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Mohan CD, Shanmugam MK, Gowda SGS, Chinnathambi A, Rangappa KS, Sethi G. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155379. [PMID: 38503157 DOI: 10.1016/j.phymed.2024.155379] [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: 10/26/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
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Affiliation(s)
- Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226 001, India
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kanchugarakoppal S Rangappa
- Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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Wang Q, Li Y, Yuan H, Peng L, Dai Z, Sun Y, Liu R, Li W, Li J, Zhu C. Hypoxia preconditioning of human amniotic mesenchymal stem cells enhances proliferation and migration and promotes their homing via the HGF/C-MET signaling axis to augment the repair of acute liver failure. Tissue Cell 2024; 87:102326. [PMID: 38442547 DOI: 10.1016/j.tice.2024.102326] [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: 10/22/2023] [Revised: 01/17/2024] [Accepted: 02/06/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND Transplantation of mesenchymal stem cells (MSCs) is a newly developed strategy for treating acute liver failure (ALF). Nonetheless, the low survival rate of MSCs after transplantation and their poor homing to damaged tissues limit the clinical application of MSCs. The research assessed whether hypoxic preconditioning (HPC) can improve the biological activity of human amniotic mesenchymal stem cells (hA-MSCs), promote their homing ability to the liver of mice with ALF, and influence liver tissue repair. METHODS Flow cytometry, CCK8, Transwell, and Western blotting assays were conducted to assess the effects of hypoxic preconditioning on the phenotype, proliferation, and migration of hA-MSCs and the changes in the c-Met and CXCR4 gene expression levels were studied. To evaluate the effects of the transplantation of hypoxic preconditioning of hA-MSCs on the homing and repair of D-galactosamine (D-GalN)/LPS-induced ALF, the mechanism was elucidated by adding c-Met, CXCR4-specific blockers (SU11274 and AMD3100). RESULTS After hypoxia pretreatment (1% oxygen volume fraction), hA-MSCs maintained the morphological characteristics of adherence and vortex colony growth and showed high CD44, CD90, and CD105 and low CD31, CD34, and CD45 expression levels. Hypoxic preconditioning of hA-MSCs significantly increased their proliferation and migration and highly expressed the c-Met and CXCR4 genes. In vivo and in vitro, this migration-promoting effect was suppressed by the c-Met specific blocker SU11274. In the acute liver failure mouse model, the HGF expression level was considerably elevated in the liver than that in the serum, lungs and kidneys. The transplantation of hypoxic preconditioned hA-MSCs introduced a remarkable improvement in the liver function and survival rate of mice with ALF and enhanced the anti-apoptosis ability of liver cells. The anti-apoptotic enhancing effect of hypoxic preconditioning was suppressed by the c-Met specific blocker SU11274. Hypoxic hA-MSCs administration was observed to have considerably increased the fluorescent cells in the liver than that recorded after administering normal oxygen-hA-MSCs. The number of hepatic fluorescent cells decreased remarkably after adding the c-Met inhibitor SU11274, compared to that recorded after hypoxic pretreatment, whereas the effect of c-Met inhibitor SU11274 on normal oxygen-hA-MSCs was not significant. CONCLUSIONS Hypoxic preconditioning depicted no impact on the morphology and phenotype features of the human amniotic mesenchymal stem cells, but it can promote their proliferation, migration, anti-apoptotic effect, and homing rate and improve the repair of acute liver failure, which might be mediated by the HGF/c-Met signaling axis.
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Affiliation(s)
- Qian Wang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuwen Li
- Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Yuan
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Linya Peng
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zixing Dai
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ye Sun
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Liu
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Wenting Li
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Jun Li
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Chuanlong Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, China.
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Tavares-Valente D, Cannone S, Greco MR, Carvalho TMA, Baltazar F, Queirós O, Agrimi G, Reshkin SJ, Cardone RA. Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell. Cancers (Basel) 2023; 15:3868. [PMID: 37568684 PMCID: PMC10417137 DOI: 10.3390/cancers15153868] [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: 05/24/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
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Affiliation(s)
- Diana Tavares-Valente
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Stefania Cannone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Tiago Miguel Amaral Carvalho
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Braga, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Gennaro Agrimi
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy; (S.C.); (M.R.G.); (T.M.A.C.); (G.A.); (R.A.C.)
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Modica C, Cortese M, Bersani F, Lombardi AM, Napoli F, Righi L, Taulli R, Basilico C, Vigna E. Genetic Ablation of the MET Oncogene Defines a Crucial Role of the HGF/MET Axis in Cell-Autonomous Functions Driving Tumor Dissemination. Cancers (Basel) 2023; 15:2742. [PMID: 37345079 DOI: 10.3390/cancers15102742] [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: 12/01/2022] [Revised: 05/03/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
Cancer cell dissemination is sustained by cell-autonomous and non-cell-autonomous functions. To disentangle the role of HGF (Hepatocyte Growth Factor) and MET ligand/receptor axis in this complex process, we genetically knocked out the MET gene in cancer cells in which MET is not the oncogenic driver. In this way, we evaluated the contribution of the HGF/MET axis to cancer cell dissemination independently of its direct activities in cells of the tumor microenvironment. The lack of MET expression in MET-/- cells has been proved by molecular characterization. From a functional point of view, HGF stimulation of MET-/- cancer cells was ineffective in eliciting intracellular signaling and in sustaining biological functions predictive of malignancy in vitro (i.e., anchorage-independent growth, invasion, and survival in the absence of matrix adhesion). Cancer cell dissemination was assessed in vivo, evaluating: (i) the ability of MET-/- lung carcinoma cells to colonize the lungs following intravenous injection and (ii) the spontaneous dissemination to distant organs of MET-/- pancreatic carcinoma cells upon orthotopic injection. In both experimental models, MET ablation affects the time of onset, the number, and the size of metastatic lesions. These results define a crucial contribution of the HGF/MET axis to cell-autonomous functions driving the metastatic process.
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Affiliation(s)
- Chiara Modica
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, TO, Italy
| | - Marco Cortese
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10043 Orbassano, TO, Italy
| | - Francesca Bersani
- Department of Oncology, University of Torino, 10043 Orbassano, TO, Italy
| | | | - Francesca Napoli
- Department of Oncology, University of Torino, 10043 Orbassano, TO, Italy
| | - Luisella Righi
- Department of Oncology, University of Torino, 10043 Orbassano, TO, Italy
| | - Riccardo Taulli
- Department of Oncology, University of Torino, 10043 Orbassano, TO, Italy
| | | | - Elisa Vigna
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10043 Orbassano, TO, Italy
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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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Wani AK, Akhtar N, Mir TUG, Singh R, Jha PK, Mallik SK, Sinha S, Tripathi SK, Jain A, Jha A, Devkota HP, Prakash A. Targeting Apoptotic Pathway of Cancer Cells with Phytochemicals and Plant-Based Nanomaterials. Biomolecules 2023; 13:biom13020194. [PMID: 36830564 PMCID: PMC9953589 DOI: 10.3390/biom13020194] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/13/2023] [Accepted: 01/15/2023] [Indexed: 01/20/2023] Open
Abstract
Apoptosis is the elimination of functionally non-essential, neoplastic, and infected cells via the mitochondrial pathway or death receptor pathway. The process of apoptosis is highly regulated through membrane channels and apoptogenic proteins. Apoptosis maintains cellular balance within the human body through cell cycle progression. Loss of apoptosis control prolongs cancer cell survival and allows the accumulation of mutations that can promote angiogenesis, promote cell proliferation, disrupt differentiation, and increase invasiveness during tumor progression. The apoptotic pathway has been extensively studied as a potential drug target in cancer treatment. However, the off-target activities of drugs and negative implications have been a matter of concern over the years. Phytochemicals (PCs) have been studied for their efficacy in various cancer cell lines individually and synergistically. The development of nanoparticles (NPs) through green synthesis has added a new dimension to the advancement of plant-based nanomaterials for effective cancer treatment. This review provides a detailed insight into the fundamental molecular pathways of programmed cell death and highlights the role of PCs along with the existing drugs and plant-based NPs in treating cancer by targeting its programmed cell death (PCD) network.
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Affiliation(s)
- Atif Khurshid Wani
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India
| | - Nahid Akhtar
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India
| | - Tahir ul Gani Mir
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India
| | - Rattandeep Singh
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India
| | - Prakash Kumar Jha
- Feed the Future Innovation Lab for Collaborative Research on Sustainable Intensification, Kansas State University, Manhattan, KS 66506, USA
| | - Shyam Kumar Mallik
- College of Medical and Allied Sciences, Purbanchal University, Morang 56600, Nepal
| | - Shruti Sinha
- UNC Blood Research Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Surya Kant Tripathi
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Abha Jain
- Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Aprajita Jha
- School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 751024, India
| | - Hari Prasad Devkota
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
- Headquarters for Admissions and Education, Kumamoto University, Kurokami, 2-39-1, Chuo-ku, Kumamoto 860-8555, Japan
- Pharmacy Program, Gandaki University, Pokhara 33700, Nepal
- Correspondence: (H.P.D.); (A.P.)
| | - Ajit Prakash
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
- Correspondence: (H.P.D.); (A.P.)
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Carvalho TMA, Di Molfetta D, Greco MR, Koltai T, Alfarouk KO, Reshkin SJ, Cardone RA. Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches. Cancers (Basel) 2021; 13:6135. [PMID: 34885243 PMCID: PMC8657427 DOI: 10.3390/cancers13236135] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/14/2022] Open
Abstract
Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.
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Affiliation(s)
- Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | | | - Khalid O. Alfarouk
- Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munwarah 42316, Saudi Arabia;
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Rosa A. Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
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Gaustad JV, Rofstad EK. Assessment of Intratumor Heterogeneity in Parametric Dynamic Contrast-Enhanced MR Images: A Comparative Study of Novel and Established Methods. Front Oncol 2021; 11:722773. [PMID: 34621674 PMCID: PMC8490776 DOI: 10.3389/fonc.2021.722773] [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: 06/09/2021] [Accepted: 09/06/2021] [Indexed: 11/13/2022] Open
Abstract
Intratumor heterogeneity is associated with aggressive disease and poor survival rates in several types of cancer. A novel method for assessing intratumor heterogeneity in medical images, named the spatial gradient method, has been developed in our laboratory. In this study, we measure intratumor heterogeneity in Ktrans maps derived by dynamic contrast-enhanced magnetic resonance imaging using the spatial gradient method, and we compare the performance of the novel method with that of histogram analyses and texture analyses using the Haralick method. Ktrans maps of 58 untreated and sunitinib-treated pancreatic ductal adenocaricoma (PDAC) xenografts from two PDAC models were investigated. Intratumor heterogeneity parameters derived by the spatial gradient method were sensitive to tumor line differences as well as sunitinib-induced changes in intratumor heterogeneity. Furthermore, the parameters provided additional information to the median value and were not severely affected by imaging noise. The parameters derived by histogram analyses were insensitive to spatial heterogeneity and were strongly correlated to the median value, and the Haralick features were severely influenced by imaging noise and did not differentiate between untreated and sunitinib-treated tumors. The spatial gradient method was superior to histogram analyses and Haralick features for assessing intratumor heterogeneity in Ktrans maps of untreated and sunitinib-treated PDAC xenografts, and can possibly be used to assess intratumor heterogeneity in other medical images and to evaluate effects of other treatments as well.
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Affiliation(s)
- Jon-Vidar Gaustad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Einar K Rofstad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
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Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13174487. [PMID: 34503294 PMCID: PMC8430573 DOI: 10.3390/cancers13174487] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Among all types of cancer, Pancreatic Ductal Adenocarcinoma (PDAC) has one of the lowest survival rates, partly due to the failure of current chemotherapeutics. This treatment failure can be attributed to the complicated nature of the tumor microenvironment, where the rich fibro-inflammatory responses can hinder drug delivery and efficacy at the tumor site. Moreover, the high molecular variations in PDAC create a large heterogeneity in the tumor microenvironment among patients. Current in vivo and in vitro options for drug testing are mostly ineffective in recapitulating the complex cellular interactions and individual variations in the PDAC tumor microenvironment, and as a result, they fail to provide appropriate models for individualized drug screening. Organ-on-a-chip technology combined with patient-derived organoids may provide the opportunity for developing personalized treatment options in PDAC. Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.
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HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13143519. [PMID: 34298732 PMCID: PMC8305254 DOI: 10.3390/cancers13143519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/30/2021] [Accepted: 07/10/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary It has been previously shown that activation of the MET receptor by its ligand, the hepatocyte growth factor (HGF), modulates the tumor-stroma cross-talk in models of pancreatic cancer. We now wish to cast light on the molecular mechanisms by which this ligand/receptor pair sustains the interaction between cancer cells and the tumor microenviroment. To this end, we compared data obtained by large-scale analysis of gene expression in pancreatic cancer cells grown in the presence of HGF versus cells grown in the presence of HGF and treated with specific inhibitors of HGF/MET signaling. By clustering differentially expressed genes according to functional groups, we identified candidate genes involved in the process. Among these, tenascin C was selected due to its activity in sustaining the malignant phenotype. Our results highlight a new role for tenascin C, which could represent the operative arm through which MET promotes activation of the stromal compartment in pancreatic cancer. Abstract Pancreatic ductal adenocarcinoma is an aggressive tumor characterized by the presence of an abundant stromal compartment contributing significantly to the malignant phenotype. Pancreatic stellate cells are peculiar fibroblasts present in the stroma and represent the predominant source of extracellular matrix proteins, pro-inflammatory cytokines, and growth factors, including hepatocyte growth factor (HGF). Exploiting a co-culture system of human pancreatic stellate cells and cancer cells, we demonstrated that fibroblast activation was reduced upon HGF/MET axis inhibition. To unveil the signaling pathways sustaining stroma modulation orchestrated by MET activation in the tumor, we analyzed the gene expression profile in pancreatic cancer cells stimulated with HGF and treated with HGF/MET inhibitors. Transcriptome analysis showed that, among all the genes modulated by HGF, a subset of 125 genes was restored to the basal level following treatment with the inhibitors. By examining these genes via ingenuity pathway analysis, tenascin C emerged as a promising candidate linking MET signaling and tumor microenvironment. MET-dependent tenascin C modulation in pancreatic cancer cells was validated at RNA and protein levels both in vitro and in vivo. In conclusion, this work identifies tenascin C as a gene modulated by MET activation, suggesting a role in MET-mediated tumor-stroma interplay occurring during pancreatic tumor progression.
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Ventura M, Bernards N, De Souza R, Fricke IB, Hendriks BS, Fitzgerald JB, Lee H, Klinz SG, Zheng J. Longitudinal PET Imaging to Monitor Treatment Efficacy by Liposomal Irinotecan in Orthotopic Patient-Derived Pancreatic Tumor Models of High and Low Hypoxia. Mol Imaging Biol 2021; 22:653-664. [PMID: 31482415 PMCID: PMC7782415 DOI: 10.1007/s11307-019-01374-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Purpose Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. Procedures Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. Results The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. Conclusions Hypoxia modulation may play a role in nal-IRI’s mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response. Electronic supplementary material The online version of this article (10.1007/s11307-019-01374-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Manuela Ventura
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | - Nicholas Bernards
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | - Raquel De Souza
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | - Inga B Fricke
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | | | | | - Helen Lee
- Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Stephan G Klinz
- Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA
- Ipsen Bioscience, Cambridge, MA, USA
| | - Jinzi Zheng
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada.
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
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12
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Varayathu H, Sarathy V, Thomas BE, Mufti SS, Naik R. Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research. Front Oncol 2021; 11:559161. [PMID: 34123767 PMCID: PMC8193928 DOI: 10.3389/fonc.2021.559161] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 04/30/2021] [Indexed: 12/22/2022] Open
Abstract
Immune checkpoint inhibitor therapy has revolutionized the field of cancer immunotherapy. Even though it has shown a durable response in some solid tumors, several patients do not respond to these agents, irrespective of predictive biomarker (PD-L1, MSI, TMB) status. Multiple preclinical, as well as early-phase clinical studies are ongoing for combining immune checkpoint inhibitors with anti-cancer and/or non-anti-cancer drugs for beneficial therapeutic interactions. In this review, we discuss the mechanistic basis behind the combination of immune checkpoint inhibitors with other drugs currently being studied in early phase clinical studies including conventional chemotherapy drugs, metronomic chemotherapy, thalidomide and its derivatives, epigenetic therapy, targeted therapy, inhibitors of DNA damage repair, other small molecule inhibitors, anti-tumor antibodies hormonal therapy, multiple checkpoint Inhibitors, microbiome therapeutics, oncolytic viruses, radiotherapy, drugs targeting myeloid-derived suppressor cells, drugs targeting Tregs, drugs targeting renin-angiotensin system, drugs targeting the autonomic nervous system, metformin, etc. We also highlight how translational research strategies can help better understand the true therapeutic potential of such combinations.
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Affiliation(s)
- Hrishi Varayathu
- Department of Translational Medicine and Therapeutics, HealthCare Global Enterprises Limited, Bangalore, India
| | - Vinu Sarathy
- Department of Medical Oncology, HealthCare Global Enterprises Limited, Bangalore, India
| | - Beulah Elsa Thomas
- Department of Clinical Pharmacology, HealthCare Global Enterprises Limited, Bangalore, India
| | - Suhail Sayeed Mufti
- Department of Translational Medicine and Therapeutics, HealthCare Global Enterprises Limited, Bangalore, India
| | - Radheshyam Naik
- Department of Medical Oncology, HealthCare Global Enterprises Limited, Bangalore, India
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13
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Modica C, Basilico C, Chiriaco C, Borrelli N, Comoglio PM, Vigna E. A receptor-antibody hybrid hampering MET-driven metastatic spread. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:32. [PMID: 33446252 PMCID: PMC7807714 DOI: 10.1186/s13046-020-01822-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022]
Abstract
Background The receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (MET addiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (MET expedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition. Methods In this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by ‘head-to-tail’ or ‘tail-to-head’ fusion of a single chain Fab derived from the DN30 MET antibody with a recombinant ‘ad-hoc’ engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope. Results The hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions. Conclusion These results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-020-01822-5.
