. Thus, CXCR4 expression of the tumor may predict response to radioiodine treatment. MATERIALS AND METHODS Retrospective review of seventy-four PTC patients, treated with total/near-total thyroidectomy and radioiodine treatment at King Chulalongkorn Memorial Hospital from January 2007 to 2013, were classified as non-radioiodine-refractory (non-RAIR) or RAIR treatment response. All histopathologic diagnoses were reviewed and paraffin blocks were retrieved for CXCR4 immunostaining, determined by automated digital imaging analysis for intensity and extension. The scores were compared between primary tumour and adjacent normal thyroid tissue as well as between the tissue of non-RAIR and that of RAIR. Factors determining type of RAI response were analyzed. RESULTS CXCR4 immunostaining scores of PTC is significantly higher than normal thyroid [2.03 (0.52) and 1.48 (0.75)] [mean (SD)] (P = 0.0001). CXCR4 immunostaining scores in RAIR are potentially higher than non-RAIR [1.95 (0.54) and 2.13 (0.47) (P = 0.149)]. Odds ratio of CXCR4 immunostaining score for predicting RAIR treatment is 1.99 (P = 0.150). CXCR4 immunostaining scores positively associate with tumor size (R = 0.298, P = 0.01); whereas no significant association with other clinicopathologic factors. CONCLUSION Our data support the notion that CXCR4 are significantly expressed in PTC tumor over normal thyroid tissues. However, there is no clinical association with radioiodine treatment response.
Collapse
|
|
12
|
Malik A, Thanekar U, Amarachintha S, Mourya R, Nalluri S, Bondoc A, Shivakumar P. "Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma. Front Oncol 2021; 10:627701. [PMID: 33718121 PMCID: PMC7943925 DOI: 10.3389/fonc.2020.627701] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of >80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.
Collapse
Affiliation(s)
- Astha Malik
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Unmesha Thanekar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Surya Amarachintha
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Shreya Nalluri
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Alexander Bondoc
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| |
Collapse
|
|
13
|
Lu G, Qiu Y, Su X. Targeting CXCL12-CXCR4 Signaling Enhances Immune Checkpoint Blockade Therapy Against Triple Negative Breast Cancer. Eur J Pharm Sci 2021; 157:105606. [PMID: 33131745 DOI: 10.1016/j.ejps.2020.105606] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/21/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
Insufficient T cell infiltration in triple-negative breast cancer (TNBC) has limited its response rate to immune checkpoint blockade (ICB) therapies and motivated the development of immunostimulatory approaches to enhance the ICB therapy. CXCR4 is a chemokine receptor highly upregulated both on cell surface and cytoplasm in tumor tissues. Activating CXCR4 has been associated with increased immunosuppression in the tumor microenvironment. Here, we developed a CXCR4-targeted liposomal formulation (Liposomal-AMD3100) to enhance therapeutic efficacy of AMD3100, a CXCR4 antagonist. Particularly, AMD3100 is not only encapsulated into the liposome but coated on the surface of the formulation to serve as a targeting moiety and a dual blocker capable of inhibiting CXCR4 activation extracellularly and intracellularly. The Liposomal-AMD3100 remodeled both immune and stromal microenvironment more efficiently compared with free AMD3100, indicating better pharmacodynamic profile of AMD3100 achieved by liposomal formulation. The combination of anti-PD-L1 with Liposomal-AMD3100 formulation exhibited an increased antitumor effect and prolonged survival time compared with monotherapies in a murine TNBC model (4T1). This work proves that immune activation via liposomal delivery of CXCR4 inhibitors has a great potential to expand ICB therapies to originally ICB-insensitive cancer types.
Collapse
Affiliation(s)
- Guowen Lu
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China.
| | - Yier Qiu
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China
| | - Xiaobao Su
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China
| |
Collapse
|
|
14
|
Lee S, Kang H, Park D, Yu J, Koh SK, Cho D, Kim D, Kang K, Jeon NL. Modeling 3D Human Tumor Lymphatic Vessel Network Using High‐Throughput Platform. Adv Biol (Weinh) 2021. [DOI: 10.1002/adbi.202000195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Somin Lee
- Interdisciplinary Program for Bioengineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| | - Habin Kang
- Interdisciplinary Program for Bioengineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| | - Dohyun Park
- Department of Mechanical Engineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| | - James Yu
- Interdisciplinary Program for Bioengineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| | - Seung Kwon Koh
- Department of Health Sciences and Technology SAIHST Sungkyunkwan University 115, Irwon‐ro, Gangnam‐gu Seoul 06355 Republic of Korea
| | - Duck Cho
- Department of Health Sciences and Technology SAIHST Sungkyunkwan University 115, Irwon‐ro, Gangnam‐gu Seoul 06355 Republic of Korea
- Department of Laboratory Medicine and Genetics Samsung Medical Center Sungkyunkwan University School of Medicine 115, Irwon‐ro, Gangnam‐gu Seoul 06355 Republic of Korea
| | - Da‐Hyun Kim
- Adult Stem Cell Research Center and Research Institute for Veterinary Science College of Veterinary Medicine Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| | - Kyung‐Sun Kang
- Adult Stem Cell Research Center and Research Institute for Veterinary Science College of Veterinary Medicine Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| | - Noo Li Jeon
- Interdisciplinary Program for Bioengineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
- Department of Mechanical Engineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
- Institute of Advanced Machinery and Design Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
- Institute of BioEngineering Seoul National University 1, Gwanak‐ro, Gwanak‐gu Seoul 08826 Republic of Korea
| |
Collapse
|
|
15
|
Cadima-Couto I, Tauzin A, Freire JM, Figueira TN, Silva RDM, Pérez-Peinado C, Cunha-Santos C, Bártolo I, Taveira N, Gano L, Correia JDG, Goncalves J, Mammano F, Andreu D, Castanho MARB, Veiga AS. Anti-HIV-1 Activity of pepRF1, a Proteolysis-Resistant CXCR4 Antagonist Derived from Dengue Virus Capsid Protein. ACS Infect Dis 2021; 7:6-22. [PMID: 33319557 DOI: 10.1021/acsinfecdis.9b00507] [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] [Indexed: 11/30/2022]
Abstract
There is an urgent need for the development of new anti-HIV drugs that can complement existing medicines to be used against resistant strains. Here, we report the anti-HIV-1 peptide pepRF1, a human serum-resistant peptide derived from the Dengue virus capsid protein. In vitro, pepRF1 shows a 50% inhibitory concentration of 1.5 nM with a potential therapeutic window higher than 53 000. This peptide is specific for CXCR4-tropic strains, preventing viral entry into target cells by binding to the viral coreceptor CXCR4, acting as an antagonist of this receptor. pepRF1 is more effective than T20, the only peptide-based HIV-1 entry inhibitor approved, and excels in inhibiting a HIV-1 strain resistant to T20. Potentially, pepRF1 can be used alone or in combination with other anti-HIV drugs. Furthermore, one can also envisage its use as a novel therapeutic strategy for other CXCR4-related diseases.
