编者按：由于肿瘤的生长需要大量血管输送血液提供营养，故科学家希望通过血管内皮生长因子（VEGF）靶向疗法“饿死”肿瘤，但是VEGF抑制剂（例如著名的贝伐珠单抗）无法改善多种癌症（包括乳腺癌）患者的生存。VEGF抑制剂耐药的可能机制，包括促炎因子和其他促血管生成因子的上调。同时，众所周知，肥胖为多种癌症的风险因素（同样包括乳腺癌）。肥胖与脂肪组织（包括乳房脂肪组织）缺氧相关，导致上述某些耐药因素产生增加。既往研究已经发现，乳腺癌肥胖患者的白细胞介素-6（IL-6）和成纤维细胞生长因子-2（FGF-2）全身浓度增加，并且此类患者的肿瘤血管对VEGF抑制剂较不敏感。因此，肥胖可能使VEGF抑制剂无效，明确具体机制有助于解决乳腺癌血管靶向疗法耐药。
2018年3月14日，美国科学促进会《科学》旗下《转化医学》在线发表美国哈佛大学医学院、麻省总医院、达纳法伯癌症中心、奥地利维也纳医科大学、葡萄牙波尔图大学和圣约翰医院、印度圣沙勿略学院和伊凡尼斯学院、巴西圣保罗大学的研究报告，发现肥胖可上调IL-6和/或FGF-2使乳腺癌VEGF抑制剂耐药。
该研究通过小鼠模型表明，肥胖可以减弱VEGF抑制剂对血管生成、肿瘤生长和转移的作用。对于小鼠乳腺癌模型，肥胖与肿瘤的脂肪细胞和髓样细胞产生IL-6增加相关。利用IL-6抑制剂可以直接影响肿瘤细胞增殖、使肿瘤血管正常化、缓解缺氧、减少免疫抑制，从而消除肥胖诱导原发和转移部位VEGF抑制剂耐药。同样，对于小鼠乳腺癌模型，肥胖与FGF-2增加相关，利用二甲双胍或特异性FGF受体抑制剂，使FGF-2表达正常化，可以减少肥胖小鼠的血管密度，并且恢复肿瘤对VEGF抑制剂的敏感性。
因此，该研究数据表明，肥胖可产生炎症因子和血管生成刺激因子，使乳腺癌对VEGF抑制剂耐药。该研究结果证明，肥胖对VEGF抑制剂的不利作用，可以通过合适的联合疗法克服，为贝伐珠单抗等VEGF抑制剂联合IL-6抑制剂和/或FGF-2抑制剂治疗乳腺癌重燃希望。
Sci Transl Med. 2018 Mar 14;10(432):eaag0945.
Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2.
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.
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Center, Harvard Medical School, Boston, MA, USA; Medical University of Vienna, Vienna, Austria; Porto University, Porto, Portugal; Hospital S. Joao, Porto, Portugal; St. Xavier's College, Thumba, Trivandrum, Kerala, India; Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India; University of Sao Paulo Medical School, Sao Paulo, Brazil.
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.
DOI: 10.1126/scitranslmed.aag0945
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