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Lutimba S, Saleem B, Aleem E, Mansour MA. In Silico Analysis of Triamterene as a Potential Dual Inhibitor of VEGFR-2 and c-Met Receptors. J Xenobiot 2024; 14:1962-1987. [PMID: 39728413 DOI: 10.3390/jox14040105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024] Open
Abstract
The vascular endothelial growth factor receptor 2 (VEGFR2) and the hepatocyte growth factor receptor (C-Met) are critical receptors for signaling pathways controlling crucial cellular processes such as cell growth, angiogenesis and tissue regeneration. However, dysregulation of these proteins has been reported in different diseases, particularly cancer, where these proteins promote tumour growth, invasiveness, metastasis and resistance to conventional therapies. The identification of dual inhibitors targeting both VEGFR-2 and c-Met has emerged as a strategic therapeutic approach to overcome the limitations and resistance mechanisms associated with single-target therapies in clinical settings. Through molecular dynamics simulations and comparative docking analysis, we tested the inhibitory potential of 2,016 Food and Drug Administration (FDA)-approved drugs targeting VEGFR-2 and/or c-Met receptors. The results revealed that entacapone and telmisartan are potent and selective inhibitors for c-Met and VEGFR-2, respectively. Interestingly, triamterene was identified as a promising dual inhibitor, demonstrating specific and significant binding affinity to both proteins. Molecular dynamics simulations revealed key interactions between the identified compounds and critical residues in the catalytic domains of both VEGFR-2 (e.g., Lys868, Asp1028, Asp1046) and c-Met (e.g., Asp1204, His1202, Asp1222), providing insights into their mechanism of action. These findings underscore the therapeutic potential of triamterene in targeting multiple signaling pathways involved in cancer progression, metastasis and poor prognosis in patients. Our study provides a foundational framework for the development of novel anticancer compounds able to target multiple pathways in cancer. Further preclinical and clinical investigations are needed to validate the efficacy of these compounds in clinical settings and to test their ability to overcome resistance and improve patient outcome.
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Affiliation(s)
- Stuart Lutimba
- Cancer Biology and Therapy Laboratory, School of Applied and Health Sciences, London South Bank University, London SE1 0AA, UK
| | - Baraya Saleem
- Cancer Biology and Therapy Laboratory, School of Applied and Health Sciences, London South Bank University, London SE1 0AA, UK
| | - Eiman Aleem
- Cancer Biology and Therapy Laboratory, School of Applied and Health Sciences, London South Bank University, London SE1 0AA, UK
| | - Mohammed A Mansour
- Cancer Biology and Therapy Laboratory, School of Applied and Health Sciences, London South Bank University, London SE1 0AA, UK
- Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
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Park SJ, Shin K, Hong TH, Lee SH, Kim IH, Kim Y, Lee M. Prognostic Significance of EGFR, HER2, and c-Met Overexpression in Surgically Treated Patients with Adenocarcinoma of the Ampulla of Vater. Cancers (Basel) 2024; 16:2756. [PMID: 39123483 PMCID: PMC11312068 DOI: 10.3390/cancers16152756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 07/28/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
Adenocarcinoma of the ampulla of Vater (AAC) is a rare malignancy with heterogeneous tumors arising from various histologic subtypes, necessitating new therapeutic strategies. This study examines epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and c-Met expression in AAC, given their potential as druggable targets. Among 87 patients who underwent curative resection, EGFR overexpression was found in 87.4%, HER2 in 11.5%, and c-Met in 50%. EGFR overexpression was more common in the pancreatobiliary subtype (p = 0.018) and associated with a higher histologic grade (p = 0.008). HER2 did not correlate with clinicopathological features, while c-Met was more common in node-negative groups (p = 0.004) and often co-expressed with EGFR (p = 0.049). EGFR-positive patients had worse disease-free (HR = 2.89; 95% CI, 1.35-6.20; p = 0.061) and overall survival (HR = 6.89; 95% CI, 2.94-16.2; p = 0.026) than EGFR-negative patients. HER2-positive AAC showed a trend towards shorter survival, although not statistically significant, and c-Met had no impact on survival outcomes. In the context of systemic disease, survival outcomes did not vary according to EGFR, HER2, and c-Met expression, but the HER2-positive group showed a trend towards inferior progression-free survival (HR = 1.90; 95% CI, 0.56-6.41; p = 0.166). This study underscores the potential of EGFR, HER2, and c-Met as targets for personalized therapy in AAC, warranting further research to evaluate targeted treatments.
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Affiliation(s)
- Se Jun Park
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea; (S.J.P.); (K.S.); (I.-H.K.)
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kabsoo Shin
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea; (S.J.P.); (K.S.); (I.-H.K.)
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Tae Ho Hong
- Department of General Surgery, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea;
| | - Sung Hak Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea;
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea; (S.J.P.); (K.S.); (I.-H.K.)
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Younghoon Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea;
| | - MyungAh Lee
- Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea; (S.J.P.); (K.S.); (I.-H.K.)
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Contreras-Zentella ML, Alatriste-Contreras MG, Suárez-Cuenca JA, Hernández-Muñoz R. Gender effect of glucose, insulin/glucagon ratio, lipids, and nitrogen-metabolites on serum HGF and EGF levels in patients with diabetes type 2. Front Mol Biosci 2024; 11:1362305. [PMID: 38654922 PMCID: PMC11035728 DOI: 10.3389/fmolb.2024.1362305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Hepatocyte growth factor (HGF) exhibits potent growth-inducing properties across various tissues, while epidermal growth factor (EGF) acts as a molecular integration point for diverse stimuli. HGF plays a crucial role in hepatic metabolism, tissue repair, and offers protective effects on epithelial and non-epithelial organs, in addition to its involvement in reducing apoptosis and inflammation, underscoring its anti-inflammatory capabilities. The HGF-Met system is instrumental in hepatic metabolism and enhancing insulin sensitivity in animal diabetes models. Similarly, the EGF and its receptor tyrosine kinase family (EGFR) are critical in regulating cell growth, proliferation, migration, and differentiation in both healthy and diseased states, with EGF also contributing to insulin sensitivity. In this observational study, we aimed to identify correlations between serum levels of HGF and EGF, insulin, glucagon, glucose, and primary serum lipids in patients with type 2 diabetes mellitus (DM), taking into account the impact of gender. We noted differences in the management of glucose, insulin, and glucagon between healthy men and women, potentially due to the distinct influences of sexual hormones on the development of type 2 DM. Additionally, metabolites such as glucose, albumin, direct bilirubin, nitrites, and ammonia might influence serum levels of growth factors and hormones. In summary, our results highlight the regulatory role of insulin and glucagon in serum glucose and lipids, along with variations in HGF and EGF levels, which are affected by gender. This link is especially significant in DM, where impaired cell proliferation or repair mechanisms lead to metabolic changes. The gender-based differences in growth factors point to their involvement in the pathophysiology of the disease.
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Affiliation(s)
- Martha Lucinda Contreras-Zentella
- Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Martha Gabriela Alatriste-Contreras
- Departamento de Métodos Cuantitativos, División de Estudios Profesionales, Facultad de Economía, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Juan Antonio Suárez-Cuenca
- Departamento de Medicina Interna, Hospital General “Xoco”, Secretaría de Salud (SS), Mexico City, Mexico
| | - Rolando Hernández-Muñoz
- Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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Wright K, Ly T, Kriet M, Czirok A, Thomas SM. Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers. Cancers (Basel) 2023; 15:cancers15061899. [PMID: 36980785 PMCID: PMC10047485 DOI: 10.3390/cancers15061899] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Cancer cells rely on the tumor microenvironment (TME), a composite of non-malignant cells, and extracellular matrix (ECM), for survival, growth, and metastasis. The ECM contributes to the biomechanical properties of the surrounding tissue, in addition to providing signals for tissue development. Cancer-associated fibroblasts (CAFs) are stromal cells in the TME that are integral to cancer progression. Subtypes of CAFs across a variety of cancers have been revealed, and each play a different role in cancer progression or suppression. CAFs secrete signaling molecules and remodel the surrounding ECM by depositing its constituents as well as degrading enzymes. In cancer, a remodeled ECM can lead to tumor-promoting effects. Not only does the remodeled ECM promote growth and allow for easier metastasis, but it can also modulate the immune system. A better understanding of how CAFs remodel the ECM will likely yield novel therapeutic targets. In this review, we summarize the key factors secreted by CAFs that facilitate tumor progression, ECM remodeling, and immune suppression.
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Affiliation(s)
- Kellen Wright
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Thuc Ly
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Matthew Kriet
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Andras Czirok
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sufi Mary Thomas
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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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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Mao Y, Zhuo R, Ma W, Dai J, Alimu P, Fang C, Xu D, Ye L, Wang W, Sun F. Fibroblasts mediate the angiogenesis of pheochromocytoma by increasing COX4I2 expression. Front Oncol 2022; 12:938123. [PMID: 36172142 PMCID: PMC9511905 DOI: 10.3389/fonc.2022.938123] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Objective Our previous work found COX4I2 was associated with angiogenesis in pheochromocytoma. The purpose of this study was to explore the role of COX4I2 in regulating angiogenesis in pheochromocytoma. Methods Distribution of COX4I2 was evaluated by scRNA-seq in one case of pheochromocytoma and the findings were verified by immunostaining. COX4I2 was further knocked down in target cells. Changes of angiogenesis-related genes were evaluated by qPCR in target cells. Results The scRNA-seq revealed high mRNA expression of COX4I2 in fibroblasts rather than tumor cells. Immunostaining of COX4I2 confirmed its distribution in fibroblasts. Knocking down COX4I2 in NIH3T3 cell line led to significant reduction of angiogenesis-related genes, especially ANG1 and HGF. Conclusions Fibroblasts mediate the angiogenesis of pheochromocytoma by increasing COX4I2 expression, possibly by affecting ANG1 and HGF.
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Affiliation(s)
- Yongxin Mao
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ran Zhuo
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenming Ma
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Dai
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Parehe Alimu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Fang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Danfeng Xu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Ye
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Fukang Sun, ; Weiqing Wang,
| | - Fukang Sun
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Fukang Sun, ; Weiqing Wang,
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Perales S, Torres C, Jimenez-Luna C, Prados J, Martinez-Galan J, Sanchez-Manas JM, Caba O. Liquid biopsy approach to pancreatic cancer. World J Gastrointest Oncol 2021; 13:1263-1287. [PMID: 34721766 PMCID: PMC8529923 DOI: 10.4251/wjgo.v13.i10.1263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/18/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to pose a major clinical challenge. There has been little improvement in patient survival over the past few decades, and it is projected to become the second leading cause of cancer mortality by 2030. The dismal 5-year survival rate of less than 10% after the diagnosis is attributable to the lack of early symptoms, the absence of specific biomarkers for an early diagnosis, and the inadequacy of available chemotherapies. Most patients are diagnosed when the disease has already metastasized and cannot be treated. Cancer interception is vital, actively intervening in the malignization process before the development of a full-blown advanced tumor. An early diagnosis of PC has a dramatic impact on the survival of patients, and improved techniques are urgently needed to detect and evaluate this disease at an early stage. It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position; however, liquid biopsies are readily available and can provide useful information for the diagnosis, prognosis, stratification, and follow-up of patients with PC and for the design of individually tailored treatments. The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates, proteins, cell-free nucleic acids, circulating tumor cells, metabolome compounds, exosomes, and platelets in blood as potential biomarkers for PC, focusing on their clinical relevance and potential for improving patient outcomes.
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Affiliation(s)
- Sonia Perales
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Joaquina Martinez-Galan
- Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada 18011, Spain
| | | | - Octavio Caba
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
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Yang Y, Gu J, Li X, Xue C, Ba L, Gao Y, Zhou J, Bai C, Sun Z, Zhao RC. HIF-1α promotes the migration and invasion of cancer-associated fibroblasts by miR-210. Aging Dis 2021; 12:1794-1807. [PMID: 34631221 PMCID: PMC8460292 DOI: 10.14336/ad.2021.0315] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/15/2021] [Indexed: 12/24/2022] Open
Abstract
Metastasis is the major cause of death in colorectal cancer (CRC) patients. Inhibition of metastasis will prolong the survival of patients with CRC. Cancer cells bring their own soil, cancer-associated fibroblasts (CAFs), to metastasize together, promoting the survival and colonization of circulating cancer cells. However, the mechanism by which CAFs metastasize remains unclear. In this study, CAFs were derived from adipose mesenchymal stem cells (MSCs) after co-culture with CRC cell lines. Transwell assays showed that CAFs have stronger migration and invasion abilities than MSCs. In a nude mouse subcutaneous xenograft model, CAFs metastasized from the primary tumour to the lung and promoted the formation of CRC metastases. The expression of HIF-1α was upregulated when MSCs differentiated into CAFs. Inhibition of HIF-1α expression inhibited the migration and invasion of CAFs. Western blot and ChIP assays were used to identify the genes regulated by HIF-1α. HIF-1α regulated the migration and invasion of CAFs by upregulating miR-210 transcription. Bioinformatics analysis and luciferase reporter assays revealed that miR-210 specifically targeted the 3'UTR of VMP1 and regulated its expression. Downregulation of VMP1 enhanced the migration and invasion of CAFs. In vivo, inhibition of miR-210 expression in CAFs reduced the metastasis of CAFs and tumour cells. Therefore, the HIF-1α/miR-210/VMP1 pathway might regulate the migration and invasion of CAFs in CRC. Inhibition of CAF metastasis might reduce CRC metastasis.
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Affiliation(s)
- Ying Yang
- 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Junjie Gu
- 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xuechun Li
- 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing 100005, China
| | - Chunling Xue
- 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing 100005, China
| | - Li Ba
- 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing 100005, China
| | - Yang Gao
- 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jianfeng Zhou
- 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Chunmei Bai
- 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zhao Sun
- 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Robert Chunhua Zhao
- 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing 100005, China
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Zhang ZS, Yang RH, Yao X, Cheng YY, Shi HX, Yao CY, Gao ZX, Qi DF, Zhang WK, Dou YY, Guo J, Hu MW, Zhao H, Fang D. HGF/c-MET pathway contributes to cisplatin-mediated PD-L1 expression in hepatocellular carcinoma. Cell Biol Int 2021; 45:2521-2533. [PMID: 34486197 DOI: 10.1002/cbin.11697] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/17/2021] [Accepted: 08/28/2021] [Indexed: 12/20/2022]
Abstract
Cisplatin has been reported to promote the expression of programmed cell death ligand-1 (PD-L1) in some cancer cells. However, the underlying mechanism through which PD-L1 is transcriptionally regulated by cisplatin in hepatocellular carcinoma (HCC) cells remains largely unknown. In the present study, we found that the expression of hepatocyte growth factor (HGF), p-Akt, p-ERK, and PD-L1 was increased in cisplatin-treated SNU-368 and SNU-739 cells. HGF stimulation also increased PD-L1 expression in these cells. Moreover, Inhibition of HGF/c-MET, PI3K/Akt, and MEK/ERK signaling pathways can dramatically block cisplatin or HGF-induced PD-L1 expression in SNU-368 and SNU-739 cells. In vivo, combination PHA665752 with cisplatin significantly reduced tumor weight with increased infiltration of CD8+ T cells in the tumor. Taken together, our study suggested that HGF/c-Met axis-induced the activation of PI3K/Akt and MEK/ERK pathways contributes to cisplatin-mediated PD-L1 expression. These findings may provide an alternative avenue for the treatment of HCC.
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Affiliation(s)
- Zhan-Sheng Zhang
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Ruo-Han Yang
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Xin Yao
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Yue-Ying Cheng
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Hong-Xiang Shi
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Chao-Yan Yao
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Zi-Xuan Gao
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - De-Fei Qi
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Wen-Ke Zhang
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Yuan-Yuan Dou
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Juan Guo
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Meng-Wen Hu
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Hui Zhao
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Dong Fang
- Department of Pharmacology, Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China.,Department of Pharmacology, Institute of Chemical Biology, School of Pharmacy, Henan University, Kaifeng, China
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Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.,Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. .,Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar. .,Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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11
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Arias-Pinilla GA, Modjtahedi H. Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities. Cancers (Basel) 2021; 13:1781. [PMID: 33917882 PMCID: PMC8068268 DOI: 10.3390/cancers13081781] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.