Collapse
Affiliation(s)
- Iris Cadima-Couto
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Alexandra Tauzin
- INSERM UMR 1124, Université de Paris, 45 rue des Saints Pères, F-75006 Paris, France
| | - João M. Freire
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Tiago N. Figueira
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Rúben D. M. Silva
- Centro de Ciências e Tecnologias Nucleares and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal
| | - Clara Pérez-Peinado
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, 08003 Barcelona, Spain
| | - Catarina Cunha-Santos
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Inês Bártolo
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Nuno Taveira
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, 2829-511 Monte de Caparica, Portugal
| | - Lurdes Gano
- Centro de Ciências e Tecnologias Nucleares and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal
| | - João D. G. Correia
- Centro de Ciências e Tecnologias Nucleares and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal
| | - Joao Goncalves
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Fabrizio Mammano
- INSERM UMR 1124, Université de Paris, 45 rue des Saints Pères, F-75006 Paris, France
| | - David Andreu
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, 08003 Barcelona, Spain
| | - Miguel A. R. B. Castanho
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Ana Salomé Veiga
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| |
Collapse
|
|
16
|
Kim JY, Kim HJ, Jung CW, Lee TS, Kim EH, Park MJ. CXCR4 uses STAT3-mediated slug expression to maintain radioresistance of non-small cell lung cancer cells: emerges as a potential prognostic biomarker for lung cancer. Cell Death Dis 2021; 12:48. [PMID: 33414415 PMCID: PMC7791104 DOI: 10.1038/s41419-020-03280-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 10/31/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022]
Abstract
Lung cancer is one of the most common reasons for cancer-induced mortality across the globe, despite major advancements in the treatment strategies including radiotherapy and chemotherapy. Existing reports suggest that CXCR4 is frequently expressed by malignant tumor and is imperative for vascularization, tumor growth, cell migration, and metastasis pertaining to poor prognosis. In this study, we infer that CXCR4 confers resistance to ionizing radiation (IR) in nonsmall cell lung cancer (NSCLC) cells. Further, on the basis of colony forming ability, one finds that drug-resistant A549/GR cells with improved CXCR4 expression exhibited more resistance to IR than A549 cells evidenced along with a reduction in the formation of γ-H2AX foci after IR. Transfection of shRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) both led to sensitization of A549/GR cells towards IR. Conversely, the overexpression of CXCR4 in A549 and H460 cell lines was found to improve clonogenic survival, and reduce the formation of γ-H2AX foci after IR. CXCR4 expression was further correlated with STAT3 activation, and suppression of STAT3 activity with siSTAT3 or a specific inhibitor (WP1066) significantly stymied the colony-forming ability and increased γ-H2AX foci formation in A549/GR cells, indicating that CXCR4-mediated STAT3 signaling plays an important role for IR resistance in NSCLC cells. Finally, CXCR4/STAT3 signaling was mediated with the upregulation of Slug and downregulation of the same with siRNA, which heightened IR sensitivity in NSCLC cells. Our data collectively suggests that CXCR4/STAT3/Slug axis is paramount for IR resistance of NSCLC cells, and can be regarded as a therapeutic target to enhance the IR sensitivity of this devastating cancer.
Collapse
Affiliation(s)
- Jeong-Yub Kim
- Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hee-Jin Kim
- Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.,School of Biomedical Science, Korea University, Seoul, Korea
| | - Chan-Woong Jung
- Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.,Department of Life Sciences, Korea University, Seoul, Korea
| | - Tae Sup Lee
- Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Eun Ho Kim
- Department of Biochemistry, School of Medicine, Daegu Catholic University, 33, 17-gil, Duryugongwon-ro, Nam-gu, Daegu, 42472, Korea.
| | - Myung-Jin Park
- Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
| |
Collapse
|
|
17
|
Urosevic J, Blasco MT, Llorente A, Bellmunt A, Berenguer-Llergo A, Guiu M, Cañellas A, Fernandez E, Burkov I, Clapés M, Cartanà M, Figueras-Puig C, Batlle E, Nebreda AR, Gomis RR. ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer. Cancer Res 2020; 80:4668-4680. [PMID: 32816905 DOI: 10.1158/0008-5472.can-19-4028] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 06/23/2020] [Accepted: 08/12/2020] [Indexed: 11/16/2022]
Abstract
Carcinoma development in colorectal cancer is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates colorectal cancer metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic colorectal cancer cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with colorectal cancer tumors. Higher levels of EMGS expression were detected in the colorectal cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain-of-function and loss-of-function studies in several colorectal cancer cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation. SIGNIFICANCE: These findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer cells as a driver of tumor-stroma interactions that favor formation of metastases in the liver.
Collapse
Affiliation(s)
- Jelena Urosevic
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain
| | - María Teresa Blasco
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain
| | - Alicia Llorente
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Anna Bellmunt
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Antoni Berenguer-Llergo
- Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marc Guiu
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Adrià Cañellas
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain
| | - Esther Fernandez
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ivan Burkov
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Maria Clapés
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Mireia Cartanà
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Cristina Figueras-Puig
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Eduard Batlle
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain.,ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Angel R Nebreda
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Roger R Gomis
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. .,CIBERONC, Spain.,ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.,School of Medicine, Universitat de Barcelona, Barcelona, Spain
| |
Collapse
|
|
18
|
Morita T, Kodama Y, Shiokawa M, Kuriyama K, Marui S, Kuwada T, Sogabe Y, Matsumori T, Kakiuchi N, Tomono T, Mima A, Ueda T, Tsuda M, Yamauchi Y, Nishikawa Y, Sakuma Y, Ota Y, Maruno T, Uza N, Nagasawa T, Chiba T, Seno H. CXCR4 in Tumor Epithelial Cells Mediates Desmoplastic Reaction in Pancreatic Ductal Adenocarcinoma. Cancer Res 2020; 80:4058-4070. [PMID: 32606001 DOI: 10.1158/0008-5472.can-19-2745] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/06/2020] [Accepted: 06/25/2020] [Indexed: 11/16/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) features abundant stromal cells with an excessive extracellular matrix (ECM), termed the desmoplastic reaction. CXCR4 is a cytokine receptor for stromal cell-derived factor-1 (CXCL12) expressed in PDAC, but its roles in PDAC and the characteristic desmoplastic reaction remain unclear. Here, we generated a mouse model of PDAC with conditional knockout of Cxcr4 (KPC-Cxcr4-KO) by crossing Cxcr4 flox mice with Pdx1-Cre;KrasLSL-G12D/+;Trp53LSL-R172H/+ (KPC-Cxcr4-WT) mice to assess the development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancers. Tumor cell characteristics of those two types were analyzed in vitro. In addition, CXCR4 expression in human pancreatic cancer specimens was evaluated by IHC staining. In KPC-Cxcr4-KO mice, the number and pathologic grade of PanIN lesions were reduced, but the frequency of pancreatic cancers did not differ from that in KPC-Cxcr4-WT mice. The pancreatic tumor phenotype in KPC-Cxcr4-KO mice was significantly larger and undifferentiated, characterized by abundant vimentin-expressing cancer cells, significantly fewer fibroblasts, and markedly less deposition of ECM. In vitro, KPC-Cxcr4-KO tumor cells exhibited higher proliferative and migratory activity than KPC-Cxcr4-WT tumor cells. Myofibroblasts induced invasion activity in KPC-Cxcr4-WT tumor cells, showing an epithelial-mesenchymal interaction, whereas KPC-Cxcr4-KO tumor cells were unaffected by myofibroblasts, suggesting their unique nature. In human pancreatic cancer, undifferentiated carcinoma did not express CXCR4 and exhibited histologic and IHC features similar to those in KPC-Cxcr4-KO mice. In summary, the CXCL12/CXCR4 axis may play an important role in the desmoplastic reaction in PDAC, and loss of CXCR4 induces phenotype changes in undifferentiated carcinoma without a desmoplastic reaction. SIGNIFICANCE: The current study uncovers CXCR4 as a key regulator of desmoplastic reaction in PDAC and opens the way for new therapeutic approaches to overcome the chemoresistance in patients with PDAC.
Collapse
Affiliation(s)
- Toshihiro Morita
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan. .,Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuko Sogabe
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Teruko Tomono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Atsushi Mima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Tatsuki Ueda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuki Yamauchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yojiro Sakuma
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuji Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takashi Nagasawa
- Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.,Kansai Electric Power Hospital, Fukushima-ku, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| |
Collapse
|
|
19
|
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination. J Hematol Oncol 2020; 13:36. [PMID: 32295630 PMCID: PMC7160905 DOI: 10.1186/s13045-020-00863-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/24/2020] [Indexed: 12/13/2022] Open
Abstract
Background Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups. Results T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model. Conclusions A novel nanoconjugate for targeted drug delivery of Auristatin reduces significantly the acute myeloid leukemic cell burden in the bone marrow and blood and blocks its dissemination to extramedullar organs in a CXCR4+ AML model. This selective drug delivery approach validates CXCR4+ AML cells as a target for clinical therapy, not only promising to improve the control of leukemic dissemination but also dramatically reducing the severe toxicity of classical AML therapy.
Collapse
|
|
20
|
Siracusano G, Tagliamonte M, Buonaguro L, Lopalco L. Cell Surface Proteins in Hepatocellular Carcinoma: From Bench to Bedside. Vaccines (Basel) 2020; 8:vaccines8010041. [PMID: 31991677 PMCID: PMC7157713 DOI: 10.3390/vaccines8010041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/16/2020] [Accepted: 01/22/2020] [Indexed: 12/20/2022] Open
Abstract
Cell surface proteins act as the go-between in carrying the information from the extracellular environment to the intracellular signaling proteins. However, these proteins are often deregulated in neoplastic diseases, including hepatocellular carcinoma. This review discusses several recent studies that have investigated the role of cell surface proteins in the occurrence and progression of HCC, highlighting the possibility to use them as biomarkers of the disease and/or targets for vaccines and therapeutics.
Collapse
Affiliation(s)
- Gabriel Siracusano
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy;
- Correspondence: ; Tel.: +39-022643-4957
| | - Maria Tagliamonte
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, “Fondazione Pascale”, 80131 Naples, Italy; (M.T.); (L.B.)
| | - Luigi Buonaguro
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, “Fondazione Pascale”, 80131 Naples, Italy; (M.T.); (L.B.)
| | - Lucia Lopalco
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy;
| |
Collapse
|
|
21
|
Takabatake K, Shimo T, Murakami J, Anqi C, Kawai H, Yoshida S, Wathone Oo M, Haruka O, Sukegawa S, Tsujigiwa H, Nakano K, Nagatsuka H. The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:ijms20225779. [PMID: 31744214 PMCID: PMC6888610 DOI: 10.3390/ijms20225779] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/11/2019] [Accepted: 11/15/2019] [Indexed: 01/08/2023] Open
Abstract
Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.
Collapse
Affiliation(s)
- Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Correspondence: ; Tel.: +81-086-235-6651
| | - Tsuyoshi Shimo
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido 0610293, Japan;
| | - Jun Murakami
- Department of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan;
| | - Chang Anqi
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin 150081, China
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Saori Yoshida
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - May Wathone Oo
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Omori Haruka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Shintaro Sukegawa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Kagawa 7608557, Japan
| | - Hidetsugu Tsujigiwa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Department of Life Science, Faculty of Science, Okayama University of Science, Okayama 7000005, Japan
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| |
Collapse
|
|
22
|
Yang J, Zhang L, Jiang Z, Ge C, Zhao F, Jiang J, Tian H, Chen T, Xie H, Cui Y, Yao M, Li H, Li J. TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression. Theranostics 2019; 9:5810-5827. [PMID: 31534521 PMCID: PMC6735379 DOI: 10.7150/thno.34973] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022] Open
Abstract
TCF12, which is known to be involved in the regulation of cell growth and differentiation, has been reported to function as an oncogene or a tumor suppressor gene in the progression of various malignant tumors. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unclear. Methods: Stable ectopic TCF12 expression or knockdown in HCC cell lines was established by lentiviral infection. Then, MTT, colony formation, migration, invasion and HUVECs tube formation assays as well as an orthotopic xenograft model were used to investigate the biologic function of TCF12 in HCC cells in vitro and in vivo. Subsequently, RNA-Seq analysis was utilized to explore the target genes regulated by TCF12. RT-qPCR, western blotting, a dual-luciferase reporter assay, Ch-IP, CHIP-Seq and functional rescue experiments were used to confirm the target gene regulated by TCF12. Finally, RT-qPCR, western blot and immunohistochemical (IHC) staining were performed to detect the expression level of TCF12 and to analyze the correlation of TCF12 with downstream genes as well as the clinical significance of TCF12 in human primary HCC. Results: Our functional studies revealed that stable overexpression of TCF12 in human HCC cells enhanced cell proliferation, migration and invasion in vitro and in vivo, whereas knockdown of TCF12 showed opposing effects. Mechanistically, CXCR4 was a downstream target of TCF12, and TCF12 directly bound to the CXCR4 promoter to regulate its expression. Moreover, CXCR4, with its ligand CXCL12, played a critical role in tumor progression induced by TCF12 via activation of the MAPK/ERK and PI3K/AKT signaling pathways. Clinically, IHC analysis revealed that TCF12 was significantly associated with poor survival of HCC patients and that TCF12 expression was closely correlated with CXCR4 expression in primary HCC tissues. Conclusion: Our findings are the first to indicate that TCF12 could promote the tumorigenesis and progression of HCC mainly by upregulating CXCR4 expression and is a prognostic indicator for patients with HCC.
Collapse
|
|
23
|
Yoshida S, Kawai H, Eguchi T, Sukegawa S, Oo MW, Anqi C, Takabatake K, Nakano K, Okamoto K, Nagatsuka H. Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer. Cells 2019; 8:cells8070761. [PMID: 31336612 PMCID: PMC6678844 DOI: 10.3390/cells8070761] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/18/2019] [Accepted: 07/20/2019] [Indexed: 01/09/2023] Open
Abstract
CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To uncover the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as tumor angiogenic inhibition triggered necrosis (TAITN), which was induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic areas with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.
Collapse
Affiliation(s)
- Saori Yoshida
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
| | - Takanori Eguchi
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
| | - Shintaro Sukegawa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
- Division of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - May Wathone Oo
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| | - Chang Anqi
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
- Department of Anatomy, Basic Medicine Science College, Harbin Medical University, Harbin 150076, China
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| | - Kuniaki Okamoto
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| |
Collapse
|
|
24
|
Céspedes MV, Unzueta U, Aviñó A, Gallardo A, Álamo P, Sala R, Sánchez-Chardi A, Casanova I, Mangues MA, Lopez-Pousa A, Eritja R, Villaverde A, Vázquez E, Mangues R. Selective depletion of metastatic stem cells as therapy for human colorectal cancer. EMBO Mol Med 2019; 10:emmm.201708772. [PMID: 30190334 PMCID: PMC6180303 DOI: 10.15252/emmm.201708772] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis‐initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22‐GFP‐H6‐FdU) that selectively delivers Floxuridine to CXCR4+ cells. In contrast to free oligo‐FdU, intravenous T22‐GFP‐H6‐FdU selectively accumulates and internalizes in CXCR4+ cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor re‐initiation capacity. Repeated T22‐GFP‐H6‐FdU administration in cell line and patient‐derived CRC models blocks intravasation and completely prevents metastases development in 38–83% of mice, while showing CXCR4 expression‐dependent and site‐dependent reduction in foci number and size in liver, peritoneal, or lung metastases in the rest of mice, compared to free oligo‐FdU. T22‐GFP‐H6‐FdU induces also higher regression of established metastases than free oligo‐FdU, with negligible distribution or toxicity in normal tissues. This targeted drug delivery approach yields potent antimetastatic effect, through selective depletion of metastatic CXCR4+ cancer cells, and validates metastatic stem cells (MetSCs) as targets for clinical therapy.
Collapse
Affiliation(s)
- María Virtudes Céspedes
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain
| | - Ugutz Unzueta
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain
| | - Anna Aviñó
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.,Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, Spain
| | - Alberto Gallardo
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.,Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Patricia Álamo
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain
| | - Rita Sala
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain
| | | | - Isolda Casanova
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain
| | - María Antònia Mangues
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain.,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.,Department of Pharmacy, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Antonio Lopez-Pousa
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.,Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Ramón Eritja
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.,Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Barcelona, Spain
| | - Antonio Villaverde
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain .,Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Esther Vázquez
- CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.,Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ramón Mangues
- Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Santa Creu i Sant Pau, Barcelona, Spain .,CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain
| |
Collapse
|
|
25
|
Li X, Zhong Q, Luo D, Du Q, Liu W. The prognostic value of CXC subfamily ligands in stage I-III patients with colorectal cancer. PLoS One 2019; 14:e0214611. [PMID: 30973890 PMCID: PMC6459597 DOI: 10.1371/journal.pone.0214611] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 03/17/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To investigate the value of CXC subfamily ligands in stage I-III patients with colorectal cancer, in order to find a new predictor for CRC patients. METHODS We used Gene Expression Omnibus (GEO) database to collect the gene expression of CXC subfamily ligands and corresponding clinical data. The survival analysis was performed by "survival" package of Rsoftware. The CRC patients' DFS and the relationship between the expression levels of CXC subfamily ligands were evaluated by the univariate Cox regression analysis. RESULTS By using microarray data, there were 14 CXC subfamily ligands identified from dataset GSE39582. Seven CXC subfamily ligands were significantly correlated with DFS in CRC patients. (p<0.05),including CXCL1, CXCL3, CXCL9, CXCL10, CXCL11, CXCL13, and CXCL14. From multivariate Cox regression analyze, four CXC subfamily ligands (CXCL9, CXCL10, CXCL11, and CXCL13) were significantly associated with CRC patients' DFS (all p<0.05). Three CXC subfamily ligands (CXCL10, CXCL11, and CXCL13) were significantly associated with CRC patients' Overall survival (OS) (all p<0.05). Both CXCL11 and CXCL13 had the similar prediction values for DFS and OS. CONCLUSION There were seven CXC subfamily ligands were significantly correlated with DFS in CRC patients. Different expression level of four CXC subfamily ligands (CXCL9, CXCL10, CXCL11, and CXCL13) and Three CXC subfamily ligands (CXCL10, CXCL11, and CXCL13) were related to CRC patients' DFS and OS. There are still needs more experiments to confirm our conclusions. Next step we will make animal experiment about the genes in order to verified the predictive value of the CXC subfamily ligands.
Collapse
Affiliation(s)
- Xiangde Li
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qiulu Zhong
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Danjing Luo
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qinghua Du
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wenqi Liu
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
|
26
|
Jiao X, Shu G, Liu H, Zhang Q, Ma Z, Ren C, Guo H, Shi J, Liu J, Zhang C, Wang Y, Gao Y. The Diagnostic Value of Chemokine/Chemokine Receptor Pairs in Hepatocellular Carcinoma and Colorectal Liver Metastasis. J Histochem Cytochem 2019; 67:299-308. [PMID: 30633620 DOI: 10.1369/0022155418824274] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chemokines and their receptors have been proposed to play important roles in tumor progression and metastasis. To investigate their roles in the progression of primary and metastatic malignant liver tumors and their prognosis, we compared expression profiles of CXCL12/CXCR4, CCL20/CCR6, and CCL21/CCR7 in hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). Immunohistochemistry was used to analyze the expression levels of the chemokine/chemokine receptor pairs in 29 HCC and 11 CRLM specimens and adjacent non-cancerous tissues, and correlations with clinicopathological variables and overall survival were determined. CCL20/CCR6 expression was higher in HCC than in adjacent non-cancerous tissues. High CCR6 expression in HCC was negatively associated with 5-year survival rate and was an independent prognostic factor for overall survival of HCC patients, whereas differences were not observed between CRLM and adjacent tissues. Furthermore, significantly higher expression of CCL21/CCR7 was found in CRLM than in HCC. In summary, the CCL20/CCR6 axis was elevated in HCC but not in CRLM, whereas the CCL21/CCR7 axis was elevated in CRLM but not in HCC.
Collapse
Affiliation(s)
- Xiaolei Jiao
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute for Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China
| | - Guiming Shu
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Hui Liu
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute for Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China
| | - Qin Zhang
- Department of Pathology, Tianjin Third Central Hospital, Tianjin, China
| | - Zhe Ma
- Department of Pathology, Tianjin Third Central Hospital, Tianjin, China
| | - Chaoyi Ren
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Hongsheng Guo
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Jingxiang Shi
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Junguo Liu
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Chuanshan Zhang
- Department of Pathology, Tianjin Third Central Hospital, Tianjin, China
| | - Yijun Wang
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Yingtang Gao
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute for Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China
| |
Collapse
|
|
27
|
Peled A, Klein S, Beider K, Burger JA, Abraham M. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine 2018; 109:11-16. [PMID: 29903571 DOI: 10.1016/j.cyto.2018.02.020] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 02/18/2018] [Accepted: 02/20/2018] [Indexed: 12/25/2022]
Abstract
The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1/CXCL12) are important players in the cross-talk among lymphoma, myeloma and leukemia cells and their microenvironments. In hematological malignancies and solid tumors, the overexpression of CXCR4 on the cell surface has been shown to be responsible for disease progression, increasing tumor cell survival and chemoresistance and metastasis to organs with high CXCL12 levels (e.g., lymph nodes and bone marrow (BM)). Furthermore, the overexpression of CXCR4 has been found to have prognostic significance for disease progression in many type of tumors including lymphoma, leukemia, glioma, and prostate, breast, colorectal, renal, and hepatocellular carcinomas. In leukemia, CXCR4 expression granted leukemic blasts a higher capacity to seed into BM niches, thereby protecting leukemic cells from chemotherapy-induced apoptosis, and was correlated with shorter disease-free survival. In contrast, neutralizing the interaction of CXCL12/CXCR4 with a variety of antagonists induced apoptosis and differentiation and increased the chemosensitivity of lymphoma, myeloma, and leukemia cells. The role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies and the clinical therapeutic potential of CXCR4 antagonists in these diseases is discussed.
Collapse
MESH Headings
- Apoptosis/immunology
- Cell Survival/physiology
- Chemokine CXCL12/metabolism
- Disease Progression
- Hematologic Neoplasms/drug therapy
- Hematologic Neoplasms/pathology
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Multiple Myeloma/pathology
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Prognosis
- Receptors, CXCR4/metabolism
- Tumor Microenvironment/physiology
Collapse
Affiliation(s)
- Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, P.O.B 12000, Jerusalem 91120, Israel.
| | - Shiri Klein
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, P.O.B 12000, Jerusalem 91120, Israel
| | - Katia Beider
- Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel
| | - Jan A Burger
- Department of Leukemia, The University of Texas Houston, TX, USA
| | - Michal Abraham
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, P.O.B 12000, Jerusalem 91120, Israel
| |
Collapse
|
|
28
|
Hu X, Luo J. Heterogeneity of tumor lymphangiogenesis: Progress and prospects. Cancer Sci 2018; 109:3005-3012. [PMID: 30007095 PMCID: PMC6172057 DOI: 10.1111/cas.13738] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/10/2018] [Indexed: 12/26/2022] Open
Abstract
Lymphangiogenesis and increased expression of lymphangiogenic growth factors are associated with high rates of lymph node (LN) metastasis and with poor prognosis in some, but not all, solid tumors. In addition to its involvement in metastasis, lymphangiogenesis has been shown to have other roles in tumor pathogenesis, such as the niche function of tumor stem cells and regulatory functions of antitumor immune responses. In contrast, evidence has accumulated that tumor-induced lymphangiogenesis displays the heterogeneity in gene signature, structure, cellular origins and functional plasticity. This review summarizes the advances in the research on the heterogeneity of tumor lymphangiogenesis and discusses how it may contribute to functional complexity and multiplicity of lymphangiogenesis in tumor progression.
Collapse
Affiliation(s)
- Xueting Hu
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, China
| | - Jincai Luo
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, China
| |
Collapse
|
|
29
|
Peng WT, Sun WY, Li XR, Sun JC, Du JJ, Wei W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:ijms19051366. [PMID: 29734668 PMCID: PMC5983678 DOI: 10.3390/ijms19051366] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 12/13/2022] Open
Abstract
Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis. We will sum up the functions of GPCRs—particularly those coupled to chemokines, prostaglandin, lysophosphatidic acid, endothelin, catecholamine, and angiotensin—in the proliferation, invasion, metastasis, and angiogenesis of hepatoma cells and the development of hepatocellular carcinoma (HCC) in this review. We also highlight the potential avenues of GPCR-based therapeutics for HCC.
Collapse
Affiliation(s)
- Wen-Ting Peng
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Xin-Ran Li
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Chang Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Jia Du
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| |
Collapse
|
|
30
|
Xu C, Zheng L, Li D, Chen G, Gu J, Chen J, Yao Q. CXCR4 overexpression is correlated with poor prognosis in colorectal cancer. Life Sci 2018; 208:333-340. [PMID: 29719205 DOI: 10.1016/j.lfs.2018.04.050] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 04/16/2018] [Accepted: 04/26/2018] [Indexed: 01/17/2023]
Abstract
AIMS Colorectal cancer threatens human health due to its high mortality resulting from metastatic progression. The expression of C-X-C chemokine receptor type 4 (CXCR4) is absent or low in most healthy tissues but high in various types of tumours. In this study, we aim to determine the prognostic significance of CXCR4 in colorectal cancer. MAIN METHODS We retrospectively examined a total of 72 tissue samples, that qRT-PCR and immunohistochemistry were performed to detect the expression of CXCR4 as well as univariate and multivariate analyses were performed to explore the overall survival. KEY FINDINGS Our data demonstrated that CXCR4 expression was associated with lymph node metastasis (P = 0.049), histological differentiation (P = 0.01), distant metastasis (P = 0.02) and DNA mismatch repair (MMR) index (P = 0.0002). However, CXCR4 expression was not associated with age, sex, tumour diameter or depth of invasion. Furthermore, both univariate and multivariate analyses confirmed that CXCR4 was an independent factor in predicting unfavourable overall survival (hazard ratio, 0.188; 95% confidence interval, 0.038-0.757). SIGNIFICANCE In conclusion, our findings suggest that CXCR4 might contribute to clinical tumour progression and may be a valuable prognostic biomarker in colorectal cancer treatment.
Collapse
Affiliation(s)
- Chao Xu
- Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Linfeng Zheng
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Dechuan Li
- Department of Colorectal Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Guoping Chen
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Jianzhong Gu
- Department of Oncology, First Affiliated Hospital of Zhejiang Traditional Medical University, Hangzhou 310003, China
| | - Jun Chen
- Department of Oncology, Yinzhou Hospital affiliated to Medical School of Ningbo University, Ningbo 315040, China.
| | - Qinghua Yao
- Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou 310022, China.
| |
Collapse
|
|
31
|
Fan W, Ye G. Microarray analysis for the identification of specific proteins and functional modules involved in the process of hepatocellular carcinoma originating from cirrhotic liver. Mol Med Rep 2018; 17:5619-5626. [PMID: 29436633 PMCID: PMC5866002 DOI: 10.3892/mmr.2018.8555] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
In order to identify the potential pathogenesis of hepatocellular carcinoma (HCC) developing from cirrhosis, a microarray‑based transcriptome profile was analyzed. The GSE63898 expression profile was downloaded from the Gene Expression Omnibus database, which included data from 228 HCC tissue samples and 168 cirrhotic tissue samples. The Robust Multi‑array Average in the Affy package of R was used for raw data processing and Student's t‑test was used to screen differentially expressed genes (DEGs). An enrichment analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery online tool, and the protein‑protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. Furthermore, the MCODE plug‑in of Cytoscape was used to conduct a sub‑module analysis. A total of 634 DEGs were identified between HCC and cirrhosis, of which 165 were upregulated and 469 were downregulated. According to the cut‑off criteria, the PPI network was constructed and Jun proto‑oncogene, AP‑1 transcription factor subunit (degree, 39), Fos proto‑oncogene, AP‑1 transcription factor subunit (degree, 34) and v‑myc avian myelocytomatosis viral oncogene homolog (degree, 32) were identified as the hub nodes of the PPI network. Based on the sub‑module analysis, four specific modules were identified. In particular, module 1 was significantly enriched in the chemokine signaling pathway, and C‑X‑C motif chemokine ligand 12, C‑C motif chemokine receptor 7 (CCR7) and C‑C motif chemokine ligand 5 (CCL5) were three important proteins in this module. Module 4 was significantly enriched in chemical carcinogenesis, and cytochrome P450 family 2 subfamily E member 1, cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily A member 6 (CYP2A6) were three important proteins in this module. In conclusion, the present study revealed that CCR7, CCL5, CYP2C9 and CYP2A6 are novel genes identified in the development of HCC; however, the actual functions of these genes require verification.
Collapse
Affiliation(s)
- Wufeng Fan
- Section of Medical Affairs, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Guangming Ye
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|
|
32
|
Zhang M, Zhu ZL, Gao XL, Wu JS, Liang XH, Tang YL. Functions of chemokines in the perineural invasion of tumors (Review). Int J Oncol 2018. [PMID: 29532850 DOI: 10.3892/ijo.2018.4311] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The perineural invasion (PNI) of malignant tumors is a form of tumor progression in which cancer cells encroach along nerves. PNI hinders curative resection. Residual tumor cells in or around nerves can bring about local recurrence, infiltration and metastasis. This behavior is usually associated with a poor clinical prognosis. Therefore, it is necessary to investigate novel ligand-receptor crosstalk between nerves and tumor cells that promote the process of PNI. Chemokines are regarded as one of pivotal factors involved in the process of PNI. The present review collates information provided by previous studies with regard to the role of chemokines in PNI. The study presents a definition of PNI in cancer, generalizes the biological characteristics and the expression of chemokines and their receptors in cancer types associated with PNI, and discusses the underlying molecular mechanisms of chemokines, the reciprocal interactions between chemokines and other factors in PNI, and the interconnectivity of the microenvironment and chemokines. The aim of the review is to thoroughly illustrate the molecular cues of chemokines in cancer with PNI and to identify novel antitumor targets.
Collapse
Affiliation(s)
- Mei Zhang
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhuo-Li Zhu
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiao-Lei Gao
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jia-Shun Wu
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
33
|
Subbotin VM. Privileged portal metastasis of hepatocellular carcinoma in light of the coevolution of a visceral portal system and liver in the chordate lineage: a search for therapeutic targets. Drug Discov Today 2018; 23:548-564. [PMID: 29330122 DOI: 10.1016/j.drudis.2018.01.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/21/2017] [Accepted: 01/04/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) disseminates systemically, but metastases occur in distant organs only in minority of patients, whereas HCC routinely metastasizes to liver and its vessels. HCC cells disseminate via hepatic veins, but portal veins are affected by metastasis more frequently than are hepatic veins, and correlates with poor prognosis. In this review, I suggest that privileged HCC portal metastasis occurs because of high levels of pancreatic family hormones and growth factors (PHGFs) in the portal blood. The analysis suggests that the appearance of the portal system carrying PHGFs in the evolution of invertebrate chordate (Amphioxus) led to the evolution of the liver in vertebrate; given that the portal pattern of HCC metastasis and selection of more-aggressive clones are PHGF dependent, PHGFs and their ligands constitute therapeutic targets.
Collapse
Affiliation(s)
- Vladimir M Subbotin
- Department of Oncology, University of Wisconsin, Madison, WI 53705, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
| |
Collapse
|
|
34
|
Kaemmerer D, Schindler R, Mußbach F, Dahmen U, Altendorf-Hofmann A, Dirsch O, Sänger J, Schulz S, Lupp A. Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets. BMC Cancer 2017; 17:896. [PMID: 29282035 PMCID: PMC5745780 DOI: 10.1186/s12885-017-3911-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 12/13/2017] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. Methods Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. Results In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. Conclusions CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy. Electronic supplementary material The online version of this article (10.1186/s12885-017-3911-3) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany
| | - Robin Schindler
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany
| | - Franziska Mußbach
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | | | - Olaf Dirsch
- Institute of Pathology, Jena University Hospital, Jena, Germany
| | - Jörg Sänger
- Institute of Pathology and Cytology Bad Berka, Bad Berka, Germany
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany.
| |
Collapse
|
|
35
|
Abstract
Central nervous system hemangioblastomas occur sporadically and in patients with von Hippel–Lindau (VHL) disease due to a VHL germline mutation. This mutation leads to enhanced transcription of chemokine receptor 4 (CXCR4), its ligand (CXCL12) and vascular endothelial growth factor A (VEGFA). We aimed to determine in VHL-related and sporadic hemangioblastomas CXCR4, CXCL12, and VEGFA protein expression and to correlate this to hemangioblastoma size and expression in normal surrounding tissue. 27 patients with a hemangioblastoma were included for analysis of immunohistochemistry of tissue, MRI and DNA. Hemangioblastomas overexpress CXCR4, CXCL12, and VEGFA compared to normal surrounding tissue. In sporadic hemangioblastomas the mean percentage of CXCR4 positive hemangioblastoma cells was 16 %, SD 8.4, in VHL-related hemangioblastomas 8 %, SD 4.4 (P = 0.002). There was no relation between preoperative tumor size and CXCR4 or CXCL12 expression. Compared to normal surrounding tissue CXCR4, CXCL12, and VEGFA were overexpressed in hemangioblastomas. Most interestingly, sporadic hemangioblastomas overexpress CXCR4 compared to VHL-related hemangioblastoma.
