肥胖是乳腺癌预后不良的强预测因子,尤其是绝经后的妇女。特别是,肥胖患者的肿瘤倾向于引发更远处的转移,尽管这一观察背后的生物学仍然知之甚少。
为了阐明肥胖微环境对转移扩散的影响,我们对C57BL/6J雌性小鼠进行卵巢切除,并给它们喂食常规饮食(RD)或高脂饮食(HFD),以产生绝经后饮食诱导的肥胖模型.然后,我们研究了Py230和EO771移植物向转移的肿瘤进展。我们分析和表型的RD和HFD肿瘤和周围的脂肪组织通过流式细胞术,qPCR,免疫组织化学(IHC)和蛋白质印迹。通过将RD和HFD肿瘤细胞交叉移植到其他RD和HFD小鼠中来评估微环境对肿瘤细胞的影响。在比较两个变量时,使用非配对学生t检验分析结果,否则我们使用单向或双向方差分析。使用相关系数计算两个变量之间的关系。
我们的研究结果表明,肥胖小鼠的肿瘤生长得更快,血管化也较少,更多的缺氧,级别较高,富含CD11b+Ly6G+中性粒细胞。总的来说,这有利于诱导上皮-间质转化和进展为低claudin乳腺癌,富含癌症干细胞的三阴性乳腺癌亚型。有趣的是,在RD小鼠中移植HFD衍生的肿瘤细胞可增强肿瘤生长和肺转移形成。
这些数据表明,肥胖的促转移作用是由原发性肿瘤中的肿瘤细胞获得的,而与继发部位的微环境无关。绝经后肥胖对原发性乳腺癌肿瘤的影响.
Obesity is a strong predictor of poor prognosis in breast cancer, especially in postmenopausal women. In particular, tumors in obese patients tend to seed more distant metastases, although the biology behind this observation remains poorly understood.
To elucidate the effects of the obese microenvironment on metastatic spread, we ovariectomized C57BL/6 J female mice and fed them either a regular diet (RD) or a high-fat diet (HFD) to generate a postmenopausal diet-induced obesity model. We then studied tumor progression to metastasis of Py230 and EO771 grafts. We analyzed and phenotyped the RD and HFD tumors and the surrounding adipose tissue by flow cytometry, qPCR, immunohistochemistry (IHC) and western blot. The influence of the microenvironment on tumor cells was assessed by performing cross-transplantation of RD and HFD tumor cells into other RD and HFD mice. The results were analyzed using the unpaired Student t test when comparing two variables, otherwise we used one-way or two-way analysis of variance. The relationship between two variables was calculated using correlation coefficients.
Our results show that tumors in obese mice grow faster, are also less vascularized, more hypoxic, of higher grade and enriched in CD11b+Ly6G+ neutrophils. Collectively, this favors induction of the epithelial-to-mesenchymal transition and progression to claudin-low breast cancer, a subtype of triple-negative breast cancer that is enriched in cancer stem cells. Interestingly, transplanting HFD-derived tumor cells in RD mice transfers enhanced tumor growth and lung metastasis formation.
These data indicate that a pro-metastatic effect of obesity is acquired by the tumor cells in the primary tumor independently of the microenvironment of the secondary site. Effects of postmenopausal obesity on primary breast cancer tumoursᅟ.