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

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Incio, Joao ^{[1, 2, 3]} ; Ligibel, Jennifer A. ^[4] ; McManus, Daniel T. ^{[1, 5]} ; Suboj, Priya ^{[1, 6]} ; Jung, Keehoon ^[1] ; Kawaguchi, Kosuke ^[1] ; Pinter, Matthias ^{[1, 7]} ; Babykutty, Suboj ^{[1, 8]} ; Chin, Shan M. ^[1] ; Vardam, Trupti D. ^{[1, 9]} ; Huang, Yuhui ^{[1, 10]} ; Rahbari, Nuh N. ^{[1, 11]} ; Roberge, Sylvie ^[1] ; Wang, Dannie ^{[1, 12]} ; Gomes-Santos, Igor L. ^{[1, 13]} ; Puchner, Stefan B. ^{[14, 15]} ; Schlett, Christopher L. ^{[14, 16]} ; Hoffmman, Udo ^[14] ; Ancukiewicz, Marek ^{[1, 17]} ; Tolaney, Sara M. ^[4] ; Krop, Ian E. ^[4] ; Duda, Dan G. ^[1] ; Boucher, Yves ^[1] ; Fukumura, Dai ^[1] ; Jain, Rakesh K. ^[1]

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^[1] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 - USA

^[2] Univ Porto, Inst Innovat & Res Hlth, Biochem Dept, Metab Nutr & Endocrinol Grp, I3S, Fac Med, P-4200135 Porto - Portugal

^[3] Hosp Sao Joao, Dept Internal Med, P-4200319 Porto - Portugal

^[4] Harvard Med Sch, Dana Farber Canc Ctr, Boston, MA 02115 - USA

^[5] NIAID, Lab Clin Immunol & Microbiol, Viral Immun & Pathogenesis Unit, NIH, 33 North Dr, Bethesda, MD 20814 - USA

^[6] St Xaviers Coll, Dept Bot & Biotechnol, Trivandrum 695586, Kerala - India

^[7] Med Univ Vienna, Div Gastroenterol & Hepatol, Dept Internal Med 3, A-1090 Vienna - Austria

^[8] Mar Ivanios Coll, Dept Zool, Trivandrum 695015, Kerala - India

^[9] Mayo Clin, Coll Med, Scottsdale, AZ 85259 - USA

^[10] Soochow Univ, Cyrus Tang Hematol Ctr, Wuzhong 215100, Jiangsu - Peoples R China

^[11] Mem Sloan Kettering Canc Ctr, Surg Oncol, 1275 York Ave, New York, NY 10065 - USA

^[12] Radius Hlth Inc, Waltham, MA 02451 - USA

^[13] Univ Sao Paulo, Med Sch, Fac Med, Inst Coracao, Hosp Clin, Heart Inst, BR-05403900 Sao Paulo - Brazil

^[14] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 - USA

^[15] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, A-1090 Vienna - Austria

^[16] Univ Hosp Heidelberg, Dept Diagnost & Intervent Radiol, D-69120 Heidelberg - Germany

^[17] Alnylam Pharmaceut, Cambridge, MA 02142 - USA

• Tipo de documento: Artigo Científico
• Fonte: Science Translational Medicine; v. 10, n. 432 MAR 14 2018.
• Citações Web of Science: 24

Resumo

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. (AU)

• Processo FAPESP: 16/21320-1 - Influência do exercício aeróbico sobre a entrega de drogas e resposta à quimioterapia baseada em doxorrubicina em câncer de mama associado à obesidade
• Beneficiário: Igor Lucas Gomes dos Santos
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado