Stephen Baylin, a professor of oncology at the Hopkins School of Medicine, along with his research team, recently published a paper on cancer-related epigenetic abnormalities in induced pluripotent stem cell (iPS) reprogramming. This research helps to explain why some iPS populations do not differentiate like native stem cells.
Pluripotent stem cells are cells capable of differentiating into any of the three germ layers present during development: endoderm, mesoderm and ectoderm. Induced somatic pluripotent stem cells (iPS), therefore, are stem cells artificially derived from adult somatic cells via genetic modifications.
However, current technology used to generate iPS includes many factors with oncogenic potential. Furthermore, higher percentages of transgeneic mice develop cancerous features, eventually resulting in death.
Completely reprogrammed human iPS phenotype is also rare amongst many more populations with only partially reprogrammed cells.
Induction of iPS from somatic cells requires the reversal of DNA methylation and reexpression of pluripotency-related genes. Numerous details can err in this process, thus resulting in the aforementioned complications.
Baylin’s research involved the usage of genome-wide analysis to identify cancer-related epigenetic abnormalities during induced cell reprogramming.
Results show that iPS may be prone to epigenetic mutations associated with neoplasia — an abnormal proliferation of cells commonly presented as tumors — during reprogramming.
“Cellular reprogramming may provide a model to study how epigenetic abnormalities may be central to the origins of cancer and may underlie the fact that neoplasia can initiate even in mature populