Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2
Tailored treatment for cancer in obesity - Antiangiogenic therapy with inhibitors of the vascular endothelial growth factor (VEGF) has not proven effective in patients with many tumor types, including breast cancer. Meanwhile, obesity is a well-known risk factor in many cancer types, and once again,...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
14 Mar 2018
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| In: |
Science translational medicine
Year: 2018, Volume: 10, Issue: 432 |
| ISSN: | 1946-6242 |
| DOI: | 10.1126/scitranslmed.aag0945 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1126/scitranslmed.aag0945 Verlag, Volltext: https://stm.sciencemag.org/content/10/432/eaag0945 
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| Author Notes: | Joao Incio, Jennifer A. Ligibel, Daniel T. McManus, Priya Suboj, Keehoon Jung, Kosuke Kawaguchi, Matthias Pinter, Suboj Babykutty, Shan M. Chin, Trupti D. Vardam, Yuhui Huang, Nuh N. Rahbari, Sylvie Roberge, Dannie Wang, Igor L. Gomes-Santos, Stefan B. Puchner, Christopher L. Schlett, Udo Hoffmman, Marek Ancukiewicz, Sara M. Tolaney, Ian E. Krop, Dan G. Duda, Yves Boucher, Dai Fukumura, Rakesh K. Jain |
| Summary: | Tailored treatment for cancer in obesity - Antiangiogenic therapy with inhibitors of the vascular endothelial growth factor (VEGF) has not proven effective in patients with many tumor types, including breast cancer. Meanwhile, obesity is a well-known risk factor in many cancer types, and once again, this includes breast cancer. Now, Incio et al. link these two observations, having discovered a mechanism by which obesity promotes resistance to VEGF inhibitor therapy through increased interleukin-6 and possibly also fibroblast growth factor 2 in the tumor microenvironment. The authors target these pathways in mouse models of cancer with and without obesity and demonstrate that the deleterious effects of obesity on VEGF inhibition can be overcome through the appropriate combination therapy. - 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. - Targeting IL-6 and potentially FGF-2 overcomes resistance to anti-VEGF therapy in breast cancer. - Targeting IL-6 and potentially FGF-2 overcomes resistance to anti-VEGF therapy in breast cancer. |
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| Item Description: | Gesehen am 23.01.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1946-6242 |
| DOI: | 10.1126/scitranslmed.aag0945 |