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- Title
Recruitment of Normal Stem Cells to an Oncogenic Phenotype by Noncontiguous Carcinogen-Transformed Epithelia Depends on the Transforming Carcinogen.
- Authors
Yuanyuan Xu; Tokar, Erik J.; Person, Rachel J.; Orihuela, Ruben G.; Ngalame, Ntube N. O.; Waalkes, Michael P.
- 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 metalloproteinase- 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 phenotype, 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. INSET: CORRECTION.
- Subjects
ANALYSIS of variance; ARSENIC; CADMIUM compounds; CARCINOGENS; CELL culture; ENZYME-linked immunosorbent assay; FLUORESCENT antibody technique; GENE expression; POLYMERASE chain reaction; STEM cells; T-test (Statistics); TUMORS; WESTERN immunoblotting; PHENOTYPES; REVERSE transcriptase polymerase chain reaction; DESCRIPTIVE statistics
- Publication
Environmental Health Perspectives, 2013, Vol 121, Issue 8, p944
- ISSN
0091-6765
- Publication type
Article
- DOI
10.1289/ehp.1306714