Collapse
|
|
36
|
Jeng KS, Jeng CJ, Jeng WJ, Chang CF, Sheen IS. Role of C-X-C chemokine ligand 12/C-X-C chemokine receptor 4 in the progression of hepatocellular carcinoma. Oncol Lett 2017; 14:1905-1910. [PMID: 28789425 DOI: 10.3892/ol.2017.6396] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 03/23/2017] [Indexed: 12/14/2022] Open
Abstract
The efficacy of the current non-surgical treatments for advanced hepatocellular carcinoma (HCC) remains limited and novel treatments are required to improve patient outcomes. The majority of HCCs develop from chronically damaged tissue that contains a high degree of inflammation and fibrosis, which promotes tumor progression and resistance to therapy. Understanding the interaction between stromal components and cancer cells (and the signaling pathways involved in this interaction) could aid the identification of novel therapeutic targets. Numerous studies have demonstrated a marked association between high C-X-C chemokine receptor 4 (CXCR4) expression and the invasiveness, progression and metastasis of HCC. The present review will investigate the different roles of CXCR4 in the progression of HCC and discuss possible future treatments. Through the C-X-C chemokine ligand 12 (CXCL12)/CXCR4 signaling pathway, ephrin A1 activation enhances the migration of endothelial progenitor cells to HCC to enable the neovascularization of tumors. There is an association between nuclear CXCR4 expression and the lymph node metastasis of HCC to distant areas. CXCR4 enhances cell migration in vitro and cell homing in vivo. CXCR4 levels are concentrated at the border of a tumor and in perivascular areas, inducing invasive behavior. The binding of CXCL12 to CXCR4 activates intracellular signaling pathways and induces crosstalk with transforming growth factor-β signaling, which enhances the migration of cancer cells. The CXCL12/CXCR4 axis also activates expression of matrix metalloproteinase 10, which further stimulates migration. CXCR4 is likely to crosstalk with the sonic hedgehog signaling pathway, contributing to tumor invasiveness and supporting the cancer stem-cell population; as a result, CXCR4 can be regarded as a cancer stem-cell marker. CXCR4 influences interstitial fluid flow-induced invasion. CXCR4 expression and HCC cell migration are promoted by α-fetoprotein, which activates AKT/mechanistic target of rapamycin signaling. CXCR4 also has the potential to affect sorafenib treatment for HCC. Targeting the CXCL12/CXCR4 signaling pathway may, therefore, be a promising strategy in HCC treatment.
Collapse
Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei 220, Taiwan, R.O.C.,Department of Medical Research, Far Eastern Memorial Hospital, New Taipei 220, Taiwan, R.O.C
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10048, Taiwan, R.O.C
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital Lin Kau Medical Center, Chang Gung University, Taoyuan 33, Taiwan, R.O.C
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei 220, Taiwan, R.O.C.,Department of Medical Research, Far Eastern Memorial Hospital, New Taipei 220, Taiwan, R.O.C
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital Lin Kau Medical Center, Chang Gung University, Taoyuan 33, Taiwan, R.O.C
| |
Collapse
|
|
37
|
Wang X, Zhang W, Ding Y, Guo X, Yuan Y, Li D. CRISPR/Cas9-mediated genome engineering of CXCR4 decreases the malignancy of hepatocellular carcinoma cells in vitro and in vivo. Oncol Rep 2017; 37:3565-3571. [PMID: 28498420 DOI: 10.3892/or.2017.5601] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 04/13/2017] [Indexed: 11/06/2022] Open
Abstract
CXC chemokine receptor 4 (CXCR4) is associated with poor clinical outcomes and decreased survival in hepatocellular carcinoma (HCC). In the present study, we targeted CXCR4 by CRISPR/Cas9 in HepG2 cells and observed the effects both in vitro and in vivo. The results indicated that after targeting CXCR4 the expression of CXCR4 was significantly decreased and the cell proliferation was inhibited. Clonogenicity and scratch cell migration assays indicated that specific downregulation of CXCR4 inhibited cell migration. This disruption of CXCR4 led to less invasiveness, the genes related to epithelial-mesenchymal transition (EMT) and cell self-renewal were also affected. Moreover, sensitivity to the anticancer drug cisplatin was significantly increased in vitro by the downregulation of CXCR4. The results of the in vivo study showed that the growth volumes were significantly smaller in neoplasms derived from CXCR4-downregulated HepG2 cells compared to those derived from wild-type cells. These results showed that targeting CXCR4 by CRISPR/Cas9 could inhibit proliferation, migration and invasion, reversed EMT, increased chemosensitivity and decrease the malignancy of HCC in vitro and in vivo.
Collapse
Affiliation(s)
- Xiaoli Wang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Wenmei Zhang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Yan Ding
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xingrong Guo
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Yahong Yuan
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Dongsheng Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| |
Collapse
|
|
38
|
He B, He Y, Shi W, Gong S, Chen X, Xiao J, Gu J, Ding W, Wang Y. Bioinformatics analysis of gene expression alterations in microRNA‑122 knockout mice with hepatocellular carcinoma. Mol Med Rep 2017; 15:3681-3689. [PMID: 28393247 PMCID: PMC5436154 DOI: 10.3892/mmr.2017.6445] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 02/06/2017] [Indexed: 12/13/2022] Open
Abstract
Reduced microRNA (miR)‑122 expression levels are frequently observed in hepatocellular carcinoma (HCC). The present study was conducted to investigate potential targets of miR‑122 and determine the underlying regulatory mechanisms of miR‑122 in HCC development. The public dataset GSE31731 was utilized, consisting of 8 miR‑122 knockout (KO) mice (miR‑122 KO) and 8 age‑matched wild‑type mice (WT group). Following data preprocessing, the differentially expressed genes (DEGs) were selected, followed by enrichment analysis. A protein‑protein interaction (PPI) network was established, and a module network was further extracted. Combining the DEGs with microRNA targeting databases permitted the screening of the overlapping targets of miR‑122. Furthermore, previously reported genes were screened out by literature mining. Transcription factors (TFs) of the targets were subsequently investigated. DEGs between miR‑122 KO and WT groups were selected, including 713 upregulated and 395 downregulated genes. Of these, upregulated genes were enriched in cell cycle‑associated processes [including nucleolar and spindle associated protein 1 (NUSAP1)], the cytokine‑cytokine receptor interaction pathway [including C‑X‑C motif chemokine receptor 4 (CXCR4) and C‑C motif chemokine receptor 2 (CCR2)], and the extracellular matrix‑receptor interaction pathway [including integrin subunit alpha V (ITGAV)]. In addition, multiple overlapping targets were highlighted in the PPI network, including NUSAP1, CXCR4, CCR2 and ITGAV. Notably, CXCR4 and CCR2 were linked in module C, enriched in the cytokine‑cytokine receptor interaction pathway. Furthermore, upregulated sex determining region Y‑box 4 (SOX4) was identified as a TF. The results of the present study may provide a theoretical basis for further studies on the mechanisms of miR‑122 in the development of HCC.
