下个十年，癌症研究最为紧迫是肥胖问题

　　

生物通报道：近年来关于肥胖与癌症的研究都集中在预防癌症的行为干预方面了，但是对于全球将近7亿的肥胖成人来说，除了减肥植物，更有效的措施是减轻他们患病风险，美国临床肿瘤学会，世界癌症研究基金会等组织指出，肥胖相关的癌症就会是下个十年，癌症研究领域最为紧迫的问题。

上篇：切断癌症与肥胖之间的必经之路

（内分泌功能障碍: 肥胖可以增加芳香化酶aromatase表达，从而导致雌二醇水平增加，促进雌激素依赖性肿瘤发展，如雌激素受体阳性乳腺癌和子宫内膜癌）

问题二：在肥胖和癌症关系中哪些是主要因素，哪些是次要因素？

要了解肥胖与癌症之间的复杂关联，就需要区分哪些主要因素，哪些是次要因素。肥胖能通过胰岛素抵抗和高水平循环胰岛素和葡萄糖水平，引起全身的代谢失调，同时还有过量的胆固醇和其它血脂，这会损坏血管生长和凝血过程，改变细胞因子表达，并加剧炎症发生，增加激素水平，如雌二醇、瘦素、以及胰岛素样生长因子-1 (IGF-1)。

过去的二十年里，科学家们利用遗传和药理方法破解了这其中的一部分奥秘。首先细胞间信号无疑是其中一个重要因素，一些临床和流行病学研究发现肥胖或2型糖尿病患者许多类型的癌症风险增加。此外，有许多的研究表明一些用于治疗2型糖尿病的药物，根据它们对高胰岛素血症及高血糖症发挥的是增强或抑制效应，可对应增加或降低癌症的风险。事实上，癌症和2型糖尿病共享许多代谢风险因子，其中高胰岛素/IGF、高血糖、葡萄糖剥夺、缺氧和炎症因子被认为有可能是这两种疾病之间的生物学关联因素。

许多癌症患者都遭受消耗性综合征（wasting syndrome），称为恶病质，患者体内的肌肉和脂肪组织被破坏。今年，根据两项果蝇肿瘤模型的研究表明，一种抑制胰岛素信号的肿瘤分泌蛋白，可能是触发这种消耗的一个因素。

这项研究表明Impl2——一个哺乳动物蛋白（可拮抗胰岛素信号）的果蝇同系物，在这种全身性消耗中起着关键作用。研究采用一个致癌基因同源物来激活Impl2，但是可能其他致癌基因也发挥类似的作用。果蝇Impl2的功能很像哺乳动物胰岛素生长因子（IGF）结合蛋白，其可以阻断胰岛素信号。一些研究表明，这些蛋白质在癌症中是上调的。

（生物通：万纹）

原文文献：

Breaking the Cancer-Obesity Link（来自http://www.the-scientist.com/）

K. Subbaramaiah et al., “Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women,” Cancer Discov, 2:356-65, 2012.
P.G. Morris et al., “Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer,” Cancer Prev Res, 4:1021-29, 2011.
S. Chen et al., “Obesity or overweight is associated with worse pathological response to neoadjuvant chemotherapy among Chinese women with breast cancer,” PLOS ONE, 7:e41380, 2012.
B. Guiu et al., “Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer,” Gut, 59:341-47, 2010.
J. Chen et al., “Insulin caused drug resistance to oxaliplatin in colon cancer cell line HT29,” J Gastrointest Oncol, 2:27-33, 2011
R.E. De Angel et al., “Stearoyl gemcitabine nanoparticles overcome obesity-induced resistance to gemcitabine in a mouse model of breast cancer,” Cancer Biol Ther, 14:357-64, 2013.
Y. Naguib et al., “Solid lipid nanoparticle formulations of docetaxel prepared with high-melting point triglycerides: In vitro and in vivo evaluation,” Mol Pharm, 11:1239-49, 2014.
L.M. Nogueira et al., “Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity,” Endocr Relat Cancer, 19:57-68, 2012.
H. Liu et al., “Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro,” Anticancer Res, 32:1627-37, 2012.
H. Liu et al., “The mTOR inhibitor RAD001 sensitizes tumor cells to the cytotoxic effect of carboplatin in breast cancer in vitro,” Anticancer Res, 31:2713-22, 2011.
C.J. Fabian et al., “Favorable modulation of benign breast tissue and serum risk biomarkers is associated with >10% weight loss in postmenopausal women,” Breast Cancer Res Treat, 142:119-32, 2013.
R.E. De Angel et al., “The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by Rad001,” Mol Carcinog, 52:446-58, 2013.
S.D. Hursting et al., “The obesity-cancer link: Lessons learned from a fatless mouse,” Cancer Res, 67:2391-93, 2007.
K. Aung et al., “Risk of developing diabetes and cardiovascular disease in metabolically unhealthy normal-wight and metabolically healthy obese individuals,” J Clin Endocrinol, 99:462-68, 2014.
P. Pajunen et al., “Metabolically healthy and unhealthy obesity phenotypes in the general population,” BMC Public Health, 11:754, 2011.