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Affiliation(s)
- Chiara Modica
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, TO, Italy
| | - Cristina Basilico
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, TO, Italy.
| | - Cristina Chiriaco
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, TO, Italy
| | - Nicla Borrelli
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, TO, Italy
| | - Paolo M Comoglio
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, TO, Italy
| | - Elisa Vigna
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, TO, Italy.,Department of Oncology, University of Turin, Turin, Italy
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Liu D, Steins A, Klaassen R, van der Zalm AP, Bennink RJ, van Tienhoven G, Besselink MG, Bijlsma MF, van Laarhoven HWM. Soluble Compounds Released by Hypoxic Stroma Confer Invasive Properties to Pancreatic Ductal Adenocarcinoma. Biomedicines 2020; 8:biomedicines8110444. [PMID: 33105540 PMCID: PMC7690284 DOI: 10.3390/biomedicines8110444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/17/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies.
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Affiliation(s)
- Dajia Liu
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Anne Steins
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Remy Klaassen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Amber P. van der Zalm
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - Roel J. Bennink
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Geertjan van Tienhoven
- Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Marc G. Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-(0)20-5664824
| | - Hanneke W. M. van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
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LC3C-Mediated Autophagy Selectively Regulates the Met RTK and HGF-Stimulated Migration and Invasion. Cell Rep 2020; 29:4053-4068.e6. [PMID: 31851933 DOI: 10.1016/j.celrep.2019.11.063] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 09/18/2019] [Accepted: 11/14/2019] [Indexed: 12/15/2022] Open
Abstract
The Met/hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) is deregulated in many cancers and is a recognized target for cancer therapies. Following HGF stimulation, the signaling output of Met is tightly controlled by receptor internalization and sorting for degradation or recycling. Here, we uncover a role for autophagy in selective degradation of Met and regulation of Met-dependent cell migration and invasion. Met engagement with the autophagic pathway is dependent on complex formation with the mammalian ATG8 family member MAP1LC3C. LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, allowing identification of LC3C domains required for rescue. Cancer cells with low LC3C levels show enhanced Met stability, signaling, and cell invasion. These findings provide mechanistic insight into RTK recruitment to autophagosomes and establish distinct roles for ATG8 proteins in this process, supporting that differential expression of ATG8 proteins can shape the functional consequences of autophagy in cancer development and progression.
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Tian G, Li G, Liu P, Wang Z, Li N. Glycolysis-Based Genes Associated with the Clinical Outcome of Pancreatic Ductal Adenocarcinoma Identified by The Cancer Genome Atlas Data Analysis. DNA Cell Biol 2020; 39:417-427. [PMID: 31968179 DOI: 10.1089/dna.2019.5089] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadly tumors in digestive tract tumors. Although there has been advancement in PDAC treatment, its prognosis still remains unsatisfactory, mainly because of dismal diagnosis. This article aims to develop new prognostic factors related to energy metabolism in PDAC and to use these genes for novel risk stratification. Hundred fifty messenger RNA (mRNA) expression profiles and clinicopathological data of PDAC were downloaded from The Cancer Genome Atlas dataset. The glycolysis pathway was the significant pathway based on the gene set enrichment analysis. We chose the glycolysis pathway-related 176 genes for further analysis. Multivariate Cox regression analysis and forward stepwise Cox regression model established a novel three-gene glycolytic signature (including MET, B3GNT3, and SPAG4) for PDAC patients' prognosis prediction. All 150 patients were classified into two groups by the median risk score. High-risk group had a worse outcome compared to the low-risk group. The risk score was also significantly correlated with age and radiotherapy. A nomogram, including the glycolytic gene signature, has shown some clinical net benefit for overall survival prediction. We also validated the validity and reliability in the Puleo dataset. This novel gene expression signature may be involved in the pathophysiology and used for risk stratification and prognosis prediction in PDAC.
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Affiliation(s)
- Guangwei Tian
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Guang Li
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Peipei Liu
- Department of Histology and Embryology, Shenyang Medical College, Shenyang, China
| | - Zihui Wang
- Department of Neuroscience, Cleveland Clinic, Cleveland, Ohio
| | - Nan Li
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China
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Gaustad JV, Simonsen TG, Wegner CS, Rofstad EK. Vascularization, Oxygenation, and the Effect of Sunitinib Treatment in Pancreatic Ductal Adenocarcinoma Xenografts. Front Oncol 2019; 9:845. [PMID: 31555596 PMCID: PMC6727195 DOI: 10.3389/fonc.2019.00845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/19/2019] [Indexed: 12/29/2022] Open
Abstract
The purpose of the study was to investigate vascularization, oxygenation, and the effect of sunitinib treatment in pancreatic ductal adenocarcinoma (PDAC). BxPC-3 and Capan-2 xenografts grown in dorsal window chambers were used as preclinical models of human PDAC. Tumor angiogenesis and the morphology and function of tumor vascular networks were studied by intravital microscopy, and tumor hypoxia was assessed by immunohistochemistry. The PDAC models differed in vessel distribution and oxygenation, and the differences were induced by the initial tumor angiogenesis. In both models, sunitinib treatment reduced intratumor and peritumor vessel densities by selectively removing small-diameter vessels. Sunitinb treatment resulted in a general decrease in vessel density and scattered hypoxia in BxPC-3 tumors, and depleted most vessels and induced massive hypoxia in central parts of Capan-2 tumors. The study demonstrates that PDAC xenografts can differ in vascularization, and the differences can impact oxygenation and effects of treatment. Neoadjuvant sunitinib treatment is inappropriate in combination with conventional therapy for human PDACs resembling the PDAC xenografts used here, because sunitinib-induced hypoxia can impair the effect of most conventional therapies.
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Affiliation(s)
- Jon-Vidar Gaustad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Trude G Simonsen
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Catherine S Wegner
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Einar K Rofstad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
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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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Kanat O, Ertas H. Shattering the castle walls: Anti-stromal therapy for pancreatic cancer. World J Gastrointest Oncol 2018; 10:202-210. [PMID: 30147846 PMCID: PMC6107476 DOI: 10.4251/wjgo.v10.i8.202] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/19/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer (PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular (e.g., stellate cells) and acellular (e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of anti-stromal therapies in the management of metastatic PC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
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Leppänen J, Helminen O, Huhta H, Kauppila JH, Isohookana J, Haapasaari KM, Parkkila S, Saarnio J, Lehenkari PP, Karttunen TJ. Weak HIF-1alpha expression indicates poor prognosis in resectable pancreatic ductal adenocarcinoma. World J Surg Oncol 2018; 16:127. [PMID: 29973215 PMCID: PMC6033289 DOI: 10.1186/s12957-018-1432-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 06/26/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND HIF-1alpha and CAIX proteins are commonly expressed under hypoxic conditions, but other regulatory factors have been described as well. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and strong stromal reaction and has a dismal prognosis with the currently available treatment modalities. METHODS We investigated the expression and prognostic role of HIF-1alpha and CAIX in PDAC series from Northern Finland (n = 69) using immunohistochemistry. RESULTS In our PDAC cases, 95 and 85% showed HIF-1alpha and CAIX expression, respectively. Low HIF-1alpha expression correlated with poor prognosis, and multivariate analysis identified weak HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216-3.893; p = 0.009). There was no correlation between HIF-1alpha and CAIX expression levels, and the latter did not relate with survival. CONCLUSIONS Our findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis. The biological mechanisms remain speculative, but such an unexpected relation with prognosis and absence of correlation between HIF-1alpha and CAIX suggests that the prognostic association of HIF-1alpha may not directly be linked with hypoxia. Accordingly, the role of HIF-1alpha might be more complex than previously thought and the use of this marker as a hypoxia-related prognostic factor should be addressed with caution.
