{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T20:01:17Z","timestamp":1772308877861,"version":"3.50.1"},"reference-count":60,"publisher":"American Association for Cancer Research (AACR)","issue":"12","funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R35-CA197743, CA080124, CA085140, CA096915, CA115767, CA126642"],"award-info":[{"award-number":["R35-CA197743, CA080124, CA085140, CA096915, CA115767, CA126642"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005979","name":"Lustgarten Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005979","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense Breast Cancer Research Innovator","doi-asserted-by":"publisher","award":["W81XWH-10-1-0016"],"award-info":[{"award-number":["W81XWH-10-1-0016"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Warshaw Institute for Pancreatic Cancer Research"},{"DOI":"10.13039\/501100001871","name":"Foundation for Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Purpose: 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.<\/jats:p>\n                  <jats:p>Experimental Design: 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.<\/jats:p>\n                  <jats:p>Results: 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.<\/jats:p>\n                  <jats:p>Conclusions: Targeting PlGF\/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993\u20133004. \u00a92016 AACR.<\/jats:p>","DOI":"10.1158\/1078-0432.ccr-15-1839","type":"journal-article","created":{"date-parts":[[2016,2,9]],"date-time":"2016-02-09T22:59:11Z","timestamp":1455058751000},"page":"2993-3004","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["PlGF\/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity"],"prefix":"10.1158","volume":"22","author":[{"given":"Joao","family":"Incio","sequence":"first","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"2I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal."},{"name":"3Department of Internal Medicine, Hospital S. Jo\u00e3o, Porto, Portugal."}]},{"given":"Josh","family":"Tam","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"4Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Nuh N.","family":"Rahbari","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"5Department of Surgery, Dresden University of Technology, Dresden, Germany."}]},{"given":"Priya","family":"Suboj","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"6Department of Botany and Biotechnology, St. Xaviers College, Thumba, Trivandrum, Kerala, India."}]},{"given":"Dan T.","family":"McManus","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"7University of Massachusetts, Boston, Massachusetts."}]},{"given":"Shan M.","family":"Chin","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Trupti D.","family":"Vardam","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"8Mayo Clinic College of Medicine, Scottsdale, Arizona."}]},{"given":"Ana","family":"Batista","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Suboj","family":"Babykutty","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"9Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India."}]},{"given":"Keehoon","family":"Jung","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Anna","family":"Khachatryan","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Tai","family":"Hato","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"10Department of Surgery, KeioUniversity School of Medicine, Tokyo, Japan."}]},{"given":"Jennifer A.","family":"Ligibel","sequence":"additional","affiliation":[{"name":"11Department of Medical Oncology, Dana\u2013Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Ian E.","family":"Krop","sequence":"additional","affiliation":[{"name":"11Department of Medical Oncology, Dana\u2013Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Stefan B.","family":"Puchner","sequence":"additional","affiliation":[{"name":"12Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"13Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna, Austria."}]},{"given":"Christopher L.","family":"Schlett","sequence":"additional","affiliation":[{"name":"12Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"14Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany."}]},{"given":"Udo","family":"Hoffmman","sequence":"additional","affiliation":[{"name":"12Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Marek","family":"Ancukiewicz","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."},{"name":"15PAREXEL International, Billerica, Massachusetts."}]},{"given":"Masabumi","family":"Shibuya","sequence":"additional","affiliation":[{"name":"16Institute of Physiology and Medicine, Jobu University, Takasaki, Gunma, Japan."}]},{"given":"Peter","family":"Carmeliet","sequence":"additional","affiliation":[{"name":"17Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, K.U. Leuven and VIB, Leuven, Belgium."}]},{"given":"Raquel","family":"Soares","sequence":"additional","affiliation":[{"name":"2I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal."}]},{"given":"Dan G.","family":"Duda","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Rakesh K.","family":"Jain","sequence":"additional","affiliation":[{"name":"1Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts."}]},{"given":"Dai","family":"Fukumura","sequence":"additional","affiliation":[{"name":"1Edwin L. 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