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Aoki Y, Wang L, Tsuda M, Saito Y, Kubota T, Oda Y, Hirano S, Gong JP, Tanaka S. Hydrogel PCDME creates pancreatic cancer stem cells in OXPHOS metabolic state with TXNIP elevation. Biochem Biophys Res Commun 2025; 751:151416. [PMID: 39914146 DOI: 10.1016/j.bbrc.2025.151416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/17/2025]
Abstract
Pancreatic cancer is known as one of the poor prognostic cancers, and the most of patients are unable to undergo radical resection due to local progression or distant metastasis at initial diagnosis. In spite of the advancements in surgery and chemotherapy, there are many cases of recurrence after surgery or chemoradiotherapy mainly due to the presence of cancer stem cells (CSCs). CSCs are potential therapeutic target, but current issue is that an identification of CSCs is difficult since they are only present in a small number of tumor cells. Here we demonstrate that hydrogel PCDME can rapidly induce pancreatic cancer cell spheroids with elevated levels of stem cell markers including Sox2, Oct3/4, and Nanog, and the growth rate was reduced. CSCs showed activation of YAP/TAZ signaling, and microarray analysis showed markedly elevated expression of thioredoxin-interacting protein (TXNIP). Primary pancreatic cancer cells also increased TXNIP in addition to stemness markers on gel. In metabolic analysis, CSCs showed a shift of energy production from glycolysis to oxidative phosphorylation (OXPHOS). Furthermore, knockdown of TXNIP on PCDME gel using shRNAs decreased growth speed and in vivo tumorigenicity, suggesting that TXNIP may be involved in CSCs induction.
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Affiliation(s)
- Yuma Aoki
- Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Lei Wang
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; World Premier International Research Center Initiative, Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan
| | - Masumi Tsuda
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; World Premier International Research Center Initiative, Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan
| | - Yusuke Saito
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan
| | - Takenori Kubota
- Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yoshitaka Oda
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Jian Ping Gong
- World Premier International Research Center Initiative, Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; World Premier International Research Center Initiative, Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan; Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Bu Y, Liang J, Li Z, Wang J, Wang J, Yu G. Cancer molecular subtyping using limited multi-omics data with missingness. PLoS Comput Biol 2024; 20:e1012710. [PMID: 39724112 PMCID: PMC11709273 DOI: 10.1371/journal.pcbi.1012710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 01/08/2025] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Diagnosing cancer subtypes is a prerequisite for precise treatment. Existing multi-omics data fusion-based diagnostic solutions build on the requisite of sufficient samples with complete multi-omics data, which is challenging to obtain in clinical applications. To address the bottleneck of collecting sufficient samples with complete data in clinical applications, we proposed a flexible integrative model (CancerSD) to diagnose cancer subtype using limited samples with incomplete multi-omics data. CancerSD designs contrastive learning tasks and masking-and-reconstruction tasks to reliably impute missing omics, and fuses available omics data with the imputed ones to accurately diagnose cancer subtypes. To address the issue of limited clinical samples, it introduces a category-level contrastive loss to extend the meta-learning framework, effectively transferring knowledge from external datasets to pretrain the diagnostic model. Experiments on benchmark datasets show that CancerSD not only gives accurate diagnosis, but also maintains a high authenticity and good interpretability. In addition, CancerSD identifies important molecular characteristics associated with cancer subtypes, and it defines the Integrated CancerSD Score that can serve as an independent predictive factor for patient prognosis.
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Affiliation(s)
- Yongqi Bu
- School of Software, Shandong University, Jinan, Shandong, China
- Joint SDU-NTU Centre for Artificial Intelligence Research, Shandong University, Jinan, Shandong, China
| | - Jiaxuan Liang
- School of Software, Shandong University, Jinan, Shandong, China
- Joint SDU-NTU Centre for Artificial Intelligence Research, Shandong University, Jinan, Shandong, China
| | - Zhen Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jianbo Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jun Wang
- Joint SDU-NTU Centre for Artificial Intelligence Research, Shandong University, Jinan, Shandong, China
| | - Guoxian Yu
- School of Software, Shandong University, Jinan, Shandong, China
- Joint SDU-NTU Centre for Artificial Intelligence Research, Shandong University, Jinan, Shandong, China
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Jasim SA, Salahdin OD, Malathi H, Sharma N, Rab SO, Aminov Z, Pramanik A, Mohammed IH, Jawad MA, Gabel BC. Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA). Cell Biochem Biophys 2024; 82:3031-3051. [PMID: 39060914 DOI: 10.1007/s12013-024-01423-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Tumor recurrence after curative therapy and hepatocellular carcinoma (HCC) cells' resistance to conventional therapies is the reasons for the worse clinical results of HCC patients. A tiny population of cancer cells with a strong potential for self-renewal, differentiation, and tumorigenesis has been identified as cancer stem cells (CSCs). The discovery of CSC surface markers and the separation of CSC subpopulations from HCC cells have been made possible by recent developments in the study of hepatic (liver) CSCs. Hepatic CSC surface markers include epithelial cell adhesion molecules (EpCAM), CD133, CD90, CD13, CD44, OV-6, ALDH, and K19. CSCs have a significant influence on the development of cancer, invasiveness, self-renewal, metastasis, and drug resistance in HCC, and thus provide a therapeutic chance to treat HCC and avoid its recurrence. Therefore, it is essential to develop treatment approaches that specifically and effectively target hepatic stem cells. Given this, one potential treatment approach is to use particular small interfering RNA (siRNA) to target CSC, disrupting their behavior and microenvironment as well as changing their epigenetic state. The characteristics of CSCs in HCC are outlined in this study, along with new treatment approaches based on siRNA that may be used to target hepatic CSCs and overcome HCC resistance to traditional therapies.
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Affiliation(s)
| | | | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University, Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh group of Colleges, Jhanjeri, 140307, Mohali, Punjab, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Israa Hussein Mohammed
- College of nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Benien C Gabel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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Iweala EEJ, Amuji DN, Oluwajembola AM, Ugbogu EA. Targeting c-Met in breast cancer: From mechanisms of chemoresistance to novel therapeutic strategies. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 7:100204. [PMID: 39524211 PMCID: PMC11543557 DOI: 10.1016/j.crphar.2024.100204] [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: 05/07/2024] [Revised: 09/28/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Breast cancer presents a significant challenge due to its heterogeneity and propensity for developing chemoresistance, particularly in the triple-negative subtype. c-Mesenchymal epithelial transition factor (c-Met), a receptor tyrosine kinase, presents a promising target for breast cancer therapy due to its involvement in disease progression and poor prognosis. However, the heterogeneous expression of c-Met within breast cancer subtypes and individual tumors complicates targeted therapy. Also, cancer cells can develop resistance to c-Met inhibitors through various mechanisms, including bypass signaling pathways and genetic mutations. The off-target effects of c-Met inhibitors further limit their clinical utility, necessitating the development of more selective agents. To overcome these challenges, personalized treatment approaches and combination therapies are being explored to improve treatment efficacy while minimizing adverse effects. Novel c-Met inhibitors with improved selectivity and reduced off-target toxicity show promise in preclinical studies. Additionally, targeted delivery systems aim to enhance drug localization and reduce systemic toxicity. Future directions involve refining inhibitor design and integrating c-Met inhibition into personalized treatment regimens guided by molecular profiling. This review explores the mechanisms by which c-Met contributes to chemoresistance in breast cancer and current challenges in targeting c-Met for breast cancer therapy. It discusses strategies to optimize treatment outcomes, ultimately improving patient prognosis and reducing mortality rates associated with this devastating disease.
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Affiliation(s)
- Emeka Eze Joshua Iweala
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
- Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Nigeria
| | - Doris Nnenna Amuji
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
- Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Nigeria
| | - Abimbola Mary Oluwajembola
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
- Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Nigeria
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Tayanloo-Beik A, Eslami A, Sarvari M, Jalaeikhoo H, Rajaeinejad M, Nikandish M, Faridfar A, Rezaei-Tavirani M, Mafi AR, Larijani B, Arjmand B. Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression. Oncol Rev 2024; 18:1411736. [PMID: 39091989 PMCID: PMC11291337 DOI: 10.3389/or.2024.1411736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/27/2024] [Indexed: 08/04/2024] Open
Abstract
The global incidence of cancer is increasing, with estimates suggesting that there will be 26 million new cases and 17 million deaths per year by 2030. Cancer stem cells (CSCs) and extracellular vesicles (EVs) are key to the resistance and advancement of cancer. They play a crucial role in tumor dynamics and resistance to therapy. CSCs, initially discovered in acute myeloid leukemia, are well-known for their involvement in tumor initiation, progression, and relapse, mostly because of their distinct characteristics, such as resistance to drugs and the ability to self-renew. EVs, which include exosomes, microvesicles, and apoptotic bodies, play a vital role in facilitating communication between cells within the tumor microenvironment (TME). They have a significant impact on cellular behaviors and contribute to genetic and epigenetic changes. This paper analyzes the mutually beneficial association between CSCs and EVs, emphasizing their role in promoting tumor spread and developing resistance mechanisms. This review aims to investigate the interaction between these entities in order to discover new approaches for attacking the complex machinery of cancer cells. It highlights the significance of CSCs and EVs as crucial targets in the advancement of novel cancer treatments, which helps stimulate additional research, promote progress in ideas for cancer treatment, and provide renewed optimism in the effort to reduce the burden of cancer.
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Affiliation(s)
- Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azin Eslami
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hasan Jalaeikhoo
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Mohsen Rajaeinejad
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
- Student Research Committee, Aja University of medical sciences, Tehran, Iran
| | - Mohsen Nikandish
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Ali Faridfar
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | | | - Ahmad Rezazadeh Mafi
- Department of Radiation Oncology, Imam Hossein Hospital, Shaheed Beheshti Medical University, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Chen Z, Miao P, Lin H, Lu Y. AHNAK2 Promotes the Progression of Pancreatic Ductal Adenocarcinoma by Maintaining the Stability of c-MET. Cancer Manag Res 2024; 16:431-444. [PMID: 38751848 PMCID: PMC11095252 DOI: 10.2147/cmar.s451486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 04/24/2024] [Indexed: 05/18/2024] Open
Abstract
Purpose Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and rapidly progresses. The overall response rate of PDAC to current treatment methods is still unsatisfactory. Thus, identifying novel targets and clarifying the underlying mechanisms associated with PDAC progression may potentially offer additional treatment strategies. AHNAK2 is aberrantly expressed in a variety of tumors and exerts pro-tumorigenic effects. However, the biological role of AHNAK2 in PDAC remains poorly understood. Methods The expression of AHNAK2 in PDAC and paired non-tumor tissues was detected by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). Lentivirus knockdown was performed to investigate the impact of AHNAK2 on the biological function of pancreatic cancer cells. The subcutaneous cell-derived xenograft (CDX) model and the KPC spontaneous mouse model with AHNAK2 silencing were used to observe the effects of AHNAK2 on tumor growth and prognosis. The expression of c-MET at protein level in response to HGF treatment was assessed using western blot. Results Our results demonstrated that AHNAK2 was highly expressed in PDAC clinical samples and associated with poor prognosis. Knockdown of AHNAK2 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells. AHNAK2 knockdown or knockout resulted in tumor growth suppression and prolonged survival in mice with PDAC. In addition, AHNAK2 and c-MET expression levels showed a significant positive correlation at the post-transcriptional level. Mechanistically, AHNAK2 promoted tumor progression by preventing c-MET degradation and persistently activating the HGF/c-MET signaling pathway. Conclusion Overall, our study revealed that AHNAK2 plays an important role in PDAC progression by modulating the c-MET signaling pathway, and targeting AHNAK2 may be an effective therapeutic strategy for PDAC.
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Affiliation(s)
- Zhaohui Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
- Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, Guangdong, People’s Republic of China
| | - Pengbiao Miao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
- Department of Pancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Hongcao Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
- Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, Guangdong, People’s Republic of China
| | - Yanan Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
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Kwon JE, Jang Y, Yun BS, Kang S, Kim YH, Kim BG, Cho NH. MET overexpression in ovarian cancer via CD24-induced downregulation of miR-181a: A signalling for cellular quiescence-like state and chemoresistance in ovarian CSCs. Cell Prolif 2024; 57:e13582. [PMID: 38030594 PMCID: PMC11056702 DOI: 10.1111/cpr.13582] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023] Open
Abstract
Increased expression of CD24 and MET, markers for cancer stem-like cells (CSCs), are each associated with ovarian cancer severity. However, whether CD24 and MET are co-expressed in ovarian CSCs and, if so, how they are related to CSC phenotype manifestation remains unknown. Our immunohistochemistry analysis showed that the co-expression of CD24 and MET was associated with poorer patient survival in ovarian cancer than those without. In addition, analyses using KM plotter and ROC plotter presented that the overexpression of CD24 or MET in ovarian cancer patients was associated with resistance to platinum-based chemotherapy. In our miRNA transcriptome and putative target genes analyses, miR-181a was downregulated in CD24-high ovarian cancer cells compared to CD24-low and predicted to bind to CD24 and MET 3'UTRs. In OV90 and SK-OV-3 cells, CD24 downregulated miR-181a expression by Src-mediated YY1 activation, leading to increased expression of MET. And, CD24 or MET knockdown or miR-181a overexpression inhibited the manifestation of CSC phenotypes, cellular quiescence-like state and chemoresistance, in OV90 and SK-OV-3 cells: increased colony formation, decreased G0/G1 phase cell population and increased sensitivity to Cisplatin and Carboplatin. Our findings suggest that CD24-miR-181a-MET may consist of a signalling route for ovarian CSCs, therefore being a combinatory set of markers and therapeutic targets for ovarian CSCs.
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Affiliation(s)
- Ji Eun Kwon
- Department of PathologyAjou University School of MedicineSuwonKorea
- Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulKorea
| | - Yeonsue Jang
- Department of PathologyYonsei University College of MedicineSeoulKorea
| | - Bo Seong Yun
- Department of Gynecology Obstetrics and Gynecology, CHA Gangnam Medical CenterCHA UniversitySeoulKorea
| | - Suki Kang
- Department of PathologyYonsei University College of MedicineSeoulKorea
| | - Yon Hee Kim
- Department of PathologySoonchunhyang University HospitalSeoulKorea
| | - Baek Gil Kim
- Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulKorea
- Department of PathologyYonsei University College of MedicineSeoulKorea
| | - Nam Hoon Cho
- Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulKorea
- Department of PathologyYonsei University College of MedicineSeoulKorea
- Severance Biomedical Science Institute (SBSI)Yonsei University College of MedicineSeoulKorea
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9
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Saleh O, Shihadeh H, Yousef A, Erekat H, Abdallh F, Al-Leimon A, Elsalhy R, Altiti A, Dajani M, AlBarakat MM. The Effect of Intratumor Heterogeneity in Pancreatic Ductal Adenocarcinoma Progression and Treatment. Pancreas 2024; 53:e450-e465. [PMID: 38728212 DOI: 10.1097/mpa.0000000000002342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis. MATERIALS AND METHODS The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered. RESULTS The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations. CONCLUSION Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.
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Affiliation(s)
- Othman Saleh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | - Hana Erekat
- School of medicine, University of Jordan, Amman
| | - Fatima Abdallh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | | | - Majd Dajani
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | - Majd M AlBarakat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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Pujari R, Dubey SK. Relevance of glyco-biomakers and glycan profiles in cancer stem cells. Glycobiology 2024; 34:cwad019. [PMID: 36864577 DOI: 10.1093/glycob/cwad019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023] Open
Abstract
Altered and aberrant glycosylation signatures have been linked to being a hallmark in a variety of human disorders including cancer. Cancer stem cells (CSCs), capable of self-renewal and differentiation, have recently been credited with a unique notion of disease genesis and implicated as the cause for initiation and recurrence of the disease in a new regime of neoplastic transformations hypothesis. Many biomarkers relating to diagnostic and prognostic intents have been discovered using the ubiquitous and abundant surface glycan patterns on CSCs. Various technological advancements have been developed to identify and determine concerns with glycosylation structure. However, the nature and purpose of the glycan moiety on these glycosylation pattern have not yet been thoroughly investigated. This review, thus, summarizes the process of glycosylation in CSCs, variations in glycosylation patterns in various stem cells, aberrant glycosylation patterns in cancer, the role of glycosylation in tumor cell adhesion, cell-matrix interactions, and signaling, as well as cancer detection and treatment. The function of carbohydrates as prospective serum biomarkers, some clinically authorized biomarkers, and potential novel biomarkers relating to cancer disease diagnosis and prognosis are also discussed in the review.
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Affiliation(s)
- Rohit Pujari
- Department of Biochemistry, C.B.S.H., G. B. Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India
| | - Shiv Kumar Dubey
- Department of Biochemistry, C.B.S.H., G. B. Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India
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Xu H, Wu D, Xiao M, Lei Y, Lei Y, Yu X, Shi S. PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells. SCIENCE ADVANCES 2024; 10:eadk6633. [PMID: 38277454 PMCID: PMC10816699 DOI: 10.1126/sciadv.adk6633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/26/2023] [Indexed: 01/28/2024]
Abstract
Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.
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Affiliation(s)
- He Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Di Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Mingming Xiao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Yubin Lei
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang Province 310024, China
| | - Yalan Lei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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12
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Sharma R, Malviya R. Cancer Stem Cells in Carcinogenesis and Potential Role in Pancreatic Cancer. Curr Stem Cell Res Ther 2024; 19:1185-1194. [PMID: 37711007 DOI: 10.2174/1574888x19666230914103420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/14/2023] [Accepted: 08/11/2023] [Indexed: 09/16/2023]
Abstract
A poor prognosis is associated with pancreatic cancer because of resistance during treatment and early distant metastases. The discovery of cancer stem cells has opened up novel avenues for research into the biology and treatment of cancer. Many investigations have pointed out the role of these types of stem cells in the oncogenesis and progression of hematologic and solid malignancies, specifically. Due to the existence of cancer stem cells in the proliferation and preservation of pancreatic tumors, such malignancies could be difficult to eradicate using conventional treatment techniques like chemotherapy and radiotherapy. It is hypothesized that pancreatic malignancies originate from a limited population of aberrant cancer stem cells to promote carcinogenesis, tumour metastasis, and therapeutic resistance. This review examines the role of pancreatic cancer stem cells in this disease and their significance in carcinogenesis, as well as the signals which modulate them, and also examines the ongoing clinical studies that are now being conducted with pancreatic stem cells.
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Affiliation(s)
- Rishav Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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13
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Wang WD, Guo YY, Yang ZL, Su GL, Sun ZJ. Sniping Cancer Stem Cells with Nanomaterials. ACS NANO 2023; 17:23262-23298. [PMID: 38010076 DOI: 10.1021/acsnano.3c07828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.
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Affiliation(s)
- Wen-Da Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Yan-Yu Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhong-Lu Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Guang-Liang Su
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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14
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Zhang N, Li Y. Receptor tyrosine kinases: biological functions and anticancer targeted therapy. MedComm (Beijing) 2023; 4:e446. [PMID: 38077251 PMCID: PMC10701465 DOI: 10.1002/mco2.446] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 10/16/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self-renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs-targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.
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Affiliation(s)
- Nan Zhang
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
- Department of Medical OncologyChongqing University Cancer HospitalChongqingChina
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15
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Tan L, Duan X, Mutyala P, Zhou T, Amin S, Zhang T, Herbst B, Askan G, Itkin T, Xiang Z, Michelassi F, Lieberman MD, Iacobuzio-Donahue CA, Leach SD, Evans T, Chen S. A targetable pathway to eliminate TRA-1-60+/TRA-1-81+ chemoresistant cancer cells. J Mol Cell Biol 2023; 15:mjad039. [PMID: 37327088 PMCID: PMC10847630 DOI: 10.1093/jmcb/mjad039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 12/18/2022] [Accepted: 06/14/2023] [Indexed: 06/18/2023] Open
Abstract
Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81, two 'stemness' cell surface markers, are highly enriched in CCCs. Furthermore, TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60-/TRA-1-81- cells. Transcriptome profiling identified UGT1A10, shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance. From a high-content chemical screen, we identified Cymarin, which downregulates UGT1A10, eliminates TRA-1-60/TRA-1-81 expression, and increases chemosensitivity both in vitro and in vivo. Finally, TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival, which highlights their potentiality for targeted therapy. Therefore, we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance, as well as a leading drug candidate to target this pathway.
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Affiliation(s)
- Lei Tan
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
- Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Xiaohua Duan
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA
| | - Pratyusha Mutyala
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ting Zhou
- The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Sadaf Amin
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Tuo Zhang
- Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA
| | - Brian Herbst
- Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Gokce Askan
- Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Tomer Itkin
- Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Zhaoying Xiang
- Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA
| | | | | | | | - Steven D Leach
- Dartmouth Cancer Center, Darmouth College, Hanover, NH 03755, USA
| | - Todd Evans
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
- Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA
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16
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Wang D, Zhang Y, Liao Z, Ge H, Güngör C, Li Y. KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas. Sci Rep 2023; 13:18250. [PMID: 37880235 PMCID: PMC10600175 DOI: 10.1038/s41598-023-44536-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 10/10/2023] [Indexed: 10/27/2023] Open
Abstract
A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients.
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Affiliation(s)
- Dan Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yingjun Zhang
- Hunan Engineering and Technology Research Center for Agricultural Big Data Analysis and Decision-Making, Hunan Agricultural University, Changsha, China
| | - Zhouning Liao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Division of Translational Immunology, III, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Heming Ge
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cenap Güngör
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yuqiang Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
- NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, China.
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17
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Zhang B, Chen X, Wang Z, Guo F, Zhang X, Huang B, Ma S, Xia S, Shang D. Identifying endoplasmic reticulum stress-related molecular subtypes and prognostic model for predicting the immune landscape and therapy response in pancreatic cancer. Aging (Albany NY) 2023; 15:10549-10579. [PMID: 37815881 PMCID: PMC10599750 DOI: 10.18632/aging.205094] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 09/09/2023] [Indexed: 10/12/2023]
Abstract
Endoplasmic reticulum stress (ERS) is caused by the accumulation of intracellular misfolded or unfolded proteins and is associated with cancer development. In this study, pan-cancer analysis revealed complex genetic variations, including copy number variation, methylation, and somatic mutations for ERS-related genes (ERGs) in 33 kinds of cancer. Consensus clustering divided pancreatic cancer (PC) patients from TCGA and GEO databases into two ERS-related subtypes: ERGcluster A and B. Compared with ERGcluster A, ERGcluster B had a more active ERS state and worse prognosis. Subsequently, the ERS-related prognostic model was established to quantify the ERS score for a single sample. The patient with a low ERS score had remarkably longer survival times. ssGSEA and CIBERSORT algorithms revealed that activated B cells and CD8+ T cells had higher infiltration in the low ERS score group, but higher infiltration of activated CD4+ T cells, activated dendritic cells, macrophages, and neutrophils in the high ERS score group. Drug sensitivity analysis indicated the low ERS score group had a better response to gemcitabine, paclitaxel, 5-fluorouracil, oxaliplatin, and irinotecan. RT-qPCR validated that MET, MUC16, and KRT7 in the model had higher expression levels in pancreatic tumour tissues. Single-cell analysis further revealed that MET, MUC16, and KRT7 were mainly expressed in cancer cells in PC tumour microenvironment. In all, we first constructed the ERS-related molecular subtypes and prognostic model in PC. Our research highlighted the vital role of ERS in PC and contributed to further research on molecular mechanisms and novel therapeutic strategies for PC in the future.
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Affiliation(s)
- Biao Zhang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xu Chen
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhizhou Wang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fangyue Guo
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Xiaonan Zhang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Bingqian Huang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Shurong Ma
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Shilin Xia
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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18
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Noraldeen SAM, Rasulova I, Lalitha R, Hussin F, Alsaab HO, Alawadi AH, Alsaalamy A, Sayyid NH, Alkhafaji AT, Mustafa YF, Shayan SK. Involving stemness factors to improve CAR T-cell-based cancer immunotherapy. Med Oncol 2023; 40:313. [PMID: 37779152 DOI: 10.1007/s12032-023-02191-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/09/2023] [Indexed: 10/03/2023]
Abstract
Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.
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Affiliation(s)
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, 54 Mustaqillik Ave., 100007, Tashkent, Uzbekistan
| | - Repudi Lalitha
- Department of Pharmaceutical Analysis, Chaitanya Deemed to be University, Hyderabad, Telangana, India.
| | - Farah Hussin
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, 21944, Taif, Saudi Arabia
| | - Ahmed Hussien Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
| | - Nidhal Hassan Sayyid
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sepideh Karkon Shayan
- Student Research Committee, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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19
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Tomizawa S, Takano S, Eto R, Takayashiki T, Kuboki S, Ohtsuka M. Semaphorin 3 C enhances putative cancer stemness and accelerates peritoneal dissemination in pancreatic cancer. Cancer Cell Int 2023; 23:155. [PMID: 37537633 PMCID: PMC10401755 DOI: 10.1186/s12935-023-03008-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/27/2023] [Indexed: 08/05/2023] Open
Abstract
PURPOSE Semaphorins, axon guidance cues in neuronal network formation, have been implicated in cancer progression. We previously identified semaphorin 3 C (SEMA3C) as a secreted protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). We, therefore, hypothesized that SEMA3C supports PDAC progression. In this study, we aimed to investigate the clinical features of SEMA3C, especially its association with chemo-resistance and peritoneal dissemination. METHODS In resected PDAC tissues, we assessed the relationship between SEMA3C expression and clinicopathological features by immunohistochemistry. In vitro studies, we have shown invasion assay, pancreatosphere formation assay, colony formation assay, cytotoxicity assay, and activation of SEMA3C downstream targets (c-Met, Akt, mTOR). In vivo, we performed a preclinical trial to confirm the efficacy of SEMA3C shRNA knockdown and Gemcitabine and nab-Paclitaxel (GnP) in an orthotopic transplantation mouse model and in peritoneal dissemination mouse model. RESULTS In resected PDAC tissues, SEMA3C expression correlated with invasion and peritoneal dissemination after surgery. SEMA3C promoted cell invasion, self-renewal, and colony formation in vitro. We further demonstrated that SEMA3C knockdown increased Gem-induced cytotoxicity by suppressing the activation of the Akt/mTOR pathway via the c-Met receptor. Combination therapy with SEMA3C knockdown and GnP reduced tumor growth and peritoneal dissemination. CONCLUSIONS SEMA3C enhances peritoneal dissemination by regulating putative cancer stemness and Gem resistance and activates phosphorylation of the Akt/mTOR pathway via c-Met. Our findings provide a new avenue for therapeutic strategies in regulating peritoneal dissemination during PDAC progression.
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Affiliation(s)
- Satoshi Tomizawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan.
| | - Ryotaro Eto
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677, Japan
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20
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Tsuji Y, Hara T, Meng S, Sato H, Arao Y, Ofusa K, Ishii H. Role of RNA methylation in the regulation of pancreatic cancer stem cells (Review). Oncol Lett 2023; 26:336. [PMID: 37427348 PMCID: PMC10326658 DOI: 10.3892/ol.2023.13922] [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: 02/02/2023] [Accepted: 04/21/2023] [Indexed: 07/11/2023] Open
Abstract
Pancreatic cancer stem cells (CSCs) play a key role in the initiation and progression of pancreatic adenocarcinoma (PDAC). CSCs are responsible for resistance to chemotherapy and radiation, and for cancer metastasis. Recent studies have indicated that RNA methylation, a type of RNA modification, predominantly occurring as m6A methylation, plays an important role in controlling the stemness of cancer cells, therapeutic resistance against chemotherapy and radiation therapy, and their overall relevance to a patient's prognosis. CSCs regulate various behaviors of cancer through cell-cell communication by secreting factors, through their receptors, and through signal transduction. Recent studies have shown that RNA methylation is involved in the biology of the heterogeneity of PDAC. The present review provides an update on the current understanding of RNA modification-based therapeutic targets against deleterious PDAC. Several key pathways and agents that can specifically target CSCs have been identified, thus providing novel insights into the early diagnosis and efficient treatment of PDAC.
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Affiliation(s)
- Yoshiko Tsuji
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Tomoaki Hara
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Sikun Meng
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiromichi Sato
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yasuko Arao
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Ken Ofusa
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
- Prophoenix Division, Food and Life-Science Laboratory, IDEA Consultants, Inc., Osaka, Osaka 559-8519, Japan
| | - Hideshi Ishii
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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21
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Ponomarev AS, Gilazieva ZE, Solovyova VV, Rizvanov AA. Molecular Mechanisms of Tumor Cell Stemness Modulation during Formation of Spheroids. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:979-994. [PMID: 37751868 DOI: 10.1134/s0006297923070106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 09/28/2023]
Abstract
Cancer stem cells (CSCs), their properties and interaction with microenvironment are of interest in modern medicine and biology. There are many studies on the emergence of CSCs and their involvement in tumor pathogenesis. The most important property inherent to CSCs is their stemness. Stemness combines ability of the cell to maintain its pluripotency, give rise to differentiated cells, and interact with environment to maintain a balance between dormancy, proliferation, and regeneration. While adult stem cells exhibit these properties by participating in tissue homeostasis, CSCs behave as their malignant equivalents. High tumor resistance to therapy, ability to differentiate, activate angiogenesis and metastasis arise precisely due to the stemness of CSCs. These cells can be used as a target for therapy of different types of cancer. Laboratory models are needed to study cancer biology and find new therapeutic strategies. A promising direction is three-dimensional tumor models or spheroids. Such models exhibit properties resembling stemness in a natural tumor. By modifying spheroids, it becomes possible to investigate the effect of therapy on CSCs, thus contributing to the development of anti-tumor drug test systems. The review examines the niche of CSCs, the possibility of their study using three-dimensional spheroids, and existing markers for assessing stemness of CSCs.
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Affiliation(s)
- Aleksei S Ponomarev
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Zarema E Gilazieva
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Valeriya V Solovyova
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Albert A Rizvanov
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia.
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22
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Galindo-Vega A, Maldonado-Lagunas V, Mitre-Aguilar IB, Melendez-Zajgla J. Tumor Microenvironment Role in Pancreatic Cancer Stem Cells. Cells 2023; 12:1560. [PMID: 37371030 DOI: 10.3390/cells12121560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/18/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a majority of patients presenting with unresectable or metastatic disease, resulting in a poor 5-year survival rate. This, in turn, is due to a highly complex tumor microenvironment and the presence of cancer stem cells, both of which induce therapy resistance and tumor relapse. Therefore, understanding and targeting the tumor microenvironment and cancer stem cells may be key strategies for designing effective PDAC therapies. In the present review, we summarized recent advances in the role of tumor microenvironment in pancreatic neoplastic progression.
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Affiliation(s)
- Aaron Galindo-Vega
- Functional Genomics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 04710, Mexico
| | | | - Irma B Mitre-Aguilar
- Biochemistry Unit, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City 14080, Mexico
| | - Jorge Melendez-Zajgla
- Functional Genomics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 04710, Mexico
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23
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Das B, Dash SR, Patel H, Sinha S, Bhal S, Paul S, Das C, Pradhan R, Ahmed I, Goutam K, Kundu CN. Quinacrine inhibits HIF-1α/VEGF-A mediated angiogenesis by disrupting the interaction between cMET and ABCG2 in patient-derived breast cancer stem cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 117:154914. [PMID: 37321076 DOI: 10.1016/j.phymed.2023.154914] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/15/2023] [Accepted: 06/02/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Breast cancer stem cells (BCSCs) have a critical role in progression of breast cancer by inducing angiogenesis. Several therapeutic strategies have been designed for the treatment of breast cancer by specifically preventing angiogenesis. But there is a dearth of study regarding the treatment procedure which can specifically target and kill the BCSCs and cause lesser harm to healthy cells of the body. A plant-based bioactive compound Quinacrine (QC) specifically kills cancer stem cells (CSCs) without harming healthy cells and also inhibits cancer angiogenesis but the detailed mechanistic study of its anti-CSCs and anti-angiogenic activity is yet to explore. HYPOTHESIS Earlier report showed that both cMET and ABCG2 play an essential role in cancer angiogenesis. Both are present on the cell surface of CSCs and share an identical ATP-binding domain. Interestingly, QC a plant based and bioactive compound which was found to inhibit the function of CSCs marker cMET and ABCG2. These relevant evidence led us to hypothesize that cMET and ABCG2 may interact with each other and induce the production of angiogenic factors, resulting in activation of cancer angiogenesis and QC might disrupt the interaction between them to stop this phenomena. METHODS Co-immunoprecipitation assay, immunofluorescence assay, and western blotting were performed by using ex vivo patient-derived breast cancer-stem-cells (PDBCSCs) and human umbilical vein endothelial cells (HUVECs). In silico study was carried out to check the interaction between cMET and ABCG2 in presence or absence of QC. Tube formation assay using HUVECs and in ovo Chorioallantoic membrane (CAM) assay using chick fertilized eggs were performed to monitor angiogenesis. In vivo patient-derived xenograft (PDX) mice model was used to validate in silico and ex vivo results. RESULTS Data revealed that in a hypoxic tumor microenvironment (TME), cMET and ABCG2 interact with each other and upregulate HIF-1α/VEGF-A axis to induce breast cancer angiogenesis. In silico and ex vivo study showed that QC disrupted the interaction between cMET and ABCG2 to inhibit the angiogenic response in endothelial cells by reducing the secretion of VEGF-A from PDBCSCs within the TME. Knockdown of cMET, ABCG2 or both, significantly downregulated the expression of HIF-1α and reduced the secretion of pro-angiogenic factor VEGF-A in the TME of PDBCSCs. Additionally, when PDBCSCs were treated with QC, similar experimental results were obtained. CONCLUSION In silico, in ovo, ex vivo and in vivo data confirmed that QC inhibited the HIF-1α/VEGF-A mediated angiogenesis in breast cancer by disrupting the interaction between cMET and ABCG2.
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Affiliation(s)
- Biswajit Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Somya Ranjan Dash
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Harun Patel
- Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule 425405, India
| | - Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Subhasmita Bhal
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Subarno Paul
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Chinmay Das
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Rajalaxmi Pradhan
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
| | - Iqrar Ahmed
- Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule 425405, India
| | - Kunal Goutam
- Department of Surgical Oncology, Acharya Harihar Regional Cancer Centre, Cuttack, Odisha 753007, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India.
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24
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Tacchini M, Sacchetti G, Guerrini A, Paganetto G. Mycochemicals against Cancer Stem Cells. Toxins (Basel) 2023; 15:360. [PMID: 37368660 DOI: 10.3390/toxins15060360] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/08/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Since ancient times, mushrooms have been considered valuable allies of human well-being both from a dietary and medicinal point of view. Their essential role in several traditional medicines is explained today by the discovery of the plethora of biomolecules that have shown proven efficacy for treating various diseases, including cancer. Numerous studies have already been conducted to explore the antitumoural properties of mushroom extracts against cancer. Still, very few have reported the anticancer properties of mushroom polysaccharides and mycochemicals against the specific population of cancer stem cells (CSCs). In this context, β-glucans are relevant in modulating immunological surveillance against this subpopulation of cancer cells within tumours. Small molecules, less studied despite their spread and assortment, could exhibit the same importance. In this review, we discuss several pieces of evidence of the association between β-glucans and small mycochemicals in modulating biological mechanisms which are proven to be involved with CSCs development. Experimental evidence and an in silico approach are evaluated with the hope of contributing to future strategies aimed at the direct study of the action of these mycochemicals on this subpopulation of cancer cells.
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Affiliation(s)
- Massimo Tacchini
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Gianni Sacchetti
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Alessandra Guerrini
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Guglielmo Paganetto
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
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25
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Perez K, Chiarella AM, Cleary JM, Horick N, Weekes C, Abrams T, Blaszkowsky L, Enzinger P, Giannakis M, Goyal L, Meyerhardt JA, Rubinson D, Yurgelun MB, Goessling W, Giantonio BJ, Brais L, Germon V, Stonely D, Raghavan S, Bakir B, Das K, Pitarresi JR, Aguirre AJ, Needle M, Rustgi AK, Wolpin BM. Phase Ib and Expansion Study of Gemcitabine, Nab-Paclitaxel, and Ficlatuzumab in Patients With Metastatic Pancreatic Cancer. Oncologist 2023; 28:425-432. [PMID: 36807743 PMCID: PMC10166179 DOI: 10.1093/oncolo/oyad002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/20/2022] [Indexed: 02/20/2023] Open
Abstract
BACKGROUND In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. METHODS Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination. RESULTS Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose-limiting toxicities were identified (N = 7 pts) and ficlatuzumab at 20 mg/kg was chosen as the maximum tolerated dose. Among the 21 patients treated at the MTD, best response by RECISTv1.1: 6 (29%) partial response, 12 (57%) stable disease, 1 (5%) progressive disease, and 2 (9%) not evaluable. Median progression-free survival and overall survival times were 11.0 months (95% CI, 7.6-11.4 months) and 16.2 months (95% CI, 9.1 months to not reached), respectively. Toxicities attributed to ficlatuzumab included hypoalbuminemia (grade 3, 16%; any grade, 52%) and edema (grade 3, 8%; any grade, 48%). Immunohistochemistry for c-Met pathway activation demonstrated higher tumor cell p-Met levels in patients who experienced response to therapy. CONCLUSION In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.
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Affiliation(s)
- Kimberly Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Anna M Chiarella
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - James M Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Nora Horick
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Colin Weekes
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Thomas Abrams
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Lawrence Blaszkowsky
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Peter Enzinger
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Lipika Goyal
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Douglas Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Wolfram Goessling
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Bruce J Giantonio
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Lauren Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Victoria Germon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Danielle Stonely
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Srivatsan Raghavan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Basil Bakir
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Koushik Das
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - Jason R Pitarresi
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | | | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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27
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YANG HONG, LI WAN, REN LIWEN, YANG YIHUI, ZHANG YIZHI, GE BINBIN, LI SHA, ZHENG XIANGJIN, LIU JINYI, ZHANG SEN, DU GUANHUA, TANG BO, WANG HONGQUAN, WANG JINHUA. Progress on diagnostic and prognostic markers of pancreatic cancer. Oncol Res 2023; 31:83-99. [PMID: 37304241 PMCID: PMC10208033 DOI: 10.32604/or.2023.028905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/15/2023] [Indexed: 06/13/2023] Open
Abstract
Pancreatic cancer is a malignant disease characterized by low survival and high recurrence rate, whose patients are mostly at the stage of locally advanced or metastatic disease when first diagnosed. Early diagnosis is particularly important because prognostic/predictive markers help guide optimal individualized treatment regimens. So far, CA19-9 is the only biomarker for pancreatic cancer approved by the FDA, but its effectiveness is limited by low sensitivity and specificity. With recent advances in genomics, proteomics, metabolomics, and other analytical and sequencing technologies, the rapid acquisition and screening of biomarkers is now possible. Liquid biopsy also occupies a significant place due to its unique advantages. In this review, we systematically describe and evaluate the available biomarkers that have the greatest potential as vital tools in diagnosing and treating pancreatic cancer.
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Affiliation(s)
- HONG YANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - WAN LI
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - LIWEN REN
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - YIHUI YANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - YIZHI ZHANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - BINBIN GE
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - SHA LI
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - XIANGJIN ZHENG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - JINYI LIU
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - SEN ZHANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - GUANHUA DU
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - BO TANG
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - HONGQUAN WANG
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - JINHUA WANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
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28
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Köseer AS, Di Gaetano S, Arndt C, Bachmann M, Dubrovska A. Immunotargeting of Cancer Stem Cells. Cancers (Basel) 2023; 15:1608. [PMID: 36900399 PMCID: PMC10001158 DOI: 10.3390/cancers15051608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development.
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Affiliation(s)
- Ayse Sedef Köseer
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01309 Dresden, Germany
| | - Simona Di Gaetano
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01309 Dresden, Germany
| | - Claudia Arndt
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Michael Bachmann
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Anna Dubrovska
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01309 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
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Correlation between hypoxia and HGF/c-MET expression in the management of pancreatic cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188869. [PMID: 36842767 DOI: 10.1016/j.bbcan.2023.188869] [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: 12/01/2022] [Revised: 01/16/2023] [Accepted: 02/07/2023] [Indexed: 02/28/2023]
Abstract
Pancreatic cancer (PC) is very deadly and difficult to treat. The presence of hypoxia has been shown to increase the probability of cancer developing and spreading. Pancreatic ductal adenocarcinoma (PDAC/PC) has traditionally viewed a highly lethal form of cancer due to its high occurrence of early metastases. Desmoplasia/stroma is often thick and collagenous, with pancreatic stellate cells as the primary source (PSCs). Cancer cells and other stromal cells interact with PSCs, promoting disease development. The hepatocyte growth factor (HGF)/c-MET pathway have been proposed as a growth factor mechanism mediating this interaction. Human growth factor (HGF) is secreted by pancreatic stellate cells (PSCs), and its receptor, c-MET, is generated by pancreatic cancer cells and endothelial cells. Hypoxia is frequent in malignant tumors, particularly pancreatic (PC). Hypoxia results from limitless tumor development and promotes survival, progression, and invasion. Hypoxic is becoming a critical driver and therapeutic target of pancreatic cancer as its hypoxia microenvironment is defined. Recent breakthroughs in cancer biology show that hypoxia promotes tumor proliferation, aggressiveness, and therapeutic resistance. Hypoxia-inducible factors (HIFs) stabilize hypoxia signaling. Hypoxia cMet is a key component of pancreatic tumor microenvironments, which also have a fibrotic response, that hypoxia, promotes and modulates. c-Met is a tyrosine-protein kinase. As describe it simply, the MET gene in humans' codes for a protein called hepatocyte growth factor receptor (HGFR). Most cancerous tumors and pancreatic cancer in particular, suffer from a lack of oxygen (PC). Due to unrestrained tumor development, hypoxia develops, actively contributing to tumor survival, progression, and invasion. As the processes by which hypoxia signaling promotes invasion and metastasis become clear, c-MET has emerged as an important determinant of pancreatic cancer malignancy and a potential pharmacological target. This manuscript provides the most current findings on the role of hypoxia and HGF/c-MET expression in the treatment of pancreatic cancer.
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Eptaminitaki GC, Zaravinos A, Stellas D, Panagopoulou M, Karaliota S, Baltsavia I, Iliopoulos I, Chatzaki E, Iliopoulos D, Baritaki S. Genome-Wide Analysis of lncRNA-mRNA Co-Expression Networks in CD133+/CD44+ Stem-like PDAC Cells. Cancers (Basel) 2023; 15:cancers15041053. [PMID: 36831395 PMCID: PMC9954787 DOI: 10.3390/cancers15041053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133-/CD44- cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby (cis or trans) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with "hub" SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC.
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Affiliation(s)
- Giasemi C. Eptaminitaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Apostolos Zaravinos
- Basic and Translational Cancer Research Center (BTCRC), Genomics and Systems Biology Laboratory, Cancer Genetics, Nicosia 1516, Cyprus
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, Cyprus
| | - Dimitris Stellas
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | - Sevasti Karaliota
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ismini Baltsavia
- Laboratory of Computational Biology, Division of Basic Sciences, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ioannis Iliopoulos
- Laboratory of Computational Biology, Division of Basic Sciences, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | | | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece
- Correspondence: ; Tel.: +30-281-039-4727
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Wang W, Zhang M, Zhang Q, Mohammadniaei M, Shen J, Sun Y. Brain-targeted antigen-generating nanoparticles improve glioblastoma prognosis. J Control Release 2022; 352:399-410. [PMID: 36309097 DOI: 10.1016/j.jconrel.2022.10.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 10/10/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022]
Abstract
The exploration of multifunctional nanomedicine has prompted interest in improving glioblastoma (GBM) prognosis. In this study, we constructed tumor microenvironment (TME)-responsive magnetic therapeutic nanoparticles (BK@MTNPs) as a multifunctional drug delivery platform. It contains the following components. [Des-arg(Sheets et al., 2020 [9])]bradykinin (BK), which contributes to the transient opening of the blood-brain barrier (BBB) and targeting of GBM cells; nanoparticles (NPs) encapsulated in MTNPs, which act as an in vivo magnetic resonance (MR) imaging agent; crizotinib, which is an inhibitor of protein kinase c-Met; and the immune drug anti-PDL1 antibody. These components were loaded into BK@MTNPs for complete tumoricidal effects. Abundant glutathione in the TME can promote BK@MTNP degradation by interrupting the disulfide bonds between cysteine residues. Such BK@MTNPs support a synergistic tumoricidal effect by inducing DNA damage, activating the transcription of the tumor suppressor gene PTEN, inhibiting glioblastoma stem cell function, activating cytotoxic T lymphocytes, and reprogramming tumor-associated macrophages. BK@MTNPs showed a significant increase in antitumor activity compared with free drugs in vitro. Furthermore, in mice bearing orthotopic GBM, treatment with BK@MTNPs resulted in marked tumor inhibition and greatly extended survival time with minimal side effects. This study demonstrates the advantages of chemo-immunotherapeutic NPs accumulated in the GBM area and their effective inhibition of GBM growth, thus establishing a delivery platform to promote antitumor immunity against GBM.
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Affiliation(s)
- Wentao Wang
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark
| | - Ming Zhang
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark; School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, PR China.
| | - Qicheng Zhang
- School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, PR China
| | - Mohsen Mohammadniaei
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark
| | - Jian Shen
- School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, PR China
| | - Yi Sun
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark.
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Evan T, Wang VMY, Behrens A. The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma. Oncogene 2022; 41:4686-4695. [PMID: 36088504 PMCID: PMC9568427 DOI: 10.1038/s41388-022-02448-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022]
Abstract
Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity.
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Affiliation(s)
- Theodore Evan
- Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | | | - Axel Behrens
- Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
- Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.
- CRUK Convergence Science Centre, Imperial College London, SW7 2AZ, London, UK.
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A Comprehensive Characterization of Stemness in Cell Lines and Primary Cells of Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2022; 23:ijms231810663. [PMID: 36142575 PMCID: PMC9503169 DOI: 10.3390/ijms231810663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 01/18/2023] Open
Abstract
The aim of this study is to provide a comprehensive characterization of stemness in pancreatic ductal adenocarcinoma (PDAC) cell lines. Seventeen cell lines were evaluated for the expression of cancer stem cell (CSC) markers. The two putative pancreatic CSC phenotypes were expressed heterogeneously ranging from 0 to 99.35% (median 3.46) for ESA+CD24+CD44+ and 0 to 1.94% (median 0.13) for CXCR4+CD133+. Cell lines were classified according to ESA+CD24+CD44+ expression as: Low-Stemness (LS; <5%, n = 9, median 0.31%); Medium-Stemness (MS; 6−20%, n = 4, median 12.4%); and High-Stemness (HS; >20%, n = 4, median 95.8%) cell lines. Higher degree of stemness was associated with in vivo tumorigenicity but not with in vitro growth kinetics, clonogenicity, and chemo-resistance. A wide characterization (chemokine receptors, factors involved in pancreatic organogenesis, markers of epithelial−mesenchymal transition, and secretome) revealed that the degree of stemness was associated with KRT19 and NKX2.2 mRNA expression, with CD49a and CA19.9/Tie2 protein expression, and with the secretion of VEGF, IL-7, IL-12p70, IL-6, CCL3, IL-10, and CXCL9. The expression of stem cell markers was also evaluated on primary tumor cells from 55 PDAC patients who underwent pancreatectomy with radical intent, revealing that CXCR4+/CD133+ and CD24+ cells, but not ESA+CD24+CD44+, are independent predictors of mortality.
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Raja Arul GL, Toruner MD, Gatenby RA, Carr RM. Ecoevolutionary biology of pancreatic ductal adenocarcinoma. Pancreatology 2022; 22:730-740. [PMID: 35821188 DOI: 10.1016/j.pan.2022.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/01/2022] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is an aggressive disease predicted to be the 2nd cause of cancer mortality in the US by 2040. While first-line therapy has improved, 5-year overall survival has only increased from 5 to ∼10%, and surgical resection is only available for ∼20% of patients as most present with advanced disease, which is invariably lethal. PDAC has well-established highly recurrent mutations in four driver genes including KRAS, TP53, CDKN2A, and SMAD4. Unfortunately, these genetic drivers are not currently therapeutically actionable. Despite extensive sequencing efforts, few additional significantly recurrent and druggable drivers have been identified. In the absence of targetable mutations, chemotherapy remains the mainstay of treatment for most patients. Further, the role of the above driver mutations on PDAC initiation and early development is well-established. However, these mutations alone cannot account for PDAC heterogeneity nor discern early from advanced disease. Taken together, management of PDAC is an example highlighting the shortcomings of the current precision medicine paradigm. PDAC, like other malignancies, represents an ecoevolutionary process. Better understanding the disease through this lens can facilitate the development of novel therapeutic strategies to better control and cure PDAC. This review aims to integrate the current understanding of PDAC pathobiology into an ecoevolutionary framework.
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Affiliation(s)
| | - Merih D Toruner
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Robert A Gatenby
- Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Ryan M Carr
- Department of Oncology, Mayo Clinic, Rochester, MN, USA.
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Rudloff U. Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma. Expert Opin Emerg Drugs 2022; 27:345-368. [PMID: 36250721 PMCID: PMC9793333 DOI: 10.1080/14728214.2022.2134346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/22/2022] [Accepted: 10/06/2022] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Pancreatic cancer is one of the deadliest solid organ cancers. In the absence of specific warning symptoms pancreatic cancer is diagnosed notoriously late. Current systemic chemotherapy regimens extend survival by a mere few months. With the advances in genetic, proteomic, and immunological profiling there is strong rationale to test kinase inhibitors to improve outcome. AREAS COVERED This review article provides a comprehensive summary of approved treatments and past, present, and future developments of kinase inhibitors in pancreatic cancer. Emerging roles of protein kinase inhibitors are discussed in the context of the unique stroma, the lack of high-prevalence therapeutic targets and rapid emergence of acquired resistance, novel immuno-oncology kinase targets, and recent medicinal chemistry advances. EXPERT OPINION Due to the to-date frequent failure of protein kinase inhibitors indiscriminately administered to unselected pancreatic cancer patients, there is a shift toward the development of these agents in molecularly defined subgroups which are more likely to respond. The development of accurate biomarkers to select patients who are the best candidates based on a detailed understanding of mechanism of action, pro-survival roles, and mediation of resistance of targeted kinases will be critical for the future development of protein kinase inhibitors in this disease.
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Affiliation(s)
- Udo Rudloff
- Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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36
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Chu TH, Ko CY, Tai PH, Chang YC, Huang CC, Wu TY, Chan HH, Wu PH, Weng CH, Lin YW, Kung ML, Fang CC, Wu JC, Wen ZH, Lee YK, Hu TH, Tai MH. Leukocyte cell-derived chemotaxin 2 regulates epithelial-mesenchymal transition and cancer stemness in hepatocellular carcinoma. J Biol Chem 2022; 298:102442. [PMID: 36055405 PMCID: PMC9530851 DOI: 10.1016/j.jbc.2022.102442] [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: 02/25/2022] [Revised: 08/07/2022] [Accepted: 08/08/2022] [Indexed: 11/27/2022] Open
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) acts as a tumor suppressor in hepatocellular carcinoma (HCC). However, the antineoplastic mechanism of LECT2, especially its influence on hepatic cancer stem cells (CSCs), remains largely unknown. In The Cancer Genome Atlas cohort, LECT2 mRNA expression was shown to be associated with stage, grade, recurrence, and overall survival in human HCC patients, and LECT2 expression was downregulated in hepatoma tissues compared with the adjacent nontumoral liver. Here, we show by immunofluorescence and immunoblot analyses that LECT2 was expressed at lower levels in tumors and in poorly differentiated HCC cell lines. Using functional assays, we also found LECT2 was capable of suppressing oncogenic behaviors such as cell proliferation, anchorage-independent growth, migration, invasiveness, and epithelial-mesenchymal transition in hepatoma cells. Moreover, we show exogenous LECT2 treatment inhibited CSC functions such as tumor sphere formation and drug efflux. Simultaneously, hepatic CSC marker expression was also downregulated, including expression of CD133 and CD44. This was supported by infection with adenovirus encoding LECT2 (Ad-LECT2) in HCC cells. Furthermore, in animal experiments, Ad-LECT2 gene therapy showed potent efficacy in treating HCC. We demonstrate LECT2 overexpression significantly promoted cell apoptosis and reduced neovascularization/CSC expansion in rat hepatoma tissues. Mechanistically, we showed using immunoblot and immunofluorescence analyses that LECT2 inhibited β-catenin signaling via the suppression of the hepatocyte growth factor/c-MET axis to diminish CSC properties in HCC cells. In summary, we reveal novel functions of LECT2 in the suppression of hepatic CSCs, suggesting a potential alternative strategy for HCC therapy.
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Affiliation(s)
- Tian-Huei Chu
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Chou-Yuan Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Po-Han Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yi-Chen Chang
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tung-Yang Wu
- Department of Chest Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Hoi-Hung Chan
- Division of Gastroenterology, Department of Medicine, Conde S. Januário Hospital, Macau, China
| | - Ping-Hsuan Wu
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chien-Hui Weng
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yu-Wei Lin
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Cheng-Chieh Fang
- Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jian-Ching Wu
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan; LabTurbo Biotech Corporation, Taipei, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yung-Kuo Lee
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Wang D, Li Y, Ge H, Ghadban T, Reeh M, Güngör C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers (Basel) 2022; 14:cancers14163998. [PMID: 36010993 PMCID: PMC9406497 DOI: 10.3390/cancers14163998] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.
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Chu PY, Huang WC, Tung SL, Tsai CY, Chen CJ, Liu YC, Lee CW, Lin YH, Lin HY, Chen CY, Yeh CT, Lin KH, Chi HC. IFITM3 promotes malignant progression, cancer stemness and chemoresistance of gastric cancer by targeting MET/AKT/FOXO3/c-MYC axis. Cell Biosci 2022; 12:124. [PMID: 35941699 PMCID: PMC9361616 DOI: 10.1186/s13578-022-00858-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/22/2022] [Indexed: 12/09/2022] Open
Abstract
Background Targeting the HGF/MET signaling pathway has been a viable therapeutic strategy for various cancer types due to hyperactivation of HGF/MET axis occurs frequently that leads to detrimental cancer progression and recurrence. Deciphering novel molecule mechanisms underlying complex HGF/MET signaling network is therefore critical to development of effective therapeutics for treating MET-dependent malignancies. Results Using isobaric mass tag-based quantitative proteomics approach, we identified IFITM3, an interferon-induced transmembrane protein that was highly expressed in micro-dissected gastric cancer (GC) tumor regions relative to adjacent non-tumor epithelia. Analyses of GC clinical specimens revealed that expression IFITM3 was closely correlated to advanced pathological stages. IFITM3 has been reported as a PIP3 scaffold protein that promotes PI3K signaling. In present study, we unprecedentedly unraveled that IFITM3 associated with MET and AKT to facilitate HGF/MET mediated AKT signaling crosstalk in suppressing FOXO3, consequently leading to c-MYC mediated GC progression. In addition, gene ontology analyses of the clinical GC cohort revealed significant correlation between IFITM3-associated genes and targets of c-MYC, which is a crucial downstream effector of HGF/MET pathway in cancer progression. Moreover, we demonstrated ectopic expression of IFITM3 suppressed FOXO3 expression, consequently led to c-MYC induction to promote tumor growth, cell metastasis, cancer stemness as well as chemoresistance. Conversely, depletion of IFITM3 resulted in suppression of HGF triggered cellular growth and migration via inhibition of AKT/c-MYC signaling in GC. Conclusions In summary, our present study unveiled a novel regulatory mechanism for c-MYC-driven oncogenesis underlined by IFITM3-mediated signaling crosstalk between MET associated AKT signaling cascade. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00858-8.
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Zuzčák M, Trnka J. Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review). Int J Oncol 2022; 61:93. [PMID: 35730611 PMCID: PMC9256076 DOI: 10.3892/ijo.2022.5383] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/10/2022] [Indexed: 11/28/2022] Open
Abstract
Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched‑chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.
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Affiliation(s)
- Michal Zuzčák
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
- Center for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
| | - Jan Trnka
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
- Center for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
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Zhang Z, Li D, Yun H, Tong J, Liu W, Chai K, Zeng T, Gao Z, Xie Y. Opportunities and challenges of targeting c-Met in the treatment of digestive tumors. Front Oncol 2022; 12:923260. [PMID: 35978812 PMCID: PMC9376446 DOI: 10.3389/fonc.2022.923260] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.
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Affiliation(s)
- Zhengchao Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Dong Li
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Jie Tong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Wei Liu
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Keqiang Chai
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Tongwei Zeng
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Zhenghua Gao
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
| | - Yongqiang Xie
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
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Yu Q, Xiu Z, Jian Y, Zhou J, Chen X, Chen X, Chen C, Chen H, Yang S, Yin L, Zeng W. microRNA-497 prevents pancreatic cancer stem cell gemcitabine resistance, migration, and invasion by directly targeting nuclear factor kappa B 1. Aging (Albany NY) 2022; 14:5908-5924. [PMID: 35896012 PMCID: PMC9365558 DOI: 10.18632/aging.204193] [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: 02/10/2022] [Accepted: 05/23/2022] [Indexed: 11/25/2022]
Abstract
Objectives: Cancer stem cells (CSCs) comprise a small population of cells in cancerous tumors and play a critical role in tumor resistance to chemotherapy. miRNAs have been reported to enhance the sensitivity of pancreatic cancer to chemotherapy. However, the underlying molecular mechanism requires better understanding. Methods: Cell viability and proliferation were examined with CCK8 assays. Quantitative real-time polymerase chain reaction was executed to assess mRNA expression. StarBase database was used to select the target genes of miRNA, which were further affirmed by dual luciferase assay. Transwell assay was used to analyze cell invasion and migration. Results: We proved that miR-497 could be obviously downregulated in pancreatic cancer tissues and CSCs from Aspc-1 and Bxpc-3 cells. In addition, inhibition of miR-497 evidently accelerated pancreatic CSC gemcitabine resistance, migration and invasion. Moreover, we revealed that nuclear factor kappa B 1 (NFκB1) was prominently upregulated in pancreatic cancer tissues and pancreatic CSCs, and NFκB1 was also identified as a direct target of miR-497. Furthermore, we demonstrated that overexpression of NFκB1 could also notably promote the viability, migration, and invasion of gemcitabine-treated pancreatic CSCs, but this effect could be partially abolished by miR-497 overexpression. Conclusions: Those findings suggest that miR-497 overexpression could suppress gemcitabine resistance and the metastasis of pancreatic CSCs and non-CSCs by directly targeting NFκB1.
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Affiliation(s)
- Qiangfeng Yu
- The Second Department of General Surgery, Zhuhai People's Hospital, Zhuhai 51900, Guangdong, China
| | - Zhe Xiu
- Department of Hepatobiliary Surgery, The Second Hospital of Longyan, Longyan 364000, Fujian, China
| | - Yizeng Jian
- Department of Hepatobiliary Surgery, The Second Hospital of Longyan, Longyan 364000, Fujian, China
| | - Jianyin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Zhongshan Hospital, Xiamen University, Xiamen 361000, Fujian, China
| | - Xiaopeng Chen
- Department of Hepatobiliary Surgery, The Second Hospital of Longyan, Longyan 364000, Fujian, China
| | - Xiang Chen
- The Third Department of Surgery, The Second Hospital of Longyan, Longyan 364000, Fujian, China
| | - Chunxiang Chen
- Department of Science and Education, The Second Hospital of Longyan, Longyan 364000, Fujian, China
| | - Hongbao Chen
- Department of Pathology, The Second Hospital of Longyan, Longyan 364000, Fujian, China
| | - Sijia Yang
- The Second Department of General Surgery, Zhuhai People's Hospital, Zhuhai 51900, Guangdong, China
| | - Libo Yin
- The First People's Hospital of Wenling, The Affiliated Wenling Hospital of Wenzhou Medical University, Wenzhou 317500, Zhejiang, China
| | - Wenlong Zeng
- Department of Hepatobiliary Surgery, The Second Hospital of Longyan, Longyan 364000, Fujian, China
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Chen C, Wu B, Wang M, Chen J, Huang Z, Shi JS. GABRP promotes CD44s-mediated gemcitabine resistance in pancreatic cancer. PeerJ 2022; 10:e12728. [PMID: 35846884 PMCID: PMC9281597 DOI: 10.7717/peerj.12728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 12/10/2021] [Indexed: 01/07/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) has the worst five-year overall survival rate among all cancer types. Acquired chemoresistance is considered one of the main reasons for this dismal prognosis, and the mechanism of chemoresistance is unknown. Methods We previously identified a subpopulation of chemoresistant CD44high-expressing PDAC cells. Subsequently, we selected the candidate gene, gamma-aminobutyric acid receptor subunit Pi (GABRP), from three Gene Expression Omnibus datasets as the potential CD44 downstream target mediating the gemcitabine resistance. Loss and gain of function such as stable knockdown of CD44 by small hairpin (sh) RNA-mediated silencing technique and overexpression (O/E) of CD44s had been studied for comparing the gemcitabine resistance among CD44high-expressing cells, shCD44 cells, CD44low-expressing cells and O/E CD44s expressing cells. Functional assays including cell viability, colony formation, invasion, quantitative PCR and western blotting techniques were performed to validate the roles of CD44 and GABRP playing in mediating the gemcitabine resistance in pancreatic cancer cells. Results CD44s depletion significantly reduced gemcitabine resistance in shCD44 single clone cells compared to CD44high-expressing cells. Knockdown of CD44 cells formed less colonies, became less invasive and remarkably decreased the mRNA level of GABRP. While overexpression of CD44s had the opposite effect on gemcitabine resistance, colony formation and invasive property. Of note, long term gemcitabine resistant pancreatic cancer cells detected increased expression of CD44 and GABRP. Clinically, GABRP expression was significantly upregulated in the tissues of patients with pancreatic cancer compared to the normal samples, and the overall survival rate of patients with low GABRP expression was longer. CD44 and GABRP co-expression was positively correlated in 178 pancreatic cancer patients. Conclusion Our findings suggest that GABRP may serve as a CD44s downstream target to diminish gemcitabine resistance in pancreatic cancer, and both CD44s and GABRP molecules have the potential to become prognostic biomarkers for PDAC patients with gemcitabine resistance.
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Affiliation(s)
- Chen Chen
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China
| | - Binfeng Wu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China
| | - Mingge Wang
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China
| | - Jinghua Chen
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhaohui Huang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Jin-Song Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China
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Han X, Zhang W, Gao H, Li T, Xu H, Li H, Li P, Wang X, Yu X, Wang W, Liu L. Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer. J Clin Lab Anal 2022; 36:e24517. [PMID: 35622458 PMCID: PMC9279986 DOI: 10.1002/jcla.24517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/13/2022] [Accepted: 05/12/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.