Collapse
Affiliation(s)
- Bosheng He
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Ying He
- Department of Ultrasound, The Tumor Hospital of Nantong University, Nantong, Jiangsu 226361, P.R. China
| | - Weixiang Shi
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Shenchu Gong
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiaohong Chen
- Department of Ultrasound, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Jing Xiao
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, Jiangsu 226019, P.R. China
| | - Jinhua Gu
- Department of Pathophysiology, Nantong University Medical School, Nantong, Jiangsu 226001, P.R. China
| | - Wenbin Ding
- Department of Radiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yilang Wang
- Department of Oncology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| |
Collapse
|
|
39
|
Proteomic Analysis of Liver Proteins in a Rat Model of Chronic Restraint Stress-Induced Depression. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7508316. [PMID: 28293639 PMCID: PMC5331273 DOI: 10.1155/2017/7508316] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 11/28/2016] [Accepted: 12/22/2016] [Indexed: 01/16/2023]
Abstract
Depression is a global mental disorder disease and greatly threatened human health and stress is considered to be one of the important factors that lead to depression. In this study, we used newly developed iTRAQ labeling and high performance liquid chromatography (HPLC) and mass spectrum united analysis technology obtained the 2176 accurate proteins. Successively, we used the GO analysis and IPA software to analyze the 98 differentially expressed proteins of liver in depression rats due to chronic restraint stress, showing a map of proteomics analysis of liver proteins from the aspects of related functions, disease and function analysis, canonical pathway analysis, and associated network. This study provide important information for comprehensively understanding the mechanisms of dysfunction or injury in the liver in depression.
Collapse
|
|
40
|
Lin GN, Jiang XM, Peng JW, Xiao JJ, Liu DY, Xia ZJ. Prognostic significance of the peripheral blood absolute monocyte count in patients with locally advanced or metastatic hepatocellular carcinoma receiving systemic chemotherapy. Asian Pac J Cancer Prev 2017; 15:6387-90. [PMID: 25124630 DOI: 10.7314/apjcp.2014.15.15.6387] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The prognostic significance of the circulating absolute monocyte count (AMC) in patients with locally advanced hepatocellular carcinoma (HCC) is uncertain. This study was designed to assess the association of circulating AMC with survival outcomes in patients diagnosed with locally advanced or metastatic HCC receiving systemic chemotherapy. MATERIALS AND METHODS Between January 1, 2005 and December 30, 2012, locally advanced or metastatic HCC patients who had Child-Pugh stage A or B disease and received systemic chemotherapy were retrospectively enrolled. Patient features including gender, age, extrahepatic metastasis, Child-Pugh stage, serum alpha-fetoprotein(AFP) level and AMC were collected to investigate their prognostic impact on overall survival(OS). RESULTS A total of 216 patients were eligible for the study. The optimal cut-off value of AMC for OS analysis was 0.38×10⁹/L. Median OS was 5.84 months in low-AMC group (95% confidence interval [CI], 5.23 to 6.45), and 5.21 months in high-AMC group (95% CI, 4.37 to 6.04; p=0.003). In COX multivariate analysis, elevated AMC remained as an independent prognostic factor for worse OS (HR, 1.578; 95% CI, 1.120 to 2.223, p=0.009). CONCLUSIONS Our results indiicate that circulating AMC is confirmed to be an independent prognostic factor for OS in patients with locally advanced or metastatic HCC receiving systemic chemotherapy.
Collapse
Affiliation(s)
- Gui-Nan Lin
- Department of Medical Oncology, Zhongshan Hospital of Sun Yat-sen University, Zhongshan City People's Hospital, Zhongshan, People's Republic of China E-mail :
| | | | | | | | | | | |
Collapse
|
|
41
|
Tanaka T, Goto K, Iino M. Diverse Functions and Signal Transduction of the Exocyst Complex in Tumor Cells. J Cell Physiol 2016; 232:939-957. [DOI: 10.1002/jcp.25619] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 09/23/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Toshiaki Tanaka
- Department of Anatomy and Cell Biology; School of Medicine; Yamagata University; Yamagata Japan
- Department of Dentistry, Oral and Maxillofacial Surgery; Plastic and Reconstructive Surgery; School of Medicine; Yamagata University; Yamagata Japan
| | - Kaoru Goto
- Department of Anatomy and Cell Biology; School of Medicine; Yamagata University; Yamagata Japan
| | - Mitsuyoshi Iino
- Department of Dentistry, Oral and Maxillofacial Surgery; Plastic and Reconstructive Surgery; School of Medicine; Yamagata University; Yamagata Japan
| |
Collapse
|
|
42
|
Toraih EA, Fawzy MS, El-Falouji AI, Hamed EO, Nemr NA, Hussein MH, Abd El Fadeal NM. Stemness-related transcriptional factors and homing gene expression profiles in hepatic differentiation and cancer. Mol Med 2016; 22:653-663. [PMID: 27623812 DOI: 10.2119/molmed.2016.00096] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/26/2016] [Indexed: 12/12/2022] Open
Abstract
Stem cell transcriptional signature activation is an essential event in the development of cancer. This study aimed to investigate the differential expression profile of three pluripotency-associated genes (OCT4, NANOG, and SOX2), G-protein-coupled chemokine receptor 4 (CXCR4) and the ligand (CXCL2), and alpha feto-protein (AFP) in hepatogenic differentiated stem cells and in sera of hepatitis C virus (HCV) and HCV-induced hepatocellular carcinoma (HCC) patients. Mesenchymal stem cells derived from umbilical cord blood were differentiated using hepatogenic differentiation media. Serum specimens were collected from 96 patients (32 cirrhotic HCV, 32 early HCC, and 32 late HCC) and 96 controls. Real-time quantitative reverse transcription polymerase chain reaction was performed for relative quantification of the 6 target genes using LIVAC method. In silico network analysis was also executed to explore the pluripotency and tumorigenic regulatory circuits in liver cancer. The expression levels of all genes declined gradually during the stages of stem cell differentiation. On univariate and multivariate analyses, NANOG, CXCR4 and AFP were significantly up-regulated in HCC patients with late clinical stage. In contrast, SOX2 and CXCL2 were markedly over-expressed in cirrhotic patients and could be used for clear demarcation between cirrhotic and HCC patients in our cases. In conclusion, our data highlight the potential role of SOX2 stem cell marker and CXCL2 chemokine in liver cell degeneration and fibrogenesis in HCV-induced hepatic cirrhosis in our sample of the Egyptian population. In addition, the significant association of NANOG and CXCR4 high-expression with late HCC, could contribute to the acquisition of stem cell-like properties in hepatic cancer and dissemination in late stages, respectively. Taken together, our results could have a potential application in HCC prognosis and treatment.
Collapse
Affiliation(s)
- Eman A Toraih
- Department of Histology and Cell Biology, Genetics Unit, Faculty of Medicine, Suez Canal University, Ismailia, Egypt, P.O. 41522
| | - Manal S Fawzy
- Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt, P.O. 41522
| | | | - Elham O Hamed
- Clinical Pathology Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Nader A Nemr
- Endemic and Infectious diseases Department, Suez Canal University, Ismailia, Egypt
| | | | - Noha M Abd El Fadeal
- Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt, P.O. 41522
| |
Collapse
|
|
43
|
Liepelt A, Tacke F. Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases. Am J Physiol Gastrointest Liver Physiol 2016; 311:G203-9. [PMID: 27313175 DOI: 10.1152/ajpgi.00193.2016] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 06/09/2016] [Indexed: 01/31/2023]
Abstract
The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.
Collapse
Affiliation(s)
- Anke Liepelt
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| |
Collapse
|
|
44
|
Mishan MA, Ahmadiankia N, Bahrami AR. CXCR4 and CCR7: Two eligible targets in targeted cancer therapy. Cell Biol Int 2016; 40:955-67. [PMID: 27248053 DOI: 10.1002/cbin.10631] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 05/26/2016] [Indexed: 12/12/2022]
Abstract
Cancer is one of the most common cause of death in the world with high negative emotional, economic, and social impacts. Conventional therapeutic methods, including chemotherapy and radiotherapy, have not proven satisfactory and relapse is common in most cases. Recent studies have focused on targeted therapy with more precise identification and targeted attacks to the cancer cells. For this purpose, chemokine receptors are proper targets and among them, CXCR4 and CCR7, with a crucial role in cancer metastasis, are being considered as desired candidates for investigation. In this review paper, the most important experimental results are highlighted on the potential targeted therapies based on CXCR4 and CCR7 chemokine receptors.
