title: Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy.
abstract: 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.
  
  
  
  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.
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Internal Medicine, Hospital S. Joao, Porto, Portugal. I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Incio
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Botany and Biotechnology, St. Xaviers College, Thumba, Trivandrum, Kerala, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Suboj
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shan M
authors.initials: SM
authors.lastname: Chin
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts.
authors.forename: Ivy X
authors.initials: IX
authors.lastname: Chen
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthias
authors.initials: M
authors.lastname: Pinter
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mei R
authors.initials: MR
authors.lastname: Ng
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hadi T
authors.initials: HT
authors.lastname: Nia
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jelena
authors.initials: J
authors.lastname: Grahovac
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shannon
authors.initials: S
authors.lastname: Kao
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India.
authors.forename: Suboj
authors.initials: S
authors.lastname: Babykutty
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Keehoon
authors.initials: K
authors.lastname: Jung
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Han
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vikash P
authors.initials: VP
authors.lastname: Chauhan
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: John D
authors.initials: JD
authors.lastname: Martin
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Julia
authors.initials: J
authors.lastname: Kahn
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vikram
authors.initials: V
authors.lastname: Desphande
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Laboratory for Quantitative Medicine, and Division of Surgical Oncology, Gillette Center for Women's Cancers, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: James
authors.initials: J
authors.lastname: Michaelson
authors.affiliation: Departments of Gastroenterology and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Theodoros P
authors.initials: TP
authors.lastname: Michelakos
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Departments of Gastroenterology and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Soares
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. jain@steele.mgh.harvard.edu dai@steele.mgh.harvard.edu.
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. jain@steele.mgh.harvard.edu dai@steele.mgh.harvard.edu.
authors.forename: Rakesh K
authors.initials: RK
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mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015992:Body Mass Index; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology; D003131:Combined Modality Therapy; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000209:etiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D053583:Interleukin-1beta; D044140:Receptor, Angiotensin, Type 1