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Affiliation(s)
- Gustavo A. Arias-Pinilla
- Department of Oncology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK;
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
| | - Helmout Modjtahedi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
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12
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Pothula SP, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Targeting HGF/c-MET Axis in Pancreatic Cancer. Int J Mol Sci 2020; 21:E9170. [PMID: 33271944 PMCID: PMC7730415 DOI: 10.3390/ijms21239170] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal-tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.
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Affiliation(s)
- Srinivasa P. Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - David Goldstein
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Romano C. Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Jeremy S. Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Minoti V. Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
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13
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Wright JW, Church KJ, Harding JW. Hepatocyte Growth Factor and Macrophage-stimulating Protein "Hinge" Analogs to Treat Pancreatic Cancer. Curr Cancer Drug Targets 2020; 19:782-795. [PMID: 30914029 DOI: 10.2174/1568009619666190326130008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 03/18/2019] [Accepted: 03/20/2019] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the "hinge regions" of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.
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Affiliation(s)
- John W Wright
- Department of Psychology, Washington State University, Pullman, WA, United States.,Department of Integrative Physiology and Neuroscience, and Program in Biotechnology, Washington State University, Pullman, WA, United States
| | - Kevin J Church
- Department of Integrative Physiology and Neuroscience, and Program in Biotechnology, Washington State University, Pullman, WA, United States
| | - Joseph W Harding
- Department of Psychology, Washington State University, Pullman, WA, United States.,Department of Integrative Physiology and Neuroscience, and Program in Biotechnology, Washington State University, Pullman, WA, United States
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14
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Lu W, Li N, Liao F. Identification of Key Genes and Pathways in Pancreatic Cancer Gene Expression Profile by Integrative Analysis. Genes (Basel) 2019; 10:genes10080612. [PMID: 31412643 PMCID: PMC6722756 DOI: 10.3390/genes10080612] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 07/31/2019] [Accepted: 08/07/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Pancreatic cancer is one of the malignant tumors that threaten human health. Methods: The gene expression profiles of GSE15471, GSE19650, GSE32676 and GSE71989 were downloaded from the gene expression omnibus database including pancreatic cancer and normal samples. The differentially expressed genes between the two types of samples were identified with the Limma package using R language. The gene ontology functional and pathway enrichment analyses of differentially-expressed genes were performed by the DAVID software followed by the construction of a protein–protein interaction network. Hub gene identification was performed by the plug-in cytoHubba in cytoscape software, and the reliability and survival analysis of hub genes was carried out in The Cancer Genome Atlas gene expression data. Results: The 138 differentially expressed genes were significantly enriched in biological processes including cell migration, cell adhesion and several pathways, mainly associated with extracellular matrix-receptor interaction and focal adhesion pathway in pancreatic cancer. The top hub genes, namely thrombospondin 1, DNA topoisomerase II alpha, syndecan 1, maternal embryonic leucine zipper kinase and proto-oncogene receptor tyrosine kinase Met were identified from the protein–protein interaction network. The expression levels of hub genes were consistent with data obtained in The Cancer Genome Atlas. DNA topoisomerase II alpha, syndecan 1, maternal embryonic leucine zipper kinase and proto-oncogene receptor tyrosine kinase Met were significantly linked with poor survival in pancreatic adenocarcinoma. Conclusions: These hub genes may be used as potential targets for pancreatic cancer diagnosis and treatment.