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Affiliation(s)
- Joni Leppänen
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
- 0000 0001 0941 4873grid.10858.34Department of Pathology, University of Oulu, PO-Box 5000, 90014 Oulu, Finland
| | - Olli Helminen
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Heikki Huhta
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Joonas H. Kauppila
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
- 0000 0004 1937 0626grid.4714.6Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Joel Isohookana
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Kirsi-Maria Haapasaari
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Seppo Parkkila
- 0000 0001 2314 6254grid.5509.9School of Medicine, University of Tampere, 33014 Tampere, Finland
- 0000 0004 0628 2985grid.412330.7Fimlab Ltd, Tampere University Hospital, 33520 Tampere, Finland
| | - Juha Saarnio
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Petri P. Lehenkari
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Tuomo J. Karttunen
- 0000 0001 0941 4873grid.10858.34Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
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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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22
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Knudsen ES, Balaji U, Freinkman E, McCue P, Witkiewicz AK. Unique metabolic features of pancreatic cancer stroma: relevance to the tumor compartment, prognosis, and invasive potential. Oncotarget 2018; 7:78396-78411. [PMID: 27623078 PMCID: PMC5346648 DOI: 10.18632/oncotarget.11893] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 07/13/2016] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The aggressiveness and therapeutic recalcitrance of this malignancy has been attributed to multiple factors including the influence of an active desmoplastic stroma. How the stromal microenvironment of PDAC contributes to the fatal nature of this disease is not well defined. In the analysis of clinical specimens, we observed diverse expression of the hypoxic marker carbonic anhydrase IX and the lactate transporter MCT4 in the stromal compartment. These stromal features were associated with the epithelial to mesenchymal phenotype in PDAC tumor cells, and with shorter patient survival. Cultured cancer-associated fibroblasts (CAFs) derived from primary PDAC exhibited a high basal level of hypoxia inducible factor 1a (HIF1α) that was both required and sufficient to modulate the expression of MCT4. This event was associated with increased transcription and protein synthesis of HIF1α in CAFs relative to PDAC cell lines, while surprisingly the protein turnover rate was equivalent. CAFs utilized glucose predominantly for glycolytic intermediates, whereas glutamine was the preferred metabolite for the TCA cycle. Unlike PDAC cell lines, CAFs were resistant to glucose withdrawal but sensitive to glutamine depletion. Consistent with the lack of reliance on glucose, CAFs could survive the acute depletion of MCT4. In co-culture and xenograft studies CAFs stimulated the invasive potential and metastatic spread of PDAC cell lines through a mechanism dependent on HIF1α and MCT4. Together, these data indicate that stromal metabolic features influence PDAC tumor cells to promote invasiveness and metastatic potential and associate with poor outcome in patients with PDAC.
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Affiliation(s)
- Erik S Knudsen
- McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.,University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.,Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - Uthra Balaji
- McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Elizaveta Freinkman
- Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Peter McCue
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Agnieszka K Witkiewicz
- McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.,University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.,Department of Medicine, University of Arizona, Tucson, AZ, USA.,Department of Pathology, University of Arizona, Tucson, AZ, USA
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23
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Wegner CS, Hauge A, Gaustad JV, Andersen LMK, Simonsen TG, Galappathi K, Rofstad EK. Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts. Acta Oncol 2017; 56:1754-1762. [PMID: 28661213 DOI: 10.1080/0284186x.2017.1343494] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor outcome. Resistance to treatment is associated with impaired vascularity, extensive hypoxia, and interstitial hypertension. In this study, the potential of dynamic contrast-enhanced (DCE)-MRI as a method for assessing the microvascular density (MVD), the fraction of hypoxic tissue, and the interstitial fluid pressure (IFP) of PDACs was investigated. MATERIAL AND METHODS Intramuscular BxPC-3, Capan-2, MIAPaCa-2, and Panc-1 PDAC xenografts were used as preclinical models of human PDACs. DCE-MRI with Gd-DOTA as contrast agent was conducted with a 7.05-T scanner, and the DCE-MRI series were analyzed voxelwise by using the Tofts pharmacokinetic model. Tumor MVD and hypoxia were measured in histological preparations by using pimonidazole as a hypoxia marker and CD31 as a marker of endothelial cells. IFP was measured with a Millar catheter. RESULTS Ktrans (the volume transfer constant of Gd-DOTA) increased with increasing MVD and decreased with increasing hypoxic fraction, but was not associated with IFP. Any association between ve (the fractional distribution volume of Gd-DOTA) and MVD, hypoxic fraction, or IFP could not be detected. CONCLUSIONS This study shows that DCE-MRI is a useful modality for assessing important features of the microenvironment of PDAC xenografts and thus provides the basis for future preclinical and clinical DCE-MRI investigations of PDAC.
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Affiliation(s)
- Catherine S. Wegner
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Anette Hauge
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Jon-Vidar Gaustad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Lise Mari K. Andersen
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Trude G. Simonsen
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Kanthi Galappathi
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Einar K. Rofstad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
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24
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Cuneo KC, Morgan MA, Griffith KA, Hawkins PG, Greenson JK, Ben-Josef E, Lawrence TS, Zalupski MM. Prognostic Value of c-MET Expression in Patients With Pancreatic Cancer Receiving Adjuvant and Neoadjuvant Chemoradiation Therapy. Int J Radiat Oncol Biol Phys 2017; 100:490-497. [PMID: 29229329 DOI: 10.1016/j.ijrobp.2017.10.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 10/04/2017] [Accepted: 10/10/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE To determine the prognostic significance of c-MET expression and develop a predictor of distant failure in patients with resectable pancreatic cancer treated with chemoradiation. METHODS AND MATERIALS We used a tissue microarray to study protein expression by immunohistochemistry in 102 patients treated surgically for pancreatic cancer. Two cores per patient were blindly scored from 0 (no staining) to 3 (strong staining) by a single pathologist. The Kaplan-Meier method was used to determine time to local and distant failure, overall survival, and progression-free survival. P values were calculated with the log-rank test. RESULTS High tumor expression of c-MET was associated with a shorter time to distant failure in patients receiving neoadjuvant (n=23) or neoadjuvant therapy (n=73) (median 8.9 months vs 22.0 months, P=.0010). We then examined the ability of incorporating 2 known biomarkers, thymidylate synthase and DPC4 (SMAD4), with c-MET to risk-stratify patients. This multi-protein predictor divided our cohort into groups of similar numbers and was predictive of distant failure (median 13.4 months vs 24.2 months, P=.0094) but not of local control. CONCLUSION c-MET is potentially predictive of distant failure. Using c-MET, DPC4, and thymidylate synthase, we developed a multi-protein predictor that could be used to risk-stratify patients and guide decisions regarding the sequencing of locoregional and systemic therapies in pancreatic cancer.
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Affiliation(s)
- Kyle C Cuneo
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
| | - Meredith A Morgan
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
| | - Kent A Griffith
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Peter G Hawkins
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
| | - Joel K Greenson
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Edgar Ben-Josef
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
| | - Mark M Zalupski
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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25
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Rucki AA, Xiao Q, Muth S, Chen J, Che X, Kleponis J, Sharma R, Anders RA, Jaffee EM, Zheng L. Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment. Mol Cancer Ther 2017; 16:2399-2409. [PMID: 28864680 DOI: 10.1158/1535-7163.mct-16-0452] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 02/08/2017] [Accepted: 08/25/2017] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment. Mol Cancer Ther; 16(11); 2399-409. ©2017 AACR.
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Affiliation(s)
- Agnieszka A Rucki
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Qian Xiao
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Surgical Oncology, the Second Affiliated Hospital of the Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute, University School of Medicine, Hangzhou, China
| | - Stephen Muth
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jianlin Chen
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xu Che
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Pancreatic and Gastric Surgery Department, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jennifer Kleponis
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rajni Sharma
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Robert A Anders
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Elizabeth M Jaffee
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,The Skip Viragh Center for Pancreatic Cancer, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lei Zheng
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland. .,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,The Skip Viragh Center for Pancreatic Cancer, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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26
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Kim JH, Kim HS, Kim BJ, Lee J, Jang HJ. Prognostic value of c-Met overexpression in pancreatic adenocarcinoma: a meta-analysis. Oncotarget 2017; 8:73098-73104. [PMID: 29069852 PMCID: PMC5641195 DOI: 10.18632/oncotarget.20392] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/07/2017] [Indexed: 12/13/2022] Open
Abstract
The overexpression of c-Met protein has been detected in pancreatic adenocarcinoma (PAC). However, its prognostic impact remains unclear. We performed this meta-analysis to evaluate the prognostic value of c-Met overexpression in PAC. A systematic computerized search of the electronic databases such as PubMed, Embase, and Google Scholar was carried out. From 5 studies, 423 patients who underwent surgical resection for PAC were included in the meta-analysis. Compared with patients with PAC showing low c-Met expression, patients with c-Met-high tumor had significantly worse disease-free survival (hazard ratio = 1.94 [95% confidence interval, 1.46–2.56], P = 0.00001) and overall survival (hazard ratio = 1.86 [95% confidence interval, 1.19–2.91], P = 0.006). In conclusion, this meta-analysis demonstrates that c-Met overexpression is a significant prognostic marker for poor survival in patients who underwent surgical resection for PAC.
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Affiliation(s)
- Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Hyeong Su Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Bum Jun Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea.,Department of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Sungnam 13574, Republic of Korea
| | - Jin Lee
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung 18450, Republic of Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung 18450, Republic of Korea
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27
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Li H, Chen YX, Wen JG, Zhou HH. Metastasis-associated in colon cancer 1: A promising biomarker for the metastasis and prognosis of colorectal cancer. Oncol Lett 2017; 14:3899-3908. [PMID: 28943898 PMCID: PMC5605967 DOI: 10.3892/ol.2017.6670] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 01/10/2017] [Indexed: 12/26/2022] Open
Abstract
Colorectal cancer (CRC) is the fourth most frequent type of malignancy in the world. Metastasis accounts for >90% mortalities in patients with CRC. The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as a novel biomarker for the prediction of metastasis and disease prognosis, particularly for patients with early-stage disease. Previous clinical studies demonstrated that MACC1 expression and polymorphisms in CRC tissues were indicators of metastasis, and that circulating transcripts in plasma were also significantly associated with the survival of patients. The present review describes the use of MACC1 beyond its utility in the clinic. By elucidating the upstream and downstream signal pathways of MACC1, the well-known mechanisms of MACC1-mediated cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) are summarized, as well as the potential signaling pathways. Furthermore, the underlying mechanisms by which the overexpression of MACC1 causes cisplatin resistance are emphasized.
