Cancer stem cells as the source of tumor associated myoepithelial cells in the tumor microenvironment developing ductal carcinoma in situ

Abstract

The heterogeneous cell population in the stromal microenvironment is considered to be attributed to the multiple sources from which the cells originate. Tumor associated myoepithelial cells (TAMEs) are one of the most important populations in the tumor microenvironment (TME) especially in breast cancer. On the other hand, cancer stem cells (CSCs) have previously been described to be the origin of tumor-associated cellular components in the TME. We prepared a cancer stem cell model converting mouse-induced pluripotent stem cells (miPSCs) in the presence of conditioned medium of breast cancer cell line MDA-MB-231 cells. The converted cells developed tumors progressing into invasive carcinoma with ductal carcinoma in situ (DCIS) like structure when transplanted into mouse mammary fat pads. The primary cultured cells from the tumor further exhibited markers of CSC such as Sox2, Oct3/4, - CD133 and EpCAM, and mammary gland-related TAME markers such as α-smooth muscle actin, cytokeratin 8, whey acidic protein, prolactin receptor and progesterone receptor as well. These results indicated that the CSCs could be an origin of TAMEs contributing to mammary gland epithelial cell differentiation and the progression to invasive carcinoma during tumor development. The gene expression profiles confirmed the enhanced signaling pathways of PI3K/AKT and MAPK, which have been demonstrated to be enriched in the CSC models, together with the estrogen receptor signaling which was peculiar to mammary gland-derived character.