INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
Service d'Hématologie Biologique, CHU Estaing, F-63000 Clermont-Ferrand, France.
Nutrients. 2019 Nov 20;11(12):2839. doi: 10.3390/nu11122839.
Obesity, a recognized risk factor for breast cancer in postmenopausal women, is associated with higher mortality rates regardless of menopausal status, which could in part be explained by therapeutic escape. Indeed, adipose microenvironment has been described to influence the efficiency of chemo- and hormonal therapies. Residual cancer stem cells could also have a key role in this process. To understand the mechanisms involved in the reduced efficacy of hormonal therapy on breast cancer cells in the presence of adipose secretome, human adipose stem cells (hMAD cell line) differentiated into mature adipocytes were co-cultured with mammary breast cancer cells and treated with hormonal therapies (tamoxifen, fulvestrant). Proliferation and apoptosis were measured (fluorescence test, impedancemetry, cytometry) and the gene expression profile was evaluated. Cancer stem cells were isolated from mammospheres made from MCF-7. The impact of chemo- and hormonal therapies and leptin was evaluated in this population. hMAD-differentiated mature adipocytes and their secretions were able to increase mammary cancer cell proliferation and to suppress the antiproliferative effect of tamoxifen, confirming previous data and validating our model. Apoptosis and cell cycle did not seem to be involved in this process. The evaluation of gene expression profiles suggested that STAT3 could be a possible target. On the contrary, leptin did not seem to be involved. The study of isolated cancer stem cells revealed that their proliferation was stimulated in the presence of anticancer therapies (tamoxifen, fulvestrant, doxorubicine) and leptin. Our study confirmed the role of adipocytes and their secretome, but above all, the role of communication between adipose and cancer cells in interfering with the efficiency of hormonal therapy. Among the pathophysiological mechanisms involved, leptin does not seem to interfere with the estrogenic pathway but seems to promote the proliferation of cancer stem cells.
肥胖是绝经后妇女乳腺癌的公认危险因素，与死亡率升高有关，无论绝经状态如何，这在一定程度上可以通过治疗逃逸来解释。事实上，脂肪微环境已被描述为影响化疗和激素治疗的效率。残留的癌症干细胞也可能在这个过程中起关键作用。为了了解在脂肪分泌组存在的情况下，激素治疗对乳腺癌细胞疗效降低的机制，我们将人脂肪基质细胞（hMAD 细胞系）分化为成熟脂肪细胞与乳腺癌细胞共培养，并进行激素治疗（他莫昔芬、氟维司群）。测量增殖和凋亡（荧光试验、阻抗法、细胞术）并评估基因表达谱。从 MCF-7 形成的肿瘤球体中分离出癌症干细胞。评估了化疗和激素治疗以及瘦素对该群体的影响。hMAD 分化的成熟脂肪细胞及其分泌物能够增加乳腺癌细胞增殖，并抑制他莫昔芬的抗增殖作用，证实了先前的数据并验证了我们的模型。凋亡和细胞周期似乎不参与这个过程。基因表达谱的评估表明 STAT3 可能是一个潜在的靶点。相反，瘦素似乎不参与其中。对分离的癌症干细胞的研究表明，在抗癌治疗（他莫昔芬、氟维司群、多柔比星）和瘦素存在的情况下，它们的增殖受到刺激。我们的研究证实了脂肪细胞及其分泌物的作用，但更重要的是，脂肪细胞和癌细胞之间的通讯在干扰激素治疗的效率方面的作用。在涉及的病理生理机制中，瘦素似乎不干扰雌激素途径，但似乎促进癌症干细胞的增殖。
Zotero 插件