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Affiliation(s)
- He Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan 410078, P.R. China
| | - Yi-Xin Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan 410078, P.R. China
| | - Jia-Gen Wen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan 410078, P.R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan 410078, P.R. China.,Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang, Hunan 421001, P.R. China
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28
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Andersen LMK, Wegner CS, Simonsen TG, Huang R, Gaustad JV, Hauge A, Galappathi K, Rofstad EK. Lymph node metastasis and the physicochemical micro-environment of pancreatic ductal adenocarcinoma xenografts. Oncotarget 2017; 8:48060-48074. [PMID: 28624797 PMCID: PMC5564626 DOI: 10.18632/oncotarget.18231] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 05/01/2017] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) patients develop lymph node metastases early and have a particularly poor prognosis. The poor prognosis has been shown to be associated with the physicochemical microenvironment of the tumor tissue, which is characterized by desmoplasia, abnormal microvasculature, extensive hypoxia, and highly elevated interstitial fluid pressure (IFP). In this study, we searched for associations between lymph node metastasis and features of the physicochemical microenvironment in an attempt to identify mechanisms leading to metastatic dissemination and growth. BxPC-3 and Capan-2 PDAC xenografts were used as preclinical models of human PDAC. In both models, lymph node metastasis was associated with high IFP rather than high fraction of hypoxic tissue or high microvascular density. Seven angiogenesis-related genes associated with high IFP-associated lymph node metastasis were detected by quantitative PCR in each of the models, and these genes were all up-regulated in high IFP/highly metastatic tumors. Three genes were mutual for the BxPC-3 and Capan-2 models: transforming growth factor beta, angiogenin, and insulin-like growth factor 1. Further comprehensive studies are needed to determine whether there is a causal relationship between the up-regulation of these genes and high IFP and/or high propensity for lymph node metastasis in PDAC.
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Affiliation(s)
- Lise Mari K. Andersen
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Catherine S. Wegner
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Trude G. Simonsen
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Ruixia Huang
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Jon-Vidar Gaustad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Anette Hauge
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Kanthi Galappathi
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Einar K. Rofstad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
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29
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MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells. Pancreas 2017; 46:557-566. [PMID: 28196027 DOI: 10.1097/mpa.0000000000000778] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs. METHODS In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. RESULTS In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. CONCLUSIONS The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.
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30
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Gao HF, Li AN, Yang JJ, Chen ZH, Xie Z, Zhang XC, Su J, Lou NN, Yan HH, Han JF, Wu YL. Soluble c-Met Levels Correlated With Tissue c-Met Protein Expression in Patients With Advanced Non-Small-Cell Lung Cancer. Clin Lung Cancer 2016; 18:85-91. [PMID: 27461774 DOI: 10.1016/j.cllc.2016.06.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 06/13/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Immunohistochemistry (IHC) and fluorescent in situ hybridization are reliable methods for identifying c-Met protein expression or c-Met gene amplification. However, each technique requires a high-quality tissue sample, which might not be available. The aim of the present study was to investigate the correlation between the soluble c-Met level and tissue c-Met protein expression and the relationship between these markers and patient prognosis. MATERIALS AND METHODS In 198 patients with advanced non-small-cell lung cancer, tumor tissue c-Met expression was determined using IHC according to the H score criteria. Positivity was defined as ≥ 50% of cells with strong staining (IHC 3+). The concentration of c-Met protein in paired plasma samples was measured using a human soluble c-Met quantitative enzyme-linked immunosorbent assay kit, and the predictive value was determined using receiver operating characteristic curve analysis. RESULTS Of the 198 patients, 140 (70.7%) had tissue c-Met- findings and 58 (29.3%) tissue c-Met+ findings. Receiver operating characteristic curve analysis showed 67.2% specificity and 65.0% sensitivity for predicting tissue c-Met positivity at a plasma c-Met cutoff of 766 ng/mL. The correlation between the soluble c-Met level and tissue c-Met protein expression was significant (Pearson's r = 0.309; P < .001). Patients with high soluble c-Met levels (> 766 ng/mL) had poorer overall survival than patients with low soluble c-Met levels (9.5 vs. 22.2 months; P < .001). Multivariate analyses demonstrated the same result (hazard ratio, 2.15; 95% confidence interval, 1.334-3.446; P = .002). CONCLUSION A significant correlation was found between the plasma soluble c-Met levels and tissue c-Met protein expression in patients with advanced non-small-cell lung cancer. A high level of soluble c-Met was associated with a poor prognosis.
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Affiliation(s)
- Hong-Fei Gao
- Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - An-Na Li
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Jin-Ji Yang
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Zhi Xie
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Xu-Chao Zhang
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Jian Su
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Na-Na Lou
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Hong-Hong Yan
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Jie-Fei Han
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
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MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts. PLoS One 2016; 11:e0155289. [PMID: 27227903 PMCID: PMC4882075 DOI: 10.1371/journal.pone.0155289] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 04/27/2016] [Indexed: 01/05/2023] Open
Abstract
TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC). The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3) following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials.
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Yeo D, Huynh N, Beutler JA, Baldwin GS, He H, Nikfarjam M. Glaucarubinone Combined with Gemcitabine Improves Pancreatic Cancer Survival in an Immunocompetent Orthotopic Murine Model. J INVEST SURG 2016; 29:366-372. [PMID: 27027695 DOI: 10.3109/08941939.2016.1160167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Pancreatic cancer continues to have a poor survival rate with an urgent need for improved treatments. Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, has recently been recognized as having anti-cancer properties that may be particularly applicable to pancreatic cancer. METHODS The effect of glaucarubinone on the growth and migration of murine pancreatic cancer cells was assessed by 3H-thymidine incorporation assay. The survival impact of glaucarubinone alone and in combination with gemcitabine chemotherapy was assessed using an immunocompetent orthotopic murine model of pancreatic cancer. RESULTS Glaucarubinone inhibited the growth of the murine pancreatic cancer cell lines LM-P and PAN02. Treatment with either glaucarubinone or gemcitabine reduced proliferation in vitro and the combination was synergistic. The combination treatment improved survival two-fold compared to gemcitabine treatment alone (p = 0.046) in PAN02 cells. CONCLUSIONS The synergistic inhibition by glaucarubinone and gemcitabine observed in vitro and the improved survival in vivo suggest that glaucarubinone may be a useful adjunct to current chemotherapy regimens.
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Affiliation(s)
- Dannel Yeo
- a Department of Surgery , University of Melbourne, Austin Health , Melbourne , Victoria , Australia
| | - Nhi Huynh
- a Department of Surgery , University of Melbourne, Austin Health , Melbourne , Victoria , Australia
| | - John A Beutler
- b Molecular Targets Laboratory, National Cancer Institute , Frederick , MD
| | - Graham S Baldwin
- a Department of Surgery , University of Melbourne, Austin Health , Melbourne , Victoria , Australia
| | - Hong He
- a Department of Surgery , University of Melbourne, Austin Health , Melbourne , Victoria , Australia
| | - Mehrdad Nikfarjam
- a Department of Surgery , University of Melbourne, Austin Health , Melbourne , Victoria , Australia
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Ziegler KM, Considine RV, True E, Swartz-Basile DA, Pitt HA, Zyromski NJ. Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism. Int J Surg 2016; 28:179-84. [PMID: 26957017 DOI: 10.1016/j.ijsu.2016.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 02/26/2016] [Accepted: 03/03/2016] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 ± 12% and 34 ± 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 ± 5% vs. 68 ± 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation.
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Affiliation(s)
| | - Robert V Considine
- Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, USA
| | - Eben True
- Department of Surgery, Indiana University School of Medicine, USA
| | | | - Henry A Pitt
- Department of Surgery, Temple University School of Medicine, USA
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Pothula SP, Xu Z, Goldstein D, Biankin AV, Pirola RC, Wilson JS, Apte MV. Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br J Cancer 2016; 114:269-80. [PMID: 26766740 PMCID: PMC4742591 DOI: 10.1038/bjc.2015.478] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 12/04/2015] [Accepted: 12/16/2015] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c-MET pathway. METHODS Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs. RESULTS We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions. CONCLUSIONS Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.
