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Sci Transl Med. 2018 Mar 14;10(432). pii: eaag0945. doi: 10.1126/scitranslmed.aag0945.

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2.

Author information

1
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
2
I3S, Institute for Innovation and Research in Health, Metabolism, Nutrition, and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto 4200-135, Portugal.
3
Department of Internal Medicine, Hospital S. João, Porto 4200-319, Portugal.
4
Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Botany and Biotechnology, St. Xavier's College, Thumba, Trivandrum, Kerala 695586, India.
6
Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria.
7
Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala 695015, India.
8
Heart Institute (Instituto do Coração-Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo), University of Sao Paulo Medical School, Sao Paulo 05403-900, Brazil.
9
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
10
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. jain@steele.mgh.harvard.edu dai@steele.mgh.harvard.edu.

Abstract

Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.

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