Arsenic-transformed malignant prostate epithelia can convert noncontiguous normal stem cells into an oncogenic phenotype.

Abstract

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.

• Authors: Yuanyuan Xu, Erik J Tokar, Yang Sun, Michael P Waalkes
• Journal: Environmental health perspectives (Environ Health Perspect) Vol. 120 Issue 6 Pg. 865-71 (Jun 2012) ISSN: 1552-9924 [Electronic] United States
• PMID: 22472196 (Publication Type: Journal Article)

Chemical References

• Interleukin-6
• Matrix Metalloproteinases
• Arsenic

Topics

• Arsenic (toxicity)
• Blotting, Western
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism)
• Epithelial Cells (drug effects, metabolism)
• Fluorescent Antibody Technique
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Humans
• Interleukin-6 (metabolism)
• Male
• Matrix Metalloproteinases (metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Prostatic Neoplasms (metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction