title: PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity.
abstract: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity.
  
  
  
  We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples.
  
  
  
  We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity.
  
  
  
  Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR.
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal. Department of Internal Medicine, Hospital S. João, Porto, Portugal.
authors: Joao
authors: J
authors: Incio
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Josh
authors: J
authors: Tam
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Surgery, Dresden University of Technology, Dresden, Germany.
authors: Nuh N
authors: NN
authors: Rahbari
authors: 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: Priya
authors: P
authors: Suboj
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. University of Massachusetts, Boston, Massachusetts.
authors: Dan T
authors: DT
authors: McManus
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Shan M
authors: SM
authors: Chin
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Mayo Clinic College of Medicine, Scottsdale, Arizona.
authors: Trupti D
authors: TD
authors: Vardam
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Ana
authors: A
authors: Batista
authors: 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: Suboj
authors: S
authors: Babykutty
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Keehoon
authors: K
authors: Jung
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Anna
authors: A
authors: Khachatryan
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Surgery, KeioUniversity School of Medicine, Tokyo, Japan.
authors: Tai
authors: T
authors: Hato
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: Jennifer A
authors: JA
authors: Ligibel
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: Ian E
authors: IE
authors: Krop
authors: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna, Austria.
authors: Stefan B
authors: SB
authors: Puchner
authors: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Christopher L
authors: CL
authors: Schlett
authors: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Udo
authors: U
authors: Hoffmman
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. PAREXEL International, Billerica, Massachusetts.
authors: Marek
authors: M
authors: Ancukiewicz
authors: Institute of Physiology and Medicine, Jobu University, Takasaki, Gunma, Japan.
authors: Masabumi
authors: M
authors: Shibuya
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, K.U. Leuven and VIB, Leuven, Belgium.
authors: Peter
authors: P
authors: Carmeliet
authors: I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.
authors: Raquel
authors: R
authors: Soares
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Dan G
authors: DG
authors: Duda
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu.
authors: Rakesh K
authors: RK
authors: Jain
authors: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu.
authors: Dai
authors: D
authors: Fukumura
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D059305:Diet, High-Fat; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009389:Neovascularization, Pathologic / Q000235:genetics; D009765:Obesity / Q000276:immunology / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology*; D000072483:Placenta Growth Factor / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; C000608037:Pgf protein, mouse; D000072483:Placenta Growth Factor; D008687:Metformin; D040281:Vascular Endothelial Growth Factor Receptor-1; D005947:Glucose