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Affiliation(s)
- Xuan Han
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wu‐Hu Zhang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - He‐Li Gao
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Tian‐Jiao Li
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Hua‐Xiang Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Hao Li
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Peng‐Cheng Li
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xu Wang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xian‐Jun Yu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wen‐Quan Wang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Liang Liu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
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Xia P, Liu DH. Cancer stem cell markers for liver cancer and pancreatic cancer. Stem Cell Res 2022; 60:102701. [PMID: 35149457 DOI: 10.1016/j.scr.2022.102701] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSC) theory has ushered in a new era of cancer research. Tumor recurrence, metastasis and chemotherapy resistance are all related to the existence of cancer stem cells. Further understanding of tumor heterogeneity will contribute to targeted treatment. Liver cancer and pancreatic cancer are common digestive gland tumors with high lethality. This article reviews the identification and isolation of CSC markers in hepatocellular carcinoma and pancreatic cancer. The markers related signal pathways are involved in the occurrence and development of tumors, and have a significant impact on the proliferation, metastasis and invasion of cancer cells, which can be used as potential molecular therapeutic targets. This study will be helpful to understand cancer stem cell like cells.
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Affiliation(s)
- Pu Xia
- Biological Anthropology Institute, College of Basic Medical Science, Liaoning Medical University, China.
| | - Da-Hua Liu
- Biological Anthropology Institute, College of Basic Medical Science, Liaoning Medical University, China
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Gulla A, Andriusaityte U, Zdanys GT, Babonaite E, Strupas K, Kelly H. The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:467. [PMID: 35454306 PMCID: PMC9032206 DOI: 10.3390/medicina58040467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 12/26/2022]
Abstract
Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.
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Affiliation(s)
- Aiste Gulla
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
- Center of Visceral Medicine and Translational Research, Department of Surgery, Georgetown University Hospital, 3800 Reservoir Road Northwest BLES Building 1st. Floor, Washington, DC 20007, USA
| | - Urte Andriusaityte
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Gabrielius Tomas Zdanys
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Elena Babonaite
- Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania; (U.A.); (G.T.Z.); (E.B.)
| | - Kestutis Strupas
- Institute of Clinical Medicine, Clinic of Gastroenterology, Surgery, Nephrology, Faculty of Medicine, Vilnius University, Santariskiu Str. 2, 08661 Vilnius, Lithuania;
| | - Helena Kelly
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland;
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To KKW, Cho WCS. Mesenchymal Epithelial Transition Factor (MET): A Key Player in Chemotherapy Resistance and an Emerging Target for Potentiating Cancer Immunotherapy. Curr Cancer Drug Targets 2022; 22:269-285. [PMID: 35255791 DOI: 10.2174/1568009622666220307105107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/10/2021] [Accepted: 01/10/2022] [Indexed: 11/22/2022]
Abstract
The MET protein is a cell surface receptor tyrosine kinase predominately expressed in epithelial cells. Upon binding of its only known ligand, hepatocyte growth factor (HGF), MET homodimerizes, phosphorylates, and stimulates intracellular signalling to drive cell proliferation. Amplification or hyperactivation of MET is frequently observed in various cancer types and it is associated with poor response to conventional and targeted chemotherapy. More recently, emerging evidence also suggests that MET/HGF signalling may play an immunosuppressive role and it could confer resistance to cancer immunotherapy. In this review, we summarized the preclinical and clinical evidence of MET's role in drug resistance to conventional chemotherapy, targeted therapy, and immunotherapy. Previous clinical trials investigating MET-targeted therapy in unselected or MET-overexpressing cancers yielded mostly unfavourable results. More recent clinical studies focusing on MET exon 14 alterations and MET amplification have produced encouraging treatment responses to MET inhibitor therapy. The translational relevance of MET inhibitor therapy to overcome drug resistance in cancer patients is discussed.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
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Huang WC, Yen JH, Sung YW, Tung SL, Chen PM, Chu PY, Shih YC, Chi HC, Huang YC, Huang SJ, Wang LH. Novel function of THEMIS2 in the enhancement of cancer stemness and chemoresistance by releasing PTP1B from MET. Oncogene 2022; 41:997-1010. [PMID: 34974522 PMCID: PMC8837547 DOI: 10.1038/s41388-021-02136-2] [Citation(s) in RCA: 6] [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: 06/22/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/11/2022]
Abstract
Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to lack of effective endocrine or targeted therapies, aggressive nature and high rate of chemoresistance. Cancer stem cells (CSCs) are considered to play critical roles in cancer recurrence and chemoresistance. THEMIS2 was identified as the sole common elevated gene in three triple negative breast cancer (TNBC) and two ovarian CSC lines. We discovered an intrinsic signaling scaffold function of THEMIS2, which acts as a novel regulator of cancer stemness in promoting multiple cancer stemness properties including sphere formation, stemness markers expression, chemoresistance and tumorigenicity with low numbers of cancer cells implantation. For the first time, we demonstrated that THEMIS2 specifically enhanced MET activating phosphorylation by suppressing the association of protein-tyrosine phosphatases 1B (PTP1B) with p-MET and MET, which accounted mainly for THEMIS2-mediated effect on cancer stemness and chemoresistance. Increased THEMIS2 expression was associated with poor survival in TNBC patients and in patients from our breast cancer cohort. We found that non-cytotoxic dosages of cryptotanshinone (CPT) could potently inhibit cancer stemness, chemoresistance and tumorigenicity by suppressing expression of THEMIS2. Notably, stable overexpression of THEMIS2 is associated with enhanced sensitivity toward Capmatinib and CPT treatment. Expression levels of THEMIS2 and p-MET protein were positively correlated in the 465 breast cancer specimens. Our study revealed the novel oncogenic role of THEMIS2 and its underlying mechanism via suppressing PTP1B association with MET and thus leading to its activation. Our findings suggest that THEMIS2 could be a biomarker for MET targeted therapy and also provide a potential clinical application using low dosages of CPT for treatment of THEMIS2 positive TNBC.
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Affiliation(s)
- Wei-Chieh Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Jia-Hau Yen
- Research Cancer Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Wen Sung
- Department of Obstetrics and Gynecologics, China Medical University Hospital, Taichung City, Taiwan
| | - Shiao-Lin Tung
- Department of Hematology and Oncology, Ton-Yen General Hospital, Hsinchu County, Taiwan
- Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan City, Taiwan
| | - Po-Ming Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Pei-Yi Chu
- Department of Pathology, Show Chwan Memorial Hospital, Chung-Shang Road, Changhua County, Taiwan
| | - Ya-Chi Shih
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Yi-Ching Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Shih-Jei Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Lu-Hai Wang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
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microRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells. Int J Mol Sci 2022; 23:ijms23031275. [PMID: 35163198 PMCID: PMC8835847 DOI: 10.3390/ijms23031275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial-mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.
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Sumbly V, Landry I. Understanding pancreatic cancer stem cells and their role in carcinogenesis: a narrative review. Stem Cell Investig 2022; 9:1. [PMID: 35242873 PMCID: PMC8832159 DOI: 10.21037/sci-2021-067] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/14/2022] [Indexed: 08/13/2023]
Abstract
OBJECTIVE The purpose of this review article is to describe the pathogenesis of pancreatic cancer and to better understand the role of abnormal stem cells in the development of pancreatic cancer. BACKGROUND Pancreatic cancer is a highly fatal disease that is caused by the uncontrolled proliferation of pancreatic exocrine or neuroendocrine glands. It is believed that pancreatic cancers arise from a small population of abnormal cancer stem cells (CSCs) that promote tumorigenesis, tumor metastasis and therapeutic resistance. The molecular markers CD133, CXCR4, DCLK1, c-MET, ABCG2 and Lgr5 are routinely used to detected and observe the behaviours of pancreatic cancer stem cells (PCSCs). METHODS A comprehensive search was performed on PubMed, Google Scholar, Scopus, Clinicaltrials.gov and Web of Science using related keywords. Articles focusing on PCSCs and pancreatic cancer pathogenesis, biochemistry and clinical trials were selected. CONCLUSIONS Although very little is known about the exact cause of pancreatic cancer, PCSCs seem to play an important role in carcinogenesis. Mutated biochemical cascades include Sonic Hedgehog, K-RAS-JNK, DLL4/Notch and Nodal/Activin. Several clinical trials are trying to determine if the transplantation of hematopoietic stem cell or peripheral stem cells could be useful for the treatment of such an aggressive tumor.
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Affiliation(s)
- Vikram Sumbly
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/NYC Health & Hospitals|Queens, Jamaica, NY, USA
| | - Ian Landry
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/NYC Health & Hospitals|Queens, Jamaica, NY, USA
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Ahamed JI, Ramkumaar G, Kamalarajan P, Narendran K, Valan M, Sundareswaran T, Sundaravadivel T, Venkatadri B, Bharathi S. Novel quinoxaline derivatives of 2, 3-diphenylquinoxaline-6-carbaldehyde and 4, 4′-(6-methylquinoxaline-2,3-diyl)bis(N,N-diphenylaniline): Synthesis, structural, DFT-computational, molecular docking, antibacterial, antioxidant, and anticancer studies. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.131418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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