Authors:
Yuanyuan Xu, Erik J. Tokar, Yang Sun, & Michael P. Waalkes
Summary:
Background - Cancer stem cells (CSCs) are likely critical to carcinogenesis, and, like normal stem cells (NSCs), are affected by microenvironmental factors. Malignant cells release extracellular factors, modifying tumor behavior. Inorganic arsenic, a human carcinogen, is associated with an overproduction of CSCs in various model systems of carcinogenesis.
Objective - We aimed to determine if NSCs are influenced by nearby arsenic-transformed malignant epithelial cells (MECs) as a possible factor in arsenic-associated CSC overabundance.
Methods - Transwell noncontact co-culture allowed the study of the effects of non-contiguous, arsenic-transformed prostate MECs on the isogenic human prostate NSC line, WPE-stem. Cancer phenotype was assessed by evaluating secreted matrix metalloproteinases (MMPs), invasiveness, colony formation, and spheroid formation. Gene expression was assessed at the protein (Western blot) or mRNA (real-time reverse transcription–polymerase chain reaction) levels.
Results - Noncontact co-culture of MECs and NSCs rapidly (≤ 3 weeks) caused hypersecretion of MMPs and marked suppression of the tumor suppressor gene PTEN in NSCs. NSCs co-cultured with MECs also showed increased invasiveness and clonogenicity and formed more free-floating spheroids and highly branched ductal-like structures in Matrigel, all typical for CSCs. MEC co-culture caused dysregulated self-renewal and differentiation-related gene expression patterns and epithelial-to-mesenchymal transition in NSCs consistent with an acquired cancer phenotype. Interleukin-6 (IL-6), a cytokine involved in tumor microenvironment control, was hypersecreted by MECs, and IL-6 exposure of NSCs resulted in the duplication of several responses in NSCs of conversion to CSCs via MEC co-culture (e.g., MMP hypersecretion, decreased PTEN).
Conclusions - Arsenic-transformed MECs recruit nearby NSCs into a cancer phenotype, thereby potentially increasing CSC number. This may be a factor in arsenic-induced CSC overabundance seen in multiple model systems.
Source:
Environmental Health Perspectives; 120(6), 865-871 (04/04/12)