Experimental and Translational Oncology Laboratory, Division of Pathology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Tumor Ecology Laboratory, Division of Pathology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700, Fribourg, Switzerland.
Breast Cancer Res. 2018 Sep 4;20(1):104. doi: 10.1186/s13058-018-1029-4.
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 CD11bLy6G 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.
肥胖是乳腺癌预后不良的一个强有力的预测因子，尤其是在绝经后妇女中。特别是肥胖患者的肿瘤往往会播散更多的远处转移灶，尽管这一观察结果背后的生物学机制仍知之甚少。
为了阐明肥胖微环境对转移扩散的影响，我们对 C57BL/6J 雌性小鼠进行了卵巢切除术，并分别用常规饮食（RD）或高脂肪饮食（HFD）喂养，以建立绝经后饮食诱导的肥胖模型。然后，我们研究了 Py230 和 EO771 移植物向转移的进展。我们通过流式细胞术、qPCR、免疫组织化学（IHC）和 Western blot 分析和表型分析 RD 和 HFD 肿瘤及周围脂肪组织。通过将 RD 和 HFD 肿瘤细胞交叉移植到其他 RD 和 HFD 小鼠中，评估微环境对肿瘤细胞的影响。当比较两个变量时，使用未配对的 Student t 检验分析结果，否则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。
我们的结果表明，肥胖小鼠的肿瘤生长更快，血管化程度更低，缺氧程度更高，CD11bLy6G 中性粒细胞更多。总的来说，这有利于上皮间质转化的诱导和向 Claudin-low 乳腺癌的进展，Claudin-low 乳腺癌是三阴性乳腺癌的一个亚型，富含癌症干细胞。有趣的是，将 HFD 来源的肿瘤细胞移植到 RD 小鼠中会增强肿瘤的生长和肺转移的形成。
这些数据表明，肥胖对肿瘤细胞的促转移作用是在原发性肿瘤中获得的，而与次级部位的微环境无关。绝经后肥胖对原发性乳腺癌肿瘤的影响。
