Recruitment of normal stem cells to an oncogenic phenotype by noncontiguous carcinogen-transformed epithelia depends on the transforming carcinogen

Abstract

Background: Cancer stem cells (CSCs) drive tumor initiation, progression, and metastasis. The microenvironment is critical to the fate of CSCs. We have found that a normal stem cell (NSC) line from human prostate (WPE-stem) is recruited into CSC-like cells by nearby, but noncontiguous, arsenic-transformed isogenic malignant epithelial cells (MECs). Objective: It is unknown whether this recruitment of NSCs into CSCs by noncontact co--culture is specific to arsenic-transformed MECs. Thus, we used co--culture to examine the effects of neighboring noncontiguous cadmium-transformed MECs (Cd--MECs) and N-methyl-N-nitrosourea-transformed MECs (MNU-MECs) on NSCs. Results: After 2 weeks of noncontact Cd--MEC co--culture, NSCs showed elevated metallo- proteinase-9 (MMP-9) and MMP-2 secretion, increased invasiveness, increased colony formation, decreased PTEN expression, and formation of aggressive, highly branched duct-like structures from single cells in Matrigel, all characteristics typical of cancer cells. These oncogenic characteristics did not occur in NSCs co--cultured with MNU-MECs. The NSCs co--cultured with Cd--MECs retained self-renewal capacity, as evidenced by multiple passages (> 3) of structures formed in Matrigel. Cd--MEC-co--cultured NSCs also showed molecular (increased VIM, SNAIL1, and TWIST1 expression; decreased E-CAD expression) and morphologic evidence of epithelial-to-mesenchymal transition typical for conversion to CSCs. Dysregulated expression of SC-renewal genes, including ABCG2, OCT--4, and WNT--3, also occurred in NSCs during oncogenic transformation induced by noncontact co--culture with Cd--MECs. Conclusions: These data indicate that Cd--MECs can recruit nearby NSCs into a CSC-like pheno- type, but MNU-MECs do not. Thus, the recruitment of NSCs into CSCs by nearby MECs is dependent on the carcinogen originally used to malignantly transform the MECs.