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Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.

ABSTRACT: Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of posttransformation behavior. These findings demonstrate that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and holds important implications for therapeutic strategies to eradicate cancer.

SUBMITTER: Chaffer CL

PROVIDER: S-EPMC3093533 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.

Chaffer Christine L CL Brueckmann Ines I Scheel Christina C Kaestli Alicia J AJ Wiggins Paul A PA Rodrigues Leonardo O LO Brooks Mary M Reinhardt Ferenc F Su Ying Y Polyak Kornelia K Arendt Lisa M LM Kuperwasser Charlotte C Bierie Brian B Weinberg Robert A RA

Proceedings of the National Academy of Sciences of the United States of America 20110415 19

Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells i ...[more]

PMID: 21498687

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Project description:BackgroundCancer 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.ObjectiveWe aimed to determine if NSCs are influenced by nearby arsenic-transformed malignant epithelial cells (MECs) as a possible factor in arsenic-associated CSC overabundance.MethodsTranswell 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.ResultsNoncontact 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).ConclusionsArsenic-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.

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Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.

Publications

Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.

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