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Affiliation(s)
- Srinivasa P Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Andrew V Biankin
- Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Romano C Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
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Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M. Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility. Cancer Lett 2016; 372:210-8. [PMID: 26805763 DOI: 10.1016/j.canlet.2016.01.016] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/31/2015] [Accepted: 01/12/2016] [Indexed: 12/18/2022]
Abstract
Desmoplasia and hypoxia in pancreatic cancer mutually affect each other and create a tumor-supportive microenvironment. Here, we show that microenvironment remodeling by hypoxic pancreatic stellate cells (PSCs) promotes cancer cell motility through alteration of extracellular matrix (ECM) fiber architecture. Three-dimensional (3-D) matrices derived from PSCs under hypoxia exhibited highly organized parallel-patterned matrix fibers compared with 3-D matrices derived from PSCs under normoxia, and promoted cancer cell motility by inducing directional migration of cancer cells due to the parallel fiber architecture. Microarray analysis revealed that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Stromal PLOD2 expression in surgical specimens of pancreatic cancer was confirmed by immunohistochemistry. RNA interference-mediated knockdown of PLOD2 in PSCs blocked parallel fiber architecture of 3-D matrices, leading to decreased directional migration of cancer cells within the matrices. In conclusion, these findings indicate that hypoxia-induced PLOD2 expression in PSCs creates a permissive microenvironment for migration of cancer cells through architectural regulation of stromal ECM in pancreatic cancer.
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Affiliation(s)
- Masafumi Sada
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
| | - Kohei Horioka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takashi Okumura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Taiki Moriyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Miyasaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takao Ohtsuka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhiro Mizumoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Metran-Nascente C, Yeung I, Vines DC, Metser U, Dhani NC, Green D, Milosevic M, Jaffray D, Hedley DW. Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake. J Nucl Med 2016; 57:361-6. [PMID: 26769863 DOI: 10.2967/jnumed.115.167650] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 11/23/2015] [Indexed: 12/21/2022] Open
Abstract
UNLABELLED Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. METHODS We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer (18)F-fluoroazomycin arabinoside (or (18)F-1-α-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [(18)F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. RESULTS Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. CONCLUSION Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents.
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Affiliation(s)
- Cristiane Metran-Nascente
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Ivan Yeung
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and
| | - Douglass C Vines
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and
| | - Ur Metser
- Department of Medical Imaging, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Neesha C Dhani
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - David Green
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and
| | - Michael Milosevic
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and
| | - David Jaffray
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and
| | - David W Hedley
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
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Sun JD, Liu Q, Ahluwalia D, Li W, Meng F, Wang Y, Bhupathi D, Ruprell AS, Hart CP. Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer. Cancer Biol Ther 2016; 16:438-49. [PMID: 25679067 PMCID: PMC4623012 DOI: 10.1080/15384047.2014.1003005] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tumors often contain hypoxic regions resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-activated prodrug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. This study evaluated the efficacy and safety profile of combining T with gemcitabine (G) and nab-paclitaxel (nP) in human pancreatic ductal adenocarcinoma (PDAC) xenograft models in mice. Antitumor activity of the G + nP + T triplet was assessed and compared with T-alone or the G + nP doublet in the Hs766t, MIA PaCa-2, PANC-1, and BxPC-3 PDAC xenograft models. Efficacy was assessed by tumor growth kinetic analysis. Body weight, blood cell counts, blood chemistry, and the von Frey neuropathy assay were analyzed to evaluate safety profiles. Pharmacodynamic changes after the treatment were determined by immunohistochemistry of cell proliferation, DNA damage, apoptosis, hypoxia, and tumor stroma density. The G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP doublet. Compared with vehicle (V), G + nP induced body weight loss, reduced neutrophil and lymphocyte counts, increased the levels of liver function parameters, and induced neurotoxicity. However, when T was added to G + nP, there was no statistically increased impairment compared to G + nP. The triplet significantly increased DNA damage, apoptosis, and tumor necrosis. Furthermore, the triplet further inhibited cell proliferation and reduced stroma density and intratumoral hypoxia. The triplet combination of G + nP + T exhibited superior efficacy but additive toxicity was not evident compared to the G + nP doublet in this study. This study provides a translational rationale for combining G, nP, and T in the clinical setting to assess efficacy and safety. A Phase I clinical trial of the triplet combination is currently underway (NCT02047500).
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Key Words
- BW, body weight
- Br-IPM, a brominated analog of isophosphoramide mustard
- CAF, cancer-associated fibroblast
- CAIX, carbonic anhydrase IX
- CR, complete response
- EMT, epithelial to mesenchymal transition
- G, gemcitabine
- HF, hypoxic fraction
- ILS, increased life span
- MT, median time to reach the size of 1000 mm3
- MTD, maximum tolerated dose
- NF, necrotic fraction
- PDAC, pancreatic ductal adenocarcinoma
- T, TH-302
- TGD1000, tumor growth delay compared to Vehicle reaching the size of 1000 mm3
- TGI, tumor growth inhibition
- TH-302
- V, vehicle
- gemcitabine
- hypoxia
- hypoxia-activated prodrug
- nP, nab-paclitaxel
- nab-paclitaxel
- pancreatic cancer
- pharmacodynamics, biomarker
- smooth muscle actin
- xenograft
- α-SMA, α
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Affiliation(s)
- Jessica D Sun
- a Threshold Pharmaceuticals , South San Francisco , CA , USA
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Joshi GK, Deitz-McElyea S, Liyanage T, Lawrence K, Mali S, Sardar R, Korc M. Label-Free Nanoplasmonic-Based Short Noncoding RNA Sensing at Attomolar Concentrations Allows for Quantitative and Highly Specific Assay of MicroRNA-10b in Biological Fluids and Circulating Exosomes. ACS NANO 2015; 9:11075-89. [PMID: 26444644 PMCID: PMC4660391 DOI: 10.1021/acsnano.5b04527] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 09/29/2015] [Indexed: 05/20/2023]
Abstract
MicroRNAs are short noncoding RNAs consisting of 18-25 nucleotides that target specific mRNA moieties for translational repression or degradation, thereby modulating numerous biological processes. Although microRNAs have the ability to behave like oncogenes or tumor suppressors in a cell-autonomous manner, their exact roles following release into the circulation are only now being unraveled and it is important to establish sensitive assays to measure their levels in different compartments in the circulation. Here, an ultrasensitive localized surface plasmon resonance (LSPR)-based microRNA sensor with single nucleotide specificity was developed using chemically synthesized gold nanoprisms attached onto a solid substrate with unprecedented long-term stability and reversibility. The sensor was used to specifically detect microRNA-10b at the attomolar (10(-18) M) concentration in pancreatic cancer cell lines, derived tissue culture media, human plasma, and media and plasma exosomes. In addition, for the first time, our label-free and nondestructive sensing technique was used to quantify microRNA-10b in highly purified exosomes isolated from patients with pancreatic cancer or chronic pancreatitis, and from normal controls. We show that microRNA-10b levels were significantly higher in plasma-derived exosomes from pancreatic ductal adenocarcinoma patients when compared with patients with chronic pancreatitis or normal controls. Our findings suggest that this unique technique can be used to design novel diagnostic strategies for pancreatic and other cancers based on the direct quantitative measurement of plasma and exosome microRNAs, and can be readily extended to other diseases with identifiable microRNA signatures.
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Affiliation(s)
- Gayatri K. Joshi
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, LD 326, Indianapolis, Indiana 46202, United States
| | - Samantha Deitz-McElyea
- Departments of Medicine, and Biochemistry and Molecular Biology, the Indiana University Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indiana University School of Medicine, 980 West Walnut Street, R3-C528, Indianapolis, Indiana 46202, United States
| | - Thakshila Liyanage
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, LD 326, Indianapolis, Indiana 46202, United States
| | - Katie Lawrence
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, LD 326, Indianapolis, Indiana 46202, United States
| | - Sonali Mali
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, LD 326, Indianapolis, Indiana 46202, United States
| | - Rajesh Sardar
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, LD 326, Indianapolis, Indiana 46202, United States
- Integrated Nanosystems Development Institute, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, Indianapolis, Indiana 46202, United States
- Address correspondence to ,
| | - Murray Korc
- Departments of Medicine, and Biochemistry and Molecular Biology, the Indiana University Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indiana University School of Medicine, 980 West Walnut Street, R3-C528, Indianapolis, Indiana 46202, United States
- Address correspondence to ,
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Kahlert C, Fiala M, Musso G, Halama N, Keim S, Mazzone M, Lasitschka F, Pecqueux M, Klupp F, Schmidt T, Rahbari N, Schölch S, Pilarsky C, Ulrich A, Schneider M, Weitz J, Koch M. Prognostic impact of a compartment-specific angiogenic marker profile in patients with pancreatic cancer. Oncotarget 2015; 5:12978-89. [PMID: 25483099 PMCID: PMC4350362 DOI: 10.18632/oncotarget.2651] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 10/27/2014] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer consists of a heterogenous bulk of tumor cells and stroma cells which contribute to tumor progression by releasing angiogenic factors. Those factors can be detected as circulating serum factors. We performed a compartment-specific analysis of tumor-derived and stroma-derived angiogenic factors to identify biomarkers and molecular targets for the treatment of pancreatic cancer. Kryo-frozen tissue from primary ductal adenocarcinomas (n = 51) was laser-microdissected to isolate tumor and stroma tissue. Expression of 17 angiogenic factors (angiopoietin-2, follistatin, GCSF, HGF, interleukin-8, leptin, PDGF-BB, PECAM-1, VEGF, matrix metalloproteinase -1, -2, -3, -7, -9, -10, -12, and -13) was analyzed using a multiplex elisa assay for tissue-derived proteins and corresponding serum. Our study reveals a compartment-specific expression profile for several angiogenic factors and matrix metalloproteinases. ROC analysis of corresponding serum samples reveals MMP-7 and MMP-12 as strong classifiers for the diagnosis of patients with pancreatic cancer vs. healthy control donors. High expression of tumor-derived PDGF-BB and MMP-1 correlates with prolonged survival in univariate and multivariate analysis. In conclusion, a distinct expression patterns for angiogenic cytokines and MMPs in pancreatic cancer and surrounding stroma may implicate them as novel targets for cancer treatment. Tumor-derived PDGF-BB and MMP-1 are significant and independent prognostic markers for poor survival.
