Pancreatic cancer stromal biology and therapy

Pancreatic cancer is one of the most lethal malignancies. Significant progresses have been made in understanding of pancreatic cancer pathogenesis, including appreciation of precursor lesions or premalignant pancreatic intraepithelial neoplasia (PanINs), description of sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and identification of major genetic and epigenetic events and the biological impact of those events on malignant behavior. However, the currently used therapeutic strategies targeting tumor epithelial cells, which are potent in cell culture and animal models, have not been successful in the clinic. Presumably, therapeutic resistance of pancreatic cancer is at least in part due to its drastic desmoplasis, which is a defining hallmark for and circumstantially contributes to pancreatic cancer development and progression. Improved understanding of the dynamic interaction between cancer cells and the stroma is important to better understanding pancreatic cancer biology and to designing effective intervention strategies. This review focuses on the origination, evolution and disruption of stromal molecular and cellular components in pancreatic cancer, and their biological effects on pancreatic cancer pathogenesis.

[1]  E. Touboul,et al.  Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  O. Volpert,et al.  Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Rustgi.  Familial pancreatic cancer: genetic advances , 2014, Genes & development.

[4]  P. Murawa,et al.  Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Jochen Gaedcke,et al.  Integration of Metabolomics and Transcriptomics Revealed a Fatty Acid Network Exerting Growth Inhibitory Effects in Human Pancreatic Cancer , 2013, Clinical Cancer Research.

[6]  Yutaka Shimada,et al.  Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours , 2003, Nature.

[7]  C. Pilarsky,et al.  Genomics of pancreatic ductal adenocarcinoma. , 2014, Hepatobiliary & pancreatic diseases international : HBPD INT.

[8]  R. Mason,et al.  Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation. , 2004, Journal of the American Society of Nephrology : JASN.

[9]  John F. McDonald,et al.  Evidence for the Importance of Personalized Molecular Profiling in Pancreatic Cancer , 2014, Pancreas.

[10]  G. Klöppel.  Chronic pancreatitis, pseudotumors and other tumor-like lesions , 2007, Modern Pathology.

[11]  L. Mishra,et al.  Activation of Vitamin D Receptor Signaling Downregulates the Expression of Nuclear FOXM1 Protein and Suppresses Pancreatic Cancer Cell Stemness , 2014, Clinical Cancer Research.

[12]  M. Selman,et al.  Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. , 2006, Proceedings of the American Thoracic Society.

[13]  R. McWilliams,et al.  Aberrant signaling pathways in pancreatic cancer: A two compartment view , 2012, Molecular carcinogenesis.

[14]  K. Xie,et al.  Transcriptional anti-angiogenesis therapy of human pancreatic cancer. , 2006, Cytokine & growth factor reviews.

[15]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[16]  Wei Hu,et al.  Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells , 2007, Acta Pharmacologica Sinica.

[17]  L. Ricci-Vitiani,et al.  Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells , 2011, Nature.

[18]  Mina J. Bissell,et al.  Myoepithelial Cells: Their Origin and Function in Breast Morphogenesis and Neoplasia , 2005, Journal of Mammary Gland Biology and Neoplasia.

[19]  A. Kate Sasser,et al.  Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression , 2009, PloS one.

[20]  P. Lankisch.  [Chronic pancreatitis]. , 1991, Der Internist.

[21]  L. Chantrill,et al.  Chronic pancreatitis: a path to pancreatic cancer. , 2014, Cancer letters.

[22]  Joel G Fletcher,et al.  Resectability of Presymptomatic Pancreatic Cancer and Its Relationship to Onset of Diabetes: A Retrospective Review of CT Scans and Fasting Glucose Values Prior to Diagnosis , 2007, The American Journal of Gastroenterology.

[23]  J. Dancey,et al.  Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  T. Brentnall.  Management strategies for patients with hereditary pancreatic cancer , 2005, Current treatment options in oncology.

[25]  M. Korc,et al.  Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. , 2008, Clinical chemistry.

[26]  M. Donadelli,et al.  Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists , 2013, Electrophoresis.

[27]  E. Van Cutsem,et al.  Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. , 2011, The Lancet. Oncology.

[28]  L. Wood,et al.  Pathology and Molecular Genetics of Pancreatic Neoplasms , 2012, Cancer journal.

[29]  A. Rosemurgy,et al.  Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  A. Biankin,et al.  Tumorigenesis and Neoplastic Progression Role of Pancreatic Stellate Cells in Pancreatic Cancer Metastasis , 2010 .

[31]  D. Tait,et al.  Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy , 2007, British Journal of Cancer.

[32]  U. Bogdahn,et al.  Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. , 2006, Cytokine & growth factor reviews.

[33]  H. Lee,et al.  Experimental Models of Pancreatitis , 2014, Clinical endoscopy.

[34]  P. Greenberg,et al.  Stromal reengineering to treat pancreas cancer. , 2014, Carcinogenesis.

[35]  K. Xie,et al.  Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: molecular basis for therapeutic implications. , 2012, Cytokine & growth factor reviews.

[36]  Maximilian Reichert,et al.  EMT and Dissemination Precede Pancreatic Tumor Formation , 2012, Cell.

[37]  K. Pogue-Geile,et al.  Pancreatitis as a risk for pancreatic cancer. , 2002, Gastroenterology clinics of North America.

[38]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[39]  W. Scheithauer,et al.  Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  M. Cooper,et al.  Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway. , 2004, The American journal of pathology.

[41]  P. Maisonneuve,et al.  Chronic Pancreatitis and Pancreatic Cancer , 2002, Digestive Diseases.

[42]  M. Gorry,et al.  Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene , 1996, Nature Genetics.

[43]  T. Pawlik,et al.  Hereditary Pancreatic and Hepatobiliary Cancers , 2011, International journal of surgical oncology.

[44]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[45]  U. Bogdahn,et al.  Targeted tumor therapy with the TGF-β2 antisense compound AP 12009 , 2006 .

[46]  H. Watanabe,et al.  Genetic progression and divergence in pancreatic carcinoma. , 2000, The American journal of pathology.

[47]  R. DePinho,et al.  Pancreatic cancer biology and genetics , 2002, Nature Reviews Cancer.

[48]  L. Buscail,et al.  Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo , 2009, PloS one.

[49]  D. Powell,et al.  Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1-C9 , 1999 .

[50]  C. Forsmark,et al.  Cystic neoplasms of the pancreas , 2000, Current treatment options in gastroenterology.

[51]  M. Bissell,et al.  Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[52]  K. Xie,et al.  The roles of FOXM1 in pancreatic stem cells and carcinogenesis , 2013, Molecular Cancer.

[53]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[54]  M. Bissell,et al.  The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. , 1995, The Journal of clinical investigation.

[55]  J. Waddell,et al.  nab-Paclitaxel Plus Gemcitabine Regimen for Pancreatic Cancer , 2014, Hospital pharmacy.

[56]  D. Goldstein,et al.  Role of pancreatic stellate cells in chemoresistance in pancreatic cancer , 2014, Front. Physiol..

[57]  Umar Mahmood,et al.  Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. , 2015, Cancer cell.

[58]  Thomas G. Caffery,et al.  Sonic Hedgehog Promotes Desmoplasia in Pancreatic Cancer , 2008, Clinical Cancer Research.

[59]  M. Andreeff,et al.  Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. , 2005, Cancer research.

[60]  B. le Bail,et al.  Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study. , 1999, Journal of hepatology.

[61]  K. Adler,et al.  The myofibroblast in pulmonary fibrosis. , 1983, Chest.

[62]  F. Motoi,et al.  Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells , 2003, Oncogene.

[63]  G. Bratthauer,et al.  Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. , 2000, Cancer research.

[64]  C. Joo,et al.  Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells. , 1999, Investigative ophthalmology & visual science.

[65]  Rong Wang,et al.  Glioblastoma stem-like cells give rise to tumour endothelium , 2010, Nature.

[66]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[67]  J. Rüschoff,et al.  Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. , 2000, The American journal of pathology.

[68]  J. Folkman.  Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[69]  Douglas B. Evans,et al.  Cancer-associated stromal fibroblasts promote pancreatic tumor progression. , 2008, Cancer research.

[70]  Neil Desai,et al.  Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  A. Maitra,et al.  Genetic Progression of Pancreatic Cancer , 2014, Cancer journal.

[72]  A. Karachristos,et al.  Surgical Management of Pancreatic Neoplasms: What’s New? , 2014, Current Gastroenterology Reports.

[73]  Pamela S. Robinson,et al.  Epidermal growth factor receptor regulates pancreatic fibrosis. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[74]  D. Powell.  Water transport revisited , 1999, The Journal of physiology.

[75]  Xu-wen Liu,et al.  Platelet-derived Growth Factor (PDGF) Receptor-α-activated c-Jun NH2-terminal Kinase-1 Is Critical for PDGF-induced p21WAF1/CIP1 Promoter Activity Independent of p53* , 2003, Journal of Biological Chemistry.

[76]  C. Iacobuzio-Donahue,et al.  Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  Lingyun Li,et al.  Antitumor Activity of TGF-β, Inhibitor is Dependent on the Microenvironment , 2007 .

[78]  Wolfgang Schima,et al.  Pancreatic adenocarcinoma , 2006, European Radiology.

[79]  R. Schilsky,et al.  Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  Hua Tian,et al.  A paracrine requirement for hedgehog signalling in cancer , 2008, Nature.

[81]  Kimberly Walter,et al.  Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. , 2010, Cancer research.

[82]  M. Makuuchi,et al.  Problems in the diagnosis and treatment of a so-called mucin-producing tumor of the pancreas. , 1998, Pancreas.

[83]  A. Desmoulière,et al.  Normal and Pathologic Soft Tissue Remodeling: Role of the Myofibroblast, with Special Emphasis on Liver and Kidney Fibrosis , 2003, Laboratory Investigation.

[84]  G. Elia,et al.  Organotypic culture model of pancreatic cancer demonstrates that stromal cells modulate E-cadherin, beta-catenin, and Ezrin expression in tumor cells. , 2009, The American journal of pathology.

[85]  J. Folkman,et al.  Fundamental concepts of the angiogenic process. , 2003, Current molecular medicine.

[86]  A B West,et al.  Myofibroblasts: paracrine cells important in health and disease. , 2000, Transactions of the American Clinical and Climatological Association.

[87]  G. Stamp,et al.  Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma , 1997, The Journal of pathology.

[88]  M. Birnstingl.  A study of pancreatography , 1959, The British journal of surgery.

[89]  M. Andreeff,et al.  Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. , 2002, Cancer research.

[90]  P. Álvarez,et al.  Transcriptional Profiling of Peripheral Blood in Pancreatic Adenocarcinoma Patients Identifies Diagnostic Biomarkers , 2014, Digestive Diseases and Sciences.

[91]  D. Sheppard,et al.  Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix , 2006, Proceedings of the National Academy of Sciences.

[92]  M. Andreeff,et al.  Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. , 2004, Journal of the National Cancer Institute.

[93]  B. Hinz,et al.  Myofibroblasts and mechano-regulation of connective tissue remodelling , 2002, Nature Reviews Molecular Cell Biology.

[94]  E. Witkowski,et al.  Outcomes in operative management of pancreatic cancer , 2014, Journal of surgical oncology.

[95]  R. Atkins,et al.  Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). , 2001, The Journal of clinical investigation.

[96]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[97]  Patrick Michl,et al.  Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma , 2013, OncoTargets and therapy.

[98]  M. Tsao,et al.  Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. , 1995, The American journal of pathology.

[99]  F. Peale,et al.  VEGF‐null cells require PDGFR α signaling‐mediated stromal fibroblast recruitment for tumorigenesis , 2004, The EMBO journal.

[100]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[101]  P. Ruszniewski,et al.  Risk of pancreatic adenocarcinoma in chronic pancreatitis , 2002, Gut.

[102]  Bond-Smith Giles,et al.  Only women with symptoms need to have their breast implants removed, says government , 2012 .

[103]  R. Kuick,et al.  The Molecular Basis of Pancreatic Fibrosis: Common Stromal Gene Expression in Chronic Pancreatitis and Pancreatic Adenocarcinoma , 2004, Pancreas.

[104]  Mauro Biffoni,et al.  Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells , 2011, Nature.

[105]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[106]  J. Pollack,et al.  Integrative genomic and functional profiling of the pancreatic cancer genome , 2013, BMC Genomics.

[107]  E. Yi,et al.  Comparative Proteomic Profiling of Pancreatic Ductal Adenocarcinoma Cell Lines , 2014, Molecules and cells.

[108]  Hidetaka Mochizuki,et al.  The Correlation Between Cytoplasmic Overexpression of Epidermal Growth Factor Receptor and Tumor Aggressiveness: Poor Prognosis in Patients With Pancreatic Ductal Adenocarcinoma , 2004, Pancreas.

[109]  C. Joo,et al.  Role of Transforming Growth Factor-β in Transdifferentiation and Fibrosis of Lens Epithelial Cells , 1999 .

[110]  Lingyun Li,et al.  Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment. , 2007, Anticancer research.

[111]  J. Nemunaitis,et al.  A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer , 2002, British Journal of Cancer.

[112]  M. Bissell,et al.  Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. , 2003, The American journal of pathology.

[113]  S. Goodman,et al.  Tumor-suppressive pathways in pancreatic carcinoma. , 1997, Cancer research.

[114]  S. Hung,et al.  Mesenchymal Stem Cell Targeting of Microscopic Tumors and Tumor Stroma Development Monitored by Noninvasive In vivo Positron Emission Tomography Imaging , 2005, Clinical Cancer Research.

[115]  M. Soleimani,et al.  Mesenchymal stem cells as vehicles for targeted delivery of anti‐angiogenic protein to solid tumors , 2011, The journal of gene medicine.

[116]  H. Friess,et al.  Improved lentiviral transduction of human mesenchymal stem cells for therapeutic intervention in pancreatic cancer , 2008, Cancer Gene Therapy.

[117]  D. Whitcomb.  Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[118]  A. Maitra,et al.  Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[119]  C. Hill,et al.  Smad4 Dependency Defines Two Classes of Transforming Growth Factor β (TGF-β) Target Genes and Distinguishes TGF-β-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses , 2005, Molecular and Cellular Biology.

[120]  Gerald C. Chu,et al.  Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. , 2006, Genes & development.

[121]  David Goldstein,et al.  Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. , 2013, The New England journal of medicine.

[122]  A. Larue,et al.  Hematopoietic origin of fibroblasts/myofibroblasts: Its pathophysiologic implications. , 2006, Blood.

[123]  Philippe Soriano,et al.  Roles of PDGF in animal development , 2003, Development.

[124]  Malte Buchholz,et al.  Stromal biology and therapy in pancreatic cancer , 2010, Gut.

[125]  D. Klimstra,et al.  K-ras mutations in pancreatic ductal proliferative lesions. , 1994, The American journal of pathology.

[126]  K. Xie,et al.  Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. , 2012, Cytokine & growth factor reviews.

[127]  G. Tortora,et al.  LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis , 2008, Molecular Cancer Therapeutics.

[128]  M. Boermeester,et al.  Treatment options for chronic pancreatitis , 2014, Nature Reviews Gastroenterology &Hepatology.

[129]  H. Thaler,et al.  Pain as a predictor of outcome in patients with operable pancreatic carcinoma. , 1997, Surgery.

[130]  J. Ringel,et al.  Transforming Growth Factor-β1 Induces Desmoplasia in an Experimental Model of Human Pancreatic Carcinoma , 2001 .

[131]  R. Hruban,et al.  Gastrointestinal Cancer : Targets and Therapy Precursors to invasive pancreatic cancer , 2012 .

[132]  G. Adler,et al.  Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[133]  A. Nicholson,et al.  Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. , 2005, The American journal of pathology.

[134]  H. Friess,et al.  Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling , 2008, Journal of cellular and molecular medicine.

[135]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[136]  D. V. Von Hoff,et al.  Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer , 2014, Expert review of gastroenterology & hepatology.

[137]  J. Folkman.  What is the evidence that tumors are angiogenesis dependent? , 1990, Journal of the National Cancer Institute.

[138]  Jiong Chen,et al.  Profiling the potential tumor markers of pancreatic ductal adenocarcinoma using 2D-DIGE and MALDI-TOF-MS: up-regulation of Complement C3 and alpha-2-HS-glycoprotein. , 2013, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[139]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[140]  K. Sugano,et al.  Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines. , 2007, American journal of physiology. Cell physiology.

[141]  S. Saga,et al.  Relation of pancreatic duct hyperplasia to carcinoma , 1979, Cancer.

[142]  Gerald C. Chu,et al.  Stromal biology of pancreatic cancer , 2007, Journal of cellular biochemistry.

[143]  J. Abbruzzese,et al.  Developmental biology informs cancer: the emerging role of the hedgehog signaling pathway in upper gastrointestinal cancers. , 2003, Cancer cell.

[144]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[145]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[146]  D. Tuveson,et al.  nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. , 2012, Cancer discovery.

[147]  R. D'Amato,et al.  Analysis of tumor‐associated stromal cells using SCID GFP transgenic mice: contribution of local and bone marrow‐derived host cells , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[148]  C. Iacobuzio-Donahue,et al.  Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. , 2007, Cancer research.

[149]  R. Toftgård,et al.  Hedgehog beyond medulloblastoma and basal cell carcinoma. , 2010, Biochimica et biophysica acta.

[150]  D. Simeone,et al.  Recent advances in pancreatic surgery , 2014, Current opinion in gastroenterology.

[151]  H. Tian,et al.  Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis , 2009, Proceedings of the National Academy of Sciences.