Collapse
Affiliation(s)
| | - Naghmeh Ahmadiankia
- Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | | |
Collapse
|
|
45
|
Moehler M, Delic M, Goepfert K, Aust D, Grabsch HI, Halama N, Heinrich B, Julie C, Lordick F, Lutz MP, Mauer M, Alsina Maqueda M, Schild H, Schimanski CC, Wagner AD, Roth A, Ducreux M. Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives. Eur J Cancer 2016; 59:160-170. [DOI: 10.1016/j.ejca.2016.02.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 01/13/2016] [Accepted: 02/23/2016] [Indexed: 12/25/2022]
|
|
46
|
Choi WT, Yang Y, Xu Y, An J. Targeting chemokine receptor CXCR4 for treatment of HIV-1 infection, tumor progression, and metastasis. Curr Top Med Chem 2016; 14:1574-89. [PMID: 25159167 DOI: 10.2174/1568026614666140827143541] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/30/2014] [Accepted: 06/06/2014] [Indexed: 12/17/2022]
Abstract
The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and for the development and dissemination of various types of cancers, including gastrointestinal, cutaneous, head and neck, pulmonary, gynecological, genitourinary, neurological, and hematological malignancies. The T-cell (T)-tropic HIV-1 strains use CXCR4 as the entry coreceptor; consequently, multiple CXCR4 antagonistic inhibitors have been developed for the treatment of acquired immune deficiency syndrome (AIDS). However, other potential applications of CXCR4 antagonists have become apparent since its discovery in 1996. In fact, increasing evidence demonstrates that epithelial and hematopoietic tumor cells exploit the interaction between CXCR4 and its natural ligand, stromal cellderived factor (SDF)-1α, which normally regulates leukocyte migration. The CXCR4 and/or SDF-1α expression patterns in tumor cells also determine the sites of metastatic spread. In addition, the activation of CXCR4 by SDF-1α promotes invasion and proliferation of tumor cells, enhances tumor-associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane. As such, the evaluation of CXCR4 and/or SDF-1α expression levels has a significant prognostic value in various types of malignancies. Several therapeutic challenges remain to be overcome before the use of CXCR4 inhibitors can be translated into clinical practice, but promising preclinical data demonstrate that CXCR4 antagonists can mobilize tumor cells from their protective microenvironments, interfere with their metastatic and tumorigenic potentials, and/or make tumor cells more susceptible to chemotherapy.
Collapse
Affiliation(s)
| | | | | | - Jing An
- Department of Pharmacology, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
| |
Collapse
|
|
47
|
Zhu M, Guo J, Li W, Lu Y, Fu S, Xie X, Xia H, Dong X, Chen Y, Quan M, Zheng S, Xie K, Li M. Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells. Oncotarget 2016; 6:12196-208. [PMID: 25682869 PMCID: PMC4494932 DOI: 10.18632/oncotarget.2906] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 12/11/2014] [Indexed: 12/28/2022] Open
Abstract
The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling.
Collapse
Affiliation(s)
- Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Junli Guo
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wei Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Yan Lu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Shigan Fu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Xieju Xie
- Department of Physiology and Pathophysiology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Hua Xia
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Xu Dong
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Yi Chen
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| | - Ming Quan
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shaojiang Zheng
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Tumor Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan 570102, P. R. China
| | - Keping Xie
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, P. R. China.,Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, P. R. China
| |
Collapse
|
|
48
|
Chen J, Xu-Monette ZY, Deng L, Shen Q, Manyam GC, Martinez-Lopez A, Zhang L, Montes-Moreno S, Visco C, Tzankov A, Yin L, Dybkaer K, Chiu A, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Choi WWL, van Krieken JH, Huh J, Ponzoni M, Ferreri AJM, Zhao X, Møller MB, Farnen JP, Winter JN, Piris MA, Pham L, Young KH. Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma. Oncotarget 2016; 6:5597-614. [PMID: 25704881 PMCID: PMC4467389 DOI: 10.18632/oncotarget.3343] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 01/04/2015] [Indexed: 12/13/2022] Open
Abstract
Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4+ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4+ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of ≤2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4+ and BCL2 translocation showed dismal outcomes resembling but independent of MYC/BCL2 double-hit DLBCL. Gene expression profiling suggested that alterations in the tumor microenvironment and immune responses, increased tumor proliferation and survival, and the dissemination of CXCR4+ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4+ associated poor prognosis.
Collapse
Affiliation(s)
- Jiayu Chen
- Medical School of Taizhou University, Taizhou, Zhejiang, China.,Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zijun Y Xu-Monette
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lijuan Deng
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qi Shen
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ganiraju C Manyam
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Li Zhang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | - Lihui Yin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - April Chiu
- Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Attilio Orazi
- Weill Medical College of Cornell University, New York, NY, USA
| | - Youli Zu
- The Methodist Hospital, Houston, TX, USA
| | - Govind Bhagat
- Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA
| | - Kristy L Richards
- University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - William W L Choi
- University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China
| | | | - Jooryung Huh
- Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea
| | | | | | - Xiaoying Zhao
- Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China
| | | | - John P Farnen
- Gundersen Lutheran Health System, La Crosse, WI, USA
| | - Jane N Winter
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Miguel A Piris
- Hospital Universitario Marques de Valdecilla, Santander, Spain
| | - Lan Pham
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ken H Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX, USA
| |
Collapse
|
|
49
|
Shah AD, Bouchard MJ, Shieh AC. Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling. PLoS One 2015; 10:e0142337. [PMID: 26560447 PMCID: PMC4641731 DOI: 10.1371/journal.pone.0142337] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/20/2015] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients.
Collapse
Affiliation(s)
- Arpit D. Shah
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, United States of America
| | - Michael J. Bouchard
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Adrian C. Shieh
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, United States of America
| |
Collapse
|
|
50
|
Rubie C, Kauffels A, Kölsch K, Glanemann M, Justinger C. CXCL12/CXCR4 display an inverse mRNA expression profile in gastric carcinoma that correlates with tumor progression. Oncol Lett 2015; 11:360-364. [PMID: 26870218 DOI: 10.3892/ol.2015.3850] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 07/16/2015] [Indexed: 02/07/2023] Open
Abstract
Chemokines and their receptors have been shown to contribute to tumor growth and metastatic spread in various gastrointestinal cancer entities. In the present study, the mRNA expression profiles and clinical significance of chemokine ligand CXCL12 and its corresponding receptor CXCR4 were investigated in patients with gastric cancer (GC). Using quantitative polymerase chain reaction, the expression profile of CXCL12/CXCR4 was analyzed in resection specimens from the patients with GC (n=66) and in corresponding normal gastric tissues. Upon investigating CXCL12/CXCR4 mRNA expression levels in the GC tissues, significant downregulation of CXCL12 expression was demonstrated (P<0.05), whereas CXCR4 mRNA expression was shown to be significantly upregulated (P<0.05). Likewise, in gastric carcinoma patients undergoing neoadjuvant chemotherapy, CXCR4 expression was found to be significantly upregulated (P<0.05), whereas in GC patients with lymph and vein infiltration, CXCL12 mRNA expression was significantly downregulated (P<0.05). These results demonstrate a significant inverse association between the development and progress of GC and CXCL12/CXCR4 mRNA expression. CXCR4 mRNA upregulation was promoted under the effect of neoadjuvant chemotherapy prior to surgery in GC patients, whereas higher tumor stages with lymph and vein infiltration negatively affected CXCL12 mRNA expression.
Collapse
Affiliation(s)
- Claudia Rubie
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Anne Kauffels
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Kathrin Kölsch
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Mathias Glanemann
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| | - Christoph Justinger
- Department of General, Visceral, Vascular and Pediatric Surgery, University of The Saarland, Homburg/Saar D-66421, Germany
| |
Collapse
|