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Clin Cancer Res. 2016 Jun 15;22(12):2993-3004. doi: 10.1158/1078-0432.CCR-15-1839. Epub 2016 Feb 9.

PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity.

Author information

1
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.
2
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.
3
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.
4
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.
5
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. University of Massachusetts, Boston, Massachusetts.
6
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
7
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Mayo Clinic College of Medicine, Scottsdale, Arizona.
8
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.
9
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.
10
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
11
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna, Austria.
12
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany.
13
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
14
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. PAREXEL International, Billerica, Massachusetts.
15
Institute of Physiology and Medicine, Jobu University, Takasaki, Gunma, Japan.
16
Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, K.U. Leuven and VIB, Leuven, Belgium.
17
I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.
18
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.

Abstract

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.

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.

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.

CONCLUSIONS:

Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR.

PMID:
26861455
PMCID:
PMC4911258
DOI:
10.1158/1078-0432.CCR-15-1839
[Indexed for MEDLINE]
Free PMC Article

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