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Affiliation(s)
- Christoph Kahlert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Maria Fiala
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Gabriel Musso
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Niels Halama
- Medical Oncology, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Germany
| | - Sophia Keim
- Medical Oncology, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Germany
| | - Massimiliano Mazzone
- Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven 3000, Belgium. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU, Leuven 3000, Belgium
| | - Felix Lasitschka
- Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany
| | - Mathieu Pecqueux
- Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany
| | - Fee Klupp
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Nuh Rahbari
- Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany
| | - Sebastian Schölch
- Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany
| | - Christian Pilarsky
- Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Juergen Weitz
- Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany
| | - Moritz Koch
- Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany
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Koyasu S, Tsuji Y, Harada H, Nakamoto Y, Nobashi T, Kimura H, Sano K, Koizumi K, Hamaji M, Togashi K. Evaluation of Tumor-associated Stroma and Its Relationship with Tumor Hypoxia Using Dynamic Contrast-enhanced CT and (18)F Misonidazole PET in Murine Tumor Models. Radiology 2015; 278:734-41. [PMID: 26393963 DOI: 10.1148/radiol.2015150416] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE To determine the relationship between the fractional interstitial volume (Fis), as calculated at dynamic contrast material-enhanced (DCE) computed tomography (CT), and tumor-associated stroma and to analyze its spatial relationship with tumor hypoxia in several xenograft tumor models. MATERIALS AND METHODS All animal experiments were approved by the animal research committee. Mice with three different xenograft tumors (U251, CFPAC-1, and BxPC-3; n = 6, n = 8, and n = 6, respectively) underwent DCE CT then hypoxia imaging with fluorine 18 ((18)F) fluoromisonidazole (FMISO) positron emission tomography (PET) within 24 hours. Immunohistochemical analysis was performed in harvested tumors to detect hypoxia markers and to quantify microvascular and stromal density. Two DCE CT parameters (amount of interstitial space associated with the amount of stroma [Fis] and flow velocity [Fv]) were identified and quantitatively validated by using immunohistochemistry. FMISO uptake within the tumor was also assessed in relation to DCE CT parameters. Imaging and immunohistochemical parameters were assessed by using the Kruskal-Wallis test, Wilcoxon rank-sum test with Bonferroni correction, and Pearson correlation coefficient. RESULTS Almost no α-smooth muscle actin-positive cells were found in the U251 xenograft, while abundant stroma was found in the entire BxPC-3 xenograft and in the periphery of the CFPAC-1 xenograft. Quantitative analysis showed a significant correlation (R = 0.83, P < .0001) between Fis and stromal density. FMISO uptake had a negative correlation with Fis (R = -0.58, P < .0001) and Fv (R = -0.53, P < .0001). CONCLUSION DCE CT can be used to quantify parameters associated with tumor-associated stroma. Tumor hypoxia was Complementarily localized in tumor-associated stroma in these models.
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Affiliation(s)
- Sho Koyasu
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshihisa Tsuji
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiroshi Harada
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yuji Nakamoto
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomomi Nobashi
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiroyuki Kimura
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kohei Sano
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Koji Koizumi
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Masatsugu Hamaji
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kaori Togashi
- From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
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Schiefer AI, Mesteri I, Berghoff AS, Haitel A, Schmidinger M, Preusser M, Birner P. Evaluation of tyrosine kinase receptors in brain metastases of clear cell renal cell carcinoma reveals cMet as a negative prognostic factor. Histopathology 2015; 67:799-805. [PMID: 25847631 DOI: 10.1111/his.12709] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 03/30/2015] [Indexed: 12/25/2022]
Abstract
AIMS Brain metastases (BMs) of clear cell renal cell carcinoma (ccRCC) are associated with a dismal prognosis, with limited treatment options. Tyrosine kinases are relevant 'druggable' biomarkers. The aim of this study was to evaluate the tyrosine kinase receptors anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-α (PDGFRA) and cMet in a large series of ccRCC BMs. METHODS AND RESULTS ALK, EGFR, PDGFRA and cMet protein expression was determined by immunohistochemistry in 53 ccRCCs BMs and 12 matched primary tumours. ALK and MET gene status and copy number alterations of chromosome 7 were studied with fluorescence in-situ hybridization (FISH). Data on the expression of hypoxia-inducible factor 1α (HIF1α) and Ki67 and microvessel density were available from previous studies. ALK was negative in all analysed specimens. EGFR was overexpressed in 41 of 51 (80.4%) BMs and in seven of eight primary tumours, PDGFRA was overexpressed in all BMs except one and in all primary tumours, and cMet was expressed in 26 of 50 (52%) BMs and in two of seven primary tumours, and did not correlate with MET amplification or polysomy 7. cMet was the only parameter associated with significantly shorter BM-specific survival (median 8 months versus 33 months, P = 0.005, Cox regression). CONCLUSIONS EGFR, PDGFRA and cMet are commonly overexpressed in ccRCC BMs. cMet overexpression correlates with significantly shorter BM-specific survival.
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Affiliation(s)
- Ana-Iris Schiefer
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Anna S Berghoff
- Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Andrea Haitel
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Manuela Schmidinger
- Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Matthias Preusser
- Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria
| | - Peter Birner
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
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Neuzillet C, Couvelard A, Tijeras-Raballand A, de Mestier L, de Gramont A, Bédossa P, Paradis V, Sauvanet A, Bachet JB, Ruszniewski P, Raymond E, Hammel P, Cros J. High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis. Histopathology 2015; 67:664-76. [PMID: 25809563 DOI: 10.1111/his.12691] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 03/14/2015] [Indexed: 12/11/2022]
Abstract
AIMS c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting. METHODS AND RESULTS c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥ 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis. CONCLUSIONS Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149.,Department of Digestive Oncology, Beaujon University Hospital, Clichy, France.,Paris 7 Denis Diderot University, Paris, France
| | - Anne Couvelard
- INSERM UMR1149.,Paris 7 Denis Diderot University, Paris, France.,Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France
| | | | | | - Armand de Gramont
- Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Pierre Bédossa
- INSERM UMR1149.,Paris 7 Denis Diderot University, Paris, France.,Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France
| | - Valérie Paradis
- INSERM UMR1149.,Paris 7 Denis Diderot University, Paris, France.,Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France
| | - Alain Sauvanet
- Paris 7 Denis Diderot University, Paris, France.,Department of Biliary and Pancreatic Surgery, Beaujon University Hospital, Clichy, France
| | - Jean-Baptiste Bachet
- Department of Gastroenterology, Pitié-Salpêtrière University Hospital, Paris, France
| | - Philippe Ruszniewski
- INSERM UMR1149.,Paris 7 Denis Diderot University, Paris, France.,Department of Gastroenterology and Pancreatology, Beaujon University Hospital, Clichy, France
| | - Eric Raymond
- Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Pascal Hammel
- INSERM UMR1149.,Department of Digestive Oncology, Beaujon University Hospital, Clichy, France.,Paris 7 Denis Diderot University, Paris, France
| | - Jérôme Cros
- INSERM UMR1149.,Paris 7 Denis Diderot University, Paris, France.,Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France
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Colbert LE, Fisher SB, Balci S, Saka B, Chen Z, Kim S, El-Rayes BF, Adsay NV, Maithel SK, Landry JC, Curran WJ. High nuclear hypoxia-inducible factor 1 alpha expression is a predictor of distant recurrence in patients with resected pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 2015; 91:631-9. [PMID: 25596110 PMCID: PMC5746186 DOI: 10.1016/j.ijrobp.2014.11.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/29/2014] [Accepted: 11/04/2014] [Indexed: 01/19/2023]
Abstract
PURPOSE To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. METHODS AND MATERIALS Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. RESULTS Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. CONCLUSIONS High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.
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Affiliation(s)
- Lauren E Colbert
- Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Sarah B Fisher
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia
| | - Serdar Balci
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Pathology, Emory University, Atlanta, Georgia
| | - Burcu Saka
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Pathology, Emory University, Atlanta, Georgia
| | - Zhengjia Chen
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia
| | - Sungjin Kim
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia
| | - Bassel F El-Rayes
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia
| | - N Volkan Adsay
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Pathology, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia
| | - Shishir K Maithel
- Winship Cancer Institute, Emory University, Atlanta, Georgia; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia
| | - Jerome C Landry
- Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia
| | - Walter J Curran
- Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia.
