Stromal biology and therapy in pancreatic cancer: a changing paradigm

Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour–stroma with translational implications for future therapy and clinical trial design.

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

[2]  M. Spector,et al.  Organoid Models of Human and Mouse Ductal Pancreatic Cancer , 2015, Cell.

[3]  I. Salmon,et al.  Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma , 2014, Clinical Cancer Research.

[4]  Mauro Ferrari,et al.  Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer , 2014, Physical biology.

[5]  Christian Veltkamp,et al.  A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer , 2014, Nature Medicine.

[6]  G. Wahl,et al.  Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy , 2014, Cell.

[7]  Bin Zhang,et al.  Cancer Immunology and Cancer Immunodiagnosis , 2014, Journal of immunology research.

[8]  Daniel Öhlund,et al.  Fibroblast heterogeneity in the cancer wound , 2014, The Journal of experimental medicine.

[9]  D. Tuveson,et al.  Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment , 2014, BioMed research international.

[10]  R. Wong,et al.  Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase , 2014, Oncogene.

[11]  H. Kocher,et al.  Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation. , 2014, World journal of gastroenterology.

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

[13]  M. Korc,et al.  Pancreatic cancer stroma: friend or foe? , 2014, Cancer cell.

[14]  Stephen A. Sastra,et al.  Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. , 2014, Cancer cell.

[15]  M. Lesina,et al.  The immune network in pancreatic cancer development and progression , 2014, Oncogene.

[16]  A. Maitra,et al.  Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. , 2014, Cancer cell.

[17]  W. Bamlet,et al.  Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. , 2014, Cancer discovery.

[18]  Mauro Ferrari,et al.  Transport properties of pancreatic cancer describe gemcitabine delivery and response. , 2014, The Journal of clinical investigation.

[19]  F. Bendtsen,et al.  Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study. , 2014, Gastroenterology.

[20]  D. Fearon The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance , 2014, Cancer immunology research.

[21]  P. Greenberg,et al.  Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity , 2014, Gut.

[22]  N. Lemoine,et al.  Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion , 2014, EMBO molecular medicine.

[23]  K. Politi,et al.  Translational therapeutics in genetically engineered mouse models of cancer. , 2014, Cold Spring Harbor protocols.

[24]  S. Lowe,et al.  A modular and flexible ESC-based mouse model of pancreatic cancer , 2014, Genes & development.

[25]  T. Gress,et al.  CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling , 2013, Oncogene.

[26]  Derek S. Chan,et al.  Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer , 2013, Proceedings of the National Academy of Sciences.

[27]  J. Gribben,et al.  Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. , 2013, Gastroenterology.

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

[29]  Triantafyllos Stylianopoulos,et al.  Combining two strategies to improve perfusion and drug delivery in solid tumors , 2013, Proceedings of the National Academy of Sciences.

[30]  H. Kocher,et al.  The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration , 2013, Oncoimmunology.

[31]  Rakesh K. Jain,et al.  Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels , 2013, Nature Communications.

[32]  Derek S. Chan,et al.  SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice , 2013, Gut.

[33]  L. De Monte,et al.  Immune infiltrates as predictive markers of survival in pancreatic cancer patients , 2013, Front. Physiol..

[34]  Zhao-You Tang,et al.  Intratumoral α-SMA Enhances the Prognostic Potency of CD34 Associated with Maintenance of Microvessel Integrity in Hepatocellular Carcinoma and Pancreatic Cancer , 2013, PloS one.

[35]  C. Pilarsky,et al.  CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer , 2013, Proceedings of the National Academy of Sciences.

[36]  C. Garlanda,et al.  Tumor associated macrophages and neutrophils in tumor progression , 2013, Journal of cellular physiology.

[37]  James O. Jones,et al.  Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia , 2013, The Journal of experimental medicine.

[38]  P. Allavena,et al.  Tumor-associated macrophages: functional diversity, clinical significance, and open questions , 2013, Seminars in Immunopathology.

[39]  F. Di Maggio,et al.  Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes , 2013, The Journal of pathology.

[40]  C. Verbeke,et al.  3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing , 2013, BMC Cancer.

[41]  M. Zucchetti,et al.  Role of macrophage targeting in the antitumor activity of trabectedin. , 2013, Cancer cell.

[42]  Lincoln D. Stein,et al.  Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes , 2012, Nature.

[43]  Isabelle Salmon,et al.  Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. , 2012, Gastroenterology.

[44]  Atsuo Ochi,et al.  MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells , 2012, The Journal of experimental medicine.

[45]  Derek S. Chan,et al.  The Pancreas Cancer Microenvironment , 2012, Clinical Cancer Research.

[46]  I. Yeh Faculty Opinions recommendation of Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. , 2012 .

[47]  Alexander A. Fingerle,et al.  The role of stroma in pancreatic cancer: diagnostic and therapeutic implications , 2012, Nature Reviews Gastroenterology &Hepatology.

[48]  N. Jhala,et al.  Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. , 2012, Cancer cell.

[49]  D. Bar-Sagi,et al.  Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. , 2012, Cancer cell.

[50]  D. Tuveson,et al.  Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions , 2012, Gut.

[51]  M. Fukuda,et al.  Faculty Opinions recommendation of Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. , 2012 .

[52]  M. Barbacid,et al.  What we have learned about pancreatic cancer from mouse models. , 2012, Gastroenterology.

[53]  G. Kristiansen,et al.  The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma , 2012, Nature.

[54]  Derek S. Chan,et al.  Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer , 2012, Gut.

[55]  Carlos Cuevas,et al.  Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[56]  L. Coussens,et al.  Accessories to the crime: functions of cells recruited to the tumor microenvironment. , 2012, Cancer cell.

[57]  D. Tuveson,et al.  Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma , 2012, The Journal of experimental medicine.

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

[59]  T. Gress,et al.  Restricted heterochromatin formation links NFATc2 repressor activity with growth promotion in pancreatic cancer. , 2012, Gastroenterology.

[60]  C. Galbán,et al.  Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. , 2012, The Journal of clinical investigation.

[61]  Hans Clevers,et al.  Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression. , 2011, Gastroenterology.

[62]  P. Mazur,et al.  Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology , 2011, Gut.

[63]  Pierre Michel,et al.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. , 2011, The New England journal of medicine.

[64]  Shizuo Akira,et al.  Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. , 2011, Cancer cell.

[65]  S. Akira,et al.  Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. , 2011, Cancer cell.

[66]  Drew A. Torigian,et al.  CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans , 2011, Science.

[67]  M. Braga,et al.  Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer , 2011, The Journal of experimental medicine.

[68]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[69]  Lia S. Campos,et al.  PiggyBac Transposon Mutagenesis: A Tool for Cancer Gene Discovery in Mice , 2010, Science.

[70]  P. O'Connor,et al.  Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models , 2010, Molecular Cancer Therapeutics.

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

[72]  Peter Olson,et al.  Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner. , 2010, Cancer cell.

[73]  P. Catalano,et al.  Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[75]  Helmut Friess,et al.  The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[76]  V. Kosma,et al.  Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. , 2008, Seminars in cancer biology.

[77]  David Goldstein,et al.  Pancreatic stellate cells: partners in crime with pancreatic cancer cells. , 2008, Cancer research.

[78]  D. Tuveson,et al.  Dynamics of the immune reaction to pancreatic cancer from inception to invasion. , 2007, Cancer research.

[79]  Murray Korc,et al.  Pancreatic cancer-associated stroma production. , 2007, American journal of surgery.

[80]  David A. Tuveson,et al.  Maximizing mouse cancer models , 2007, Nature Reviews Cancer.

[81]  Gary Clark,et al.  Correlation between Development of Rash and Efficacy in Patients Treated with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib in Two Large Phase III Studies , 2007, Clinical Cancer Research.

[82]  W. Scheithauer,et al.  Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[84]  H. Moses,et al.  Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. , 2006, Genes & development.

[85]  H. Einsele,et al.  Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  Prasenjit Dey,et al.  Genetics and biology of pancreatic ductal adenocarcinoma , 2006, Genes & development.

[87]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[88]  Ralph Weissleder,et al.  Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[89]  R. Labianca,et al.  Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[90]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[91]  A. Buck,et al.  Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. , 2005, Gastroenterology.

[92]  W. Miller,et al.  Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[93]  R. DePinho,et al.  Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. , 2003, Genes & development.

[94]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[95]  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.

[96]  Daniel G Haller,et al.  Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[97]  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.

[98]  G. Colucci,et al.  Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma , 2002, Cancer.

[99]  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.

[100]  R H Hruban,et al.  Progression model for pancreatic cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[101]  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.

[102]  Scott E. Kern,et al.  DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1 , 1996, Science.

[103]  N. Pellegata,et al.  K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. , 1994, Cancer research.

[104]  D. Shibata,et al.  Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes , 1988, Cell.

[105]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[106]  C. O'neill,et al.  Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. , 1966, Journal of cell science.

[107]  A. Jemal,et al.  Cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[108]  John R. Mackey,et al.  Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. , 2014, Journal of the National Cancer Institute.

[109]  Stephen A. Sastra,et al.  Quantification of murine pancreatic tumors by high-resolution ultrasound. , 2013, Methods in molecular biology.

[110]  R. DePinho,et al.  Genetics and biology of pancreatic ductal adenocarcinoma , 2006, Genes & development.

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