International Journal of Oncology, 2016.

Genistein-induced differentiation of breast cancer stem/progenitor cells through a paracrine mechanism

Yanchen Liu, Tianbiao Zou, Shuhuai Wang, et al

The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China

It is believed that breast cancer stem cells (BCSCs), like normal stem cell counterparts, have the capacity of self-renewal and differentiation. Simultaneously, estrogen receptor (ER)-negative (-) BCSCs are affected by surrounding differentiated ER-positive (+) tumor cells by virtue of paracrine signaling within the tumor micro-environment. Genistein (GEN), as a sort of phytoestrogen, can act on ER+ breast cancer cells but the role of GEN in the differentiation of neighboring ER- BCSCs has not been defined. Transwell co-culture system was utilized so as to elaborate the interaction between well-differentiated ER+ breast cancer cells (MCF-7) and ER- breast cancer stem/progenitor cells (mammospheres derived from MDA-MB-231 cells). GEN-induced differentiation of BCSCs was analyzed by mammospheres formation assay, flow cytometry and RT-PCR after a 3 day solo-culture or co-culture. We find that GEN sized 2 µM, and 40 nM, effectively promotes morphological alteration of mammospheres, reduces the ratio of subset of CD44+/CD24-/ESA+ cells and upregulates the expression of differentiated cell markers of mammospheres in co-culture system, but not in solo-culture condition. Besides, we demonstrate that the differentiation-inducing effect of GEN on mammospheres is associated with PI3K/Akt and MEK/ERK signaling pathways which are activated by amphiregulin released from ER+ cancer cells. These results indicate that GEN was able to induce the differentiation of breast cancer stem/progenitor cells through interaction with ER+ cancer cells by a paracrine mechanism.

希腊《国际肿瘤杂志》2016

染料木黄酮通过旁分泌机制诱导分化的乳腺癌干/祖细胞

刘燕辰，邹田表，王树槐等

第一附属医院哈尔滨医院军医大学，黑龙江省哈尔滨市中国

乳腺癌干细胞（BCSC），如正常干细胞对应物，具有自我更新和分化的能力。同时，由于肿瘤微环境中的旁分泌信号，雌激素受体（ER） - 阴性（-）BCSCs受周围分化的ER阳性（+）肿瘤细胞的影响。染料木黄酮（GEN）作为一种植物雌激素，可以作用于ER+乳腺癌细胞，但是在相邻ER-BCSCs的分化中的作用还没有被定义。利用Transwell共培养系统以阐明高分化ER +乳腺癌细胞（MCF-7）和ER-乳腺癌干/祖细胞（源自MDA-MB-231细胞的乳腺球）之间的相互作用。在3天独立培养或共培养后，通过球囊形成测定，流式细胞术和RT-PCR分析BCSCs的GEN诱导的分化。我们发现GEN大小2μM和40nM有效促进球囊的形态改变，减少CD44+/CD24-/ESA+细胞亚群的比例，并上调共培养系统中球囊的分化细胞标志物的表达，但不是在独奏文化条件。此外，我们证明GEN对乳腺球细胞的分化诱导作用与PI3K/Akt和MEK/ERK信号通路相关，其由从ER+癌细胞释放的双调蛋白激活。这些结果表明GEN能够通过与旁分泌机制的ER+癌细胞的相互作用诱导乳腺癌干细胞/祖细胞的分化。