CD133+ cancer stem cell-like cells derived from uterine carcinosarcoma (malignant mixed mullerian tumour)
Cancer stem cells (CSCs) that display tumour-initiating properties have recently been identified. CD133, a surface glycoprotein linked to organspecific stem cells, has been described as a marker of CSCs in different tumour types. We herein identify and characterize CSCs in human uterine carcinosarcoma (malignant mixed mullerian tumour), which is one of the most aggressive and therapy-resistant gynaecological malignancies and is considered to be of mesodermal origin. CD133+ and CD133 - cells were isolated from cell culture by FACS or magnetic bead sorting using the MACS system (Miltenyi Biotech). The CD133+ population was increased in uterine carcinosarcoma, and this population showed biphasic properties in the primary tumour. CD133+ cells predominantly formed spheres in culture and were able to differentiate into mesenchymal lineages. CD133+ cells were more resistant to cisplatin/paclitaxel-induced cytotoxicity in comparison with CD133 cells. A real time polymerase chain reaction analysis of the genes implicated in stem cell maintenance revealed that CD133+ cells express significantly higher levels of Oct4, Nanog, Sox2, and Bmi1 than CD133- cells. Moreover, CD133+ cells showed a high expression level of Pax2 and Wnt4, which are genes essential for mullerian duct formation. These CD133+ cells form serially transplantable tumours in vivo and the resulting CD133+ tumours replicated the EpCAM, vimentin, and oestrogen and progesterone receptor expression of the parent tumour, indicating that CSCs likely differentiated into cells comprising the uterine carcinosarcoma tissue. Moreover, strong CD133 expression in both epithelial and mesenchymal elements in primary tumour demonstrated significant prognostic value. These findings suggest that CD133+ cells have the characteristics of CSCs and mullerian mesenchymal progenitors.