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Targeting cMET with INC280 impairs tumour growth and improves efficacy of gemcitabine in a pancreatic cancer model. BMC Cancer 2015; 15:71. [PMID: 25884642 PMCID: PMC4340491 DOI: 10.1186/s12885-015-1064-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/30/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Expression and activation of the cMET receptor have been implicated in tumor progression and resistance to chemotherapy in human pancreatic cancer. In this regard we assessed the effects of targeting cMET in pancreatic cancer models in vitro and in vivo. METHODS Human (L3.6pl, BxP3, HPAF-II, MiaPaCa2) and murine (Panc02) pancreatic cancer cell lines, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) were used for the experiments. Furthermore, the human pancreatic cancer cell line MiaPaCa2 with acquired resistance to gemcitabine was employed (MiaPaCa2(G250)). For targeting the cMET receptor, the oral available, ATP-competitive inhibitor INC280 was used. Effects of cMET inhibition on cancer and stromal cells were determined by growth assays, western blotting, motility assays and ELISA. Moreover, orthotopic xenogeneic and syngeneic mouse (BALB-C nu/nu; C57BL/6) models were used to assess in vivo efficacy of targeting cMET alone and in combination with gemcitabine. RESULTS Treatment with INC280 impairs activation of signaling intermediates in pancreatic cancer cells and ECs, particularly when cells were stimulated with hepatocyte growth factor (HGF). Moreover, motility of cancer cells and ECs in response to HGF was reduced upon treatment with INC280. Only minor effects on VSMCs were detected. Interestingly, MiaPaCa2(G250) showed an increase in cMET expression and cMET inhibition abrogated HGF-induced effects on growth, motility and signaling as well as DFX-hypoxia HIF-1alpha and MDR-1 expression in vitro. In vivo, therapy with INC280 alone led to inhibition of orthotopic tumor growth in xenogeneic and syngeneic models. Similar to in vitro results, cMET expression was increased upon treatment with gemcitabine, and combination of the cMET inhibitor with gemcitabine improved anti-neoplastic capacity in an orthotopic syngeneic model. Immunohistochemical analysis revealed a significant inhibition of tumor cell proliferation (Ki67) and tumor vascularization (CD31). Finally, combination of gemcitabine with INC280 significantly prolonged survival in the orthotopic syngeneic tumor model even when treatment with the cMET inhibitor was initiated at an advanced stage of disease. CONCLUSIONS These data provide evidence that targeting cMET in combination with gemcitabine may be effective in human pancreatic cancer and warrants further clinical evaluation.
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Longchar A, Prasad SB. Biochemical changes associated with ascorbic acid-cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice. Toxicol Rep 2015; 2:489-503. [PMID: 28962385 PMCID: PMC5598450 DOI: 10.1016/j.toxrep.2015.01.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 01/27/2015] [Accepted: 01/27/2015] [Indexed: 12/20/2022] Open
Abstract
Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA) in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL) in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH), catalase activity and increased lipid peroxidation (LPO) in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects) in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT), liver function test (LFT) and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.
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Affiliation(s)
- Amenla Longchar
- Cell and Tumor Biology Laboratory, Department of Zoology, North-Eastern Hill University, Shillong 793 022, India
| | - Surya Bali Prasad
- Cell and Tumor Biology Laboratory, Department of Zoology, North-Eastern Hill University, Shillong 793 022, India
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Spina A, De Pasquale V, Cerulo G, Cocchiaro P, Della Morte R, Avallone L, Pavone LM. HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation. Biomedicines 2015; 3:71-88. [PMID: 28536400 PMCID: PMC5344235 DOI: 10.3390/biomedicines3010071] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/09/2014] [Indexed: 02/07/2023] Open
Abstract
Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF) is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease.
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Affiliation(s)
- Anna Spina
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
| | - Valeria De Pasquale
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
| | - Giuliana Cerulo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Pasquale Cocchiaro
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Rossella Della Morte
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Luigi Avallone
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy.
| | - Luigi Michele Pavone
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
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Baek G, Tse YF, Hu Z, Cox D, Buboltz N, McCue P, Yeo CJ, White MA, DeBerardinis RJ, Knudsen ES, Witkiewicz AK. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep 2014; 9:2233-49. [PMID: 25497091 DOI: 10.1016/j.celrep.2014.11.025] [Citation(s) in RCA: 152] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 11/04/2014] [Accepted: 11/17/2014] [Indexed: 12/11/2022] Open
Abstract
KRAS mutation, which occurs in ∼ 95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate the metabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions.
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Affiliation(s)
- GuemHee Baek
- Department of Pathology, UT Southwestern, Dallas, TX 75390, USA
| | - Yan F Tse
- Department of Pathology, UT Southwestern, Dallas, TX 75390, USA
| | - Zeping Hu
- Children's Medical Center Research Institute at UT Southwestern, Dallas, TX 75390, USA
| | - Derek Cox
- Department of Pathology, UT Southwestern, Dallas, TX 75390, USA
| | - Noah Buboltz
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Peter McCue
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Charles J Yeo
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Michael A White
- Department of Cell Biology, UT Southwestern, Dallas, TX 75390, USA
| | - Ralph J DeBerardinis
- Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA; Children's Medical Center Research Institute at UT Southwestern, Dallas, TX 75390, USA
| | - Erik S Knudsen
- Department of Pathology, UT Southwestern, Dallas, TX 75390, USA; Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA
| | - Agnieszka K Witkiewicz
- Department of Pathology, UT Southwestern, Dallas, TX 75390, USA; Simmons Cancer Center, UT Southwestern, Dallas, TX 75390, USA.
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Nakamura I, Hama S, Itakura S, Takasaki I, Nishi T, Tabuchi Y, Kogure K. Lipocalin2 as a plasma marker for tumors with hypoxic regions. Sci Rep 2014; 4:7235. [PMID: 25467539 PMCID: PMC4252902 DOI: 10.1038/srep07235] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 10/30/2014] [Indexed: 11/12/2022] Open
Abstract
Hypoxic tumors have been identified as appropriate indicators of tumor malignancy. However, no convenient plasma marker for hypoxic tumors has been described. Therefore, to identify a novel, convenient plasma marker for hypoxic tumors, we used microarray analysis to compare gene expression profiles of normoxic and hypoxic tumor tissues of mice bearing melanomas. Among the upregulated genes detected in hypoxic tumors, we chose to study the secretory protein lipocalin2 (LCN2) as a marker for hypoxic tumors. LCN2 protein levels in the plasma of mice bearing hypoxic tumors were significantly increased compared with those in mice bearing normoxic tumors. Interestingly, LCN2 mRNA levels were 17-fold higher in HIF-1α-positive hypoxic tumors than in HIF-1α-negative normoxic tumors. Furthermore, LCN2 mRNA levels were significantly higher in the B16-F1 cells and various human tumor cells cultured under hypoxic conditions than in cells cultured under normoxic conditions, while no changes in mRNA expression were observed in nontumor NIH-3T3 cells, even under hypoxic conditions. In cultured cells, the expression pattern of LCN2 was mostly consistent with that of HIF-1α, whereas that of a conventional hypoxic marker, carbonic anhydrase IX, was not. Collectively, our data suggested that LCN2 was a useful plasma marker for hypoxic tumors.
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Affiliation(s)
- Ibuki Nakamura
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Susumu Hama
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Shoko Itakura
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Ichiro Takasaki
- Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama, Japan
| | - Takayuki Nishi
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Yoshiaki Tabuchi
- Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama, Japan
| | - Kentaro Kogure
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
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Oyanagi J, Kojima N, Sato H, Higashi S, Kikuchi K, Sakai K, Matsumoto K, Miyazaki K. Inhibition of transforming growth factor-β signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. Exp Cell Res 2014; 326:267-79. [DOI: 10.1016/j.yexcr.2014.04.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/11/2014] [Accepted: 04/14/2014] [Indexed: 12/26/2022]
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Abstract
Intratumoral hypoxia is a common feature of solid tumors. Recent advances in cancer biology indicate that hypoxia is not only a consequence of unrestrained tumor growth, but also plays an active role in promoting tumor progression, malignancy, and resistance to therapy. Hypoxia signaling is mediated by the hypoxia-inducible factors (HIFs), which are not only stabilized under hypoxia, but also by activated oncogenes or inactivated tumor suppressors under normoxia. Hypoxia is a prominent feature of the tumor microenvironment of pancreatic tumors, also characterized by the presence of a fibrotic reaction that promotes, and is also modulated by, hypoxia. As the mechanisms by which hypoxia signaling impacts invasion and metastasis in pancreatic cancer are being elucidated, hypoxia is emerging as a key determinant of pancreatic cancer malignancy as well as an important target for therapy. Herein we present an overview of recent advances in the understanding of the impact that hypoxia has in pancreatic cancer invasion and metastasis.
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Affiliation(s)
- Angela Yuen
- Tumor Microenvironment and Metastasis Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
| | - Begoña Díaz
- Tumor Microenvironment and Metastasis Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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