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Posted 25 April 2012
This article highlighted in New Scientist, reports that “ARSENIC is a carcinogen that packs a double punch: cells that it has made cancerous send out signals that in turn make healthy stem cells become malignant.”
Arsenic double whammy for cancer
Michael Waalkes and his colleagues at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, had noticed that tumours triggered by arsenic contained unusually large numbers of cancer stem cells.
To find out why, the researchers turned cells from the human prostate gland cancerous with arsenic, before growing them in close proximity to, but not touching, healthy stem cells from the prostate. Even though these cells hadn’t themselves been exposed to arsenic, within three weeks they had turned into cancer stem cells (Environmental Health Perspectives, DOI: 10.1289/ehp.1204987).
Waalkes suspects a signalling molecule called interleukin-6 may be involved. “But I would not want to say it is the sole factor.”
Arsenic-Transformed Malignant Prostate Epithelia Can Convert Noncontiguous Normal Stem Cells into an Oncogenic Phenotype
Background: Cancer stem cells (CSCs) are likely critical to carcinogenesis, and, like normal stem cells (NSCs), are impacted by microenvironment. Malignant cells release extracellular factors modifying tumor behavior. Inorganic arsenic, a human carcinogen, over-produces CSCs in various model systems of carcinogenesis. Here, we determine if NSCs are influenced by nearby arsenic-transformed malignant epithelial cells (MECs) as a possible factor in arsenic associated CSC overabundance.
Methods: Transwell non-contact 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 secreted MMPs, invasiveness, colony formation and spheroid formation. Gene expression was assessed at the protein (western blot) or mRNA (RT-PCR) levels.
Results: Non-contact co-culture of MECs and NSCs rapidly (≤ 3 weeks) caused hyper-secretion 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 acquired cancer phenotype. Interleukin-6, a cytokine involved in tumor microenvironment control, was hyper-secreted by MECs and interleukin-6 exposure duplicated several responses in NSCs of conversion to CSCs via MEC co-culture (MMP hyper-secretion, decreased PTEN, etc.).
Conclusions: These results indicate that 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.
Xu Y, Tokar EJ, Sun Y, Waalkes MP 2012. Arsenic-Transformed Malignant Prostate Epithelia Can Convert Noncontiguous Normal Stem Cells into an Oncogenic Phenotype. Environ Health Perspect :-. http://dx.doi.org/10.1289/ehp.1204987
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