Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy.

UNLABELLED It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity. SIGNIFICANCE Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803.

[1]  R. Jain,et al.  Obesity and Cancer: An Angiogenic and Inflammatory Link , 2016, Microcirculation.

[2]  P. Carmeliet,et al.  PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity , 2016, Clinical Cancer Research.

[3]  K. Felix,et al.  Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression , 2016, International journal of biological sciences.

[4]  R. Jain,et al.  Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages , 2015, PloS one.

[5]  V. LeBleu,et al.  EMT Program is Dispensable for Metastasis but Induces Chemoresistance in Pancreatic Cancer , 2015, Nature.

[6]  Caroline H. Diep,et al.  Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer , 2015, Clinical Cancer Research.

[7]  R. DePinho,et al.  Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. , 2014, Cancer cell.

[8]  A. Giatromanolaki,et al.  Neutrophil extracellular traps promote differentiation and function of fibroblasts , 2014, The Journal of pathology.

[9]  Y. Ueno,et al.  Pancreatic Fat Accumulation, Fibrosis, and Acinar Cell Injury in the Zucker Diabetic Fatty Rat Fed a Chronic High-Fat Diet , 2014, Pancreas.

[10]  X. Yuan,et al.  The IL-6–STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression , 2014, Cell Death and Disease.

[11]  Y. Kanai,et al.  Association of Pancreatic Fatty Infiltration With Pancreatic Ductal Adenocarcinoma , 2014, Clinical and Translational Gastroenterology.

[12]  K. Flegal,et al.  Prevalence of childhood and adult obesity in the United States, 2011-2012. , 2014, JAMA.

[13]  C. Roland,et al.  A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. , 2013, Gastroenterology.

[14]  P. Kraft,et al.  Prediagnostic body mass index and pancreatic cancer survival. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  K. Clément,et al.  Fibrosis and adipose tissue dysfunction. , 2013, Cell metabolism.

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

[17]  Y Quijano,et al.  Stromal disrupting effects of nab-paclitaxel in pancreatic cancer , 2013, British Journal of Cancer.

[18]  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.

[19]  B. Rueda,et al.  Tumor Angiogenesis Regulators , 2013 .

[20]  P. Scherer,et al.  Adipocytes: impact on tumor growth and potential sites for therapeutic intervention. , 2013, Pharmacology & therapeutics.

[21]  A. Palucka,et al.  Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet? , 2013, Science.

[22]  Philippe Valet,et al.  Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. , 2012, Cancer letters.

[23]  S. Hursting.  Minireview: the year in obesity and cancer. , 2012, Molecular endocrinology.

[24]  S. Hursting,et al.  Obesity, metabolic dysregulation, and cancer: a growing concern and an inflammatory (and microenvironmental) issue , 2012, Annals of the New York Academy of Sciences.

[25]  Triantafyllos Stylianopoulos,et al.  Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors , 2012, Proceedings of the National Academy of Sciences.

[26]  Manuel Hidalgo,et al.  Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas , 2012, Clinical Cancer Research.

[27]  M. Büchler,et al.  Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. , 2012, JAMA.

[28]  K. Lillemoe,et al.  Obesity, But Not High-Fat Diet, Promotes Murine Pancreatic Cancer Growth , 2012, Journal of Gastrointestinal Surgery.

[29]  R. Gibbs,et al.  Genomic sequencing of key genes in mouse pancreatic cancer cells. , 2012, Current molecular medicine.

[30]  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.

[31]  P. Bracci.  Obesity and pancreatic cancer: Overview of epidemiologic evidence and biologic mechanisms , 2012, Molecular carcinogenesis.

[32]  P. A. van den Brandt,et al.  A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk , 2011, International journal of cancer.

[33]  Olca Basturk,et al.  Tumor-infiltrating neutrophils in pancreatic neoplasia , 2011, Modern Pathology.

[34]  Yuan Yuan Wang,et al.  Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. , 2011, Cancer research.

[35]  M. Smits,et al.  The clinical significance of pancreatic steatosis , 2011, Nature Reviews Gastroenterology &Hepatology.

[36]  R. Jain,et al.  Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors , 2011, Proceedings of the National Academy of Sciences.

[37]  Daisuke Koya,et al.  Biology of Obesity: Lessons from Animal Models of Obesity , 2011, Journal of biomedicine & biotechnology.

[38]  W. Bamlet,et al.  Obesity adversely affects survival in pancreatic cancer patients , 2010, Cancer.

[39]  H. Pitt,et al.  Insulin, Leptin, and Tumoral Adipocytes Promote Murine Pancreatic Cancer Growth , 2010, Journal of Gastrointestinal Surgery.

[40]  Jon W. Huss,et al.  BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources , 2009, Genome Biology.

[41]  H. Lan,et al.  Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor–&bgr;–Dependent and –Independent Smad Pathways: The Role of Smad3 , 2009, Hypertension.

[42]  G. Cheng,et al.  Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. , 2009, Cancer cell.

[43]  H. Pitt,et al.  Obesity potentiates the growth and dissemination of pancreatic cancer. , 2009, Surgery.

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

[45]  K. Lillemoe,et al.  Pancreatic steatosis promotes dissemination and lethality of pancreatic cancer. , 2009, Journal of the American College of Surgeons.

[46]  R. Jain,et al.  Blockade of VEGFR2 and Not VEGFR1 Can Limit Diet-Induced Fat Tissue Expansion: Role of Local versus Bone Marrow-Derived Endothelial Cells , 2009, PloS one.

[47]  A. Walch,et al.  Inflammation and mitochondrial fatty acid β-oxidation link obesity to early tumor promotion , 2009, Proceedings of the National Academy of Sciences.

[48]  Lixin Wei,et al.  Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells , 2008, BMC Cancer.

[49]  H. Pitt,et al.  A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

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

[51]  H. Pitt,et al.  Nonalcoholic fatty pancreas disease. , 2007, HPB : the official journal of the International Hepato Pancreato Biliary Association.

[52]  Raquel Soares,et al.  Angiogenesis and chronic inflammation: cause or consequence? , 2007, Angiogenesis.

[53]  M. Matsuda,et al.  Adipose Tissue Hypoxia in Obesity and Its Impact on Adipocytokine Dysregulation , 2007, Diabetes.

[54]  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.

[55]  K. Sugano,et al.  Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway. , 2006, Biochemical and biophysical research communications.

[56]  J. Testa,et al.  Perturbations of the AKT signaling pathway in human cancer , 2005, Oncogene.

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

[58]  K. Venkatasubbarao,et al.  Alterations of cell signaling pathways in pancreatic cancer. , 2004, Frontiers in bioscience : a journal and virtual library.

[59]  K. Sugano,et al.  Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation. , 2004, Biochemical and biophysical research communications.

[60]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[61]  R. Jain,et al.  Paracrine Regulation of Angiogenesis and Adipocyte Differentiation During In Vivo Adipogenesis , 2003, Circulation research.

[62]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[63]  A. Masamune,et al.  Inhibition of p38 Mitogen-Activated Protein Kinase Blocks Activation of Rat Pancreatic Stellate Cells , 2003, Journal of Pharmacology and Experimental Therapeutics.

[64]  C. Wright,et al.  The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors , 2002, Nature Genetics.

[65]  S. Raiden,et al.  Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits neutrophil recruitment in the lung triggered by fMLP , 2000, Journal of leukocyte biology.

[66]  S. Raiden,et al.  Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits the binding of N-formylmethionyl-leucyl-phenylalanine to neutrophil receptors. , 1997, The Journal of pharmacology and experimental therapeutics.

[67]  J. Rodin,et al.  Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. , 1995, Metabolism: clinical and experimental.

[68]  H. Dvorak.  Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. , 1986, The New England journal of medicine.

[69]  M Intaglietta,et al.  Tissue perfusion inhomogeneity during early tumor growth in rats. , 1979, Journal of the National Cancer Institute.

[70]  M. Korc,et al.  Signaling pathways in pancreatic cancer. , 2011, Critical reviews in eukaryotic gene expression.

[71]  Jeffrey S. Morris,et al.  Body Mass Index and Risk , Age of Onset , and Survival in Patients With Pancreatic Cancer , 2009 .

[72]  R. Jain,et al.  Blockade of VEGFR 2 and Not VEGFR 1 Can Limit Diet-Induced Fat Tissue Expansion : Role of Local versus Bone Marrow-Derived Endothelial Cells , 2009 .

[73]  A. Masamune,et al.  Inhibition of p 38 Mitogen-Activated Protein Kinase Blocks Activation of Rat Pancreatic Stellate Cells , 2002 .

[74]  P. Gullino,et al.  Studies on the exchange of fluids between host and tumor. III. Regulation of blood flow in hepatomas and other rat tumors. , 1962, Journal of the National Cancer Institute.