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Affiliation(s)
- Wenzong Lu
- Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi'an Technological University, Xi'an 710021, China.
| | - Ning Li
- Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi'an Technological University, Xi'an 710021, China
| | - Fuyuan Liao
- Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi'an Technological University, Xi'an 710021, China
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15
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Lakkakula BVKS, Farran B, Lakkakula S, Peela S, Yarla NS, Bramhachari PV, Kamal MA, Saddala MS, Nagaraju GP. Small molecule tyrosine kinase inhibitors and pancreatic cancer—Trials and troubles. Semin Cancer Biol 2019; 56:149-167. [PMID: 30314681 DOI: 10.1016/j.semcancer.2018.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
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16
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Norleual, a hepatocyte growth factor and macrophage stimulating protein dual antagonist, increases pancreatic cancer sensitivity to gemcitabine. Anticancer Drugs 2019; 29:295-306. [PMID: 29389804 DOI: 10.1097/cad.0000000000000598] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients.
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17
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MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk. Int J Mol Sci 2018; 19:ijms19123920. [PMID: 30544501 PMCID: PMC6321305 DOI: 10.3390/ijms19123920] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/04/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023] Open
Abstract
The ‘onco-receptor’ MET (Hepatocyte Growth Factor Receptor) is involved in the activation of the invasive growth program that is essential during embryonic development and critical for wound healing and organ regeneration during adult life. When aberrantly activated, MET and its stroma-secreted ligand HGF (Hepatocyte Growth Factor) concur to tumor onset, progression, and metastasis in solid tumors, thus representing a relevant target for cancer precision medicine. In the vast majority of tumors, wild-type MET behaves as a ‘stress-response’ gene, and relies on ligand stimulation to sustain cancer cell ‘scattering’, invasion, and protection form apoptosis. Moreover, the MET/HGF axis is involved in the crosstalk between cancer cells and the surrounding microenvironment. Pancreatic cancer (namely, pancreatic ductal adenocarcinoma, PDAC) is an aggressive malignancy characterized by an abundant stromal compartment that is associated with early metastases and resistance to conventional and targeted therapies. Here, we discuss the role of the MET/HGF axis in tumor progression and dissemination considering as a model pancreatic cancer, and provide a proof of concept for the application of dual MET/HGF inhibition as an adjuvant therapy in pancreatic cancer patients.
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18
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Chen ST, Kuo TC, Liao YY, Lin MC, Tien YW, Huang MC. Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. Oncogene 2018; 37:6041-6053. [PMID: 29993037 PMCID: PMC6237765 DOI: 10.1038/s41388-018-0403-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/28/2018] [Accepted: 06/14/2018] [Indexed: 12/18/2022]
Abstract
Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.
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Affiliation(s)
- Syue-Ting Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Yu Liao
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Chun Lin
- Department of Otolaryngology, National Taiwan University Hospital, Hsinchu, Hsinchu, Taiwan
- National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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19
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Lazzari G, Nicolas V, Matsusaki M, Akashi M, Couvreur P, Mura S. Multicellular spheroid based on a triple co-culture: A novel 3D model to mimic pancreatic tumor complexity. Acta Biomater 2018; 78:296-307. [PMID: 30099198 DOI: 10.1016/j.actbio.2018.08.008] [Citation(s) in RCA: 167] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 07/11/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022]
Abstract
The preclinical drug screening of pancreatic cancer treatments suffers from the absence of appropriate models capable to reproduce in vitro the heterogeneous tumor microenvironment and its stiff desmoplasia. Driven by this pressing need, we describe in this paper the conception and the characterization of a novel 3D tumor model consisting of a triple co-culture of pancreatic cancer cells (PANC-1), fibroblasts (MRC-5) and endothelial cells (HUVEC), which assembled to form a hetero-type multicellular tumor spheroid (MCTS). By histological analyses and Selective Plain Illumination Microscopy (SPIM) we have monitored the spatial distribution of each cell type and the evolution of the spheroid composition. Results revealed the presence of a core rich in fibroblasts and fibronectin in which endothelial cells were homogeneously distributed. The integration of the three cell types enabled to reproduce in vitro with fidelity the influence of the surrounding environment on the sensitivity of cancer cells to chemotherapy. To our knowledge, this is the first time that a scaffold-free pancreatic cancer spheroid model combining both tumor and multiple stromal components has been designed. It holds the possibility to become an advantageous tool for a pertinent assessment of the efficacy of various therapeutic strategies. STATEMENT OF SIGNIFICANCE Pancreatic tumor microenvironment is characterized by abundant fibrosis and aberrant vasculature. Aiming to reproduce in vitro these features, cancer cells have been already co-cultured with fibroblasts or endothelial cells separately but the integration of both these essential components of the pancreatic tumor microenvironment in a unique system, although urgently needed, was still missing. In this study, we successfully integrated cellular and acellular microenvironment components (i.e., fibroblasts, endothelial cells, fibronectin) in a hetero-type scaffold-free multicellular tumor spheroid. This new 3D triple co-culture model closely mimicked the resistance to treatments observed in vivo, resulting in a reduction of cancer cell sensitivity to the anticancer treatment.
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20
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Noguchi K, Konno M, Eguchi H, Kawamoto K, Mukai R, Nishida N, Koseki J, Wada H, Akita H, Satoh T, Marubashi S, Nagano H, Doki Y, Mori M, Ishii H. c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. Oncol Lett 2018; 16:1892-1898. [PMID: 30008881 DOI: 10.3892/ol.2018.8793] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/28/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer.
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Affiliation(s)
- Kozo Noguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ryouta Mukai
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shigeru Marubashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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21
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Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans 2017; 45:229-236. [PMID: 28202677 DOI: 10.1042/bst20160387] [Citation(s) in RCA: 376] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/13/2016] [Accepted: 12/08/2016] [Indexed: 02/07/2023]
Abstract
Cancer-associated fibroblasts (CAFs) are major components of the surrounding stroma of carcinomas that emerge in the tumor microenvironment as a result of signals derived from the cancer cells. Biochemical cross-talk between cancer cells and CAFs as well as mechanical remodeling of the stromal extracellular matrix (ECM) by CAFs are important contributors to tumor cell migration and invasion, which are critical for cancer progression from a primary tumor to metastatic disease. In this review, we discuss key paracrine signaling pathways between CAFs and cancer cells that promote cancer cell migration and invasion. In addition, we discuss physical changes that CAFs exert on the stromal ECM to facilitate migration and invasion of cancer cells.
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22
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Chen C, Wang X, Fang J, Xue J, Xiong X, Huang Y, Hu J, Ling K. EGFR-induced phosphorylation of type Iγ phosphatidylinositol phosphate kinase promotes pancreatic cancer progression. Oncotarget 2017; 8:42621-42637. [PMID: 28388589 PMCID: PMC5522093 DOI: 10.18632/oncotarget.16730] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 01/24/2017] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is one of the deadliest malignancies and effective treatment has always been lacking. In current study, we investigated how the type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) participates in the progression of pancreatic ductal adenocarcinoma (PDAC) for novel therapeutic potentials against this lethal disease. We found that PIPKIγ is up-regulated in all tested PDAC cell lines. The growth factor (including EGFR)-induced tyrosine phosphorylation of PIPKIγ is significantly elevated in in situ and metastatic PDAC tissues. Loss of PIPKIγ inhibits the aggressiveness of PDAC cells by restraining the activities of AKT and STAT3, as well as MT1-MMP expression. Therefore when planted into the pancreas of nude mice, PIPKIγ-depleted PDAC cells exhibits substantially repressed tumor growth and metastasis comparing to control PDAC cells. Results from further studies showed that the phosphorylation-deficient PIPKIγ mutant, unlike its wild-type counterpart, cannot rescue PDAC progression inhibited by PIPKIγ depletion. These findings indicate that PIPKIγ, functioning downstream of EGFR signaling, is critical to the progression of PDAC, and suggest that PIPKIγ is potentially a valuable therapeutic target for PDAC treatment.
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Affiliation(s)
- Chunhua Chen
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
- These authors have contributed equally to this work
| | - Xiangling Wang
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
- These authors have contributed equally to this work
| | - Juemin Fang
- Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- These authors have contributed equally to this work
| | - Junli Xue
- Shanghai East Hospital, Tongji University, Shanghai, China
| | - Xunhao Xiong
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Yan Huang
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jinghua Hu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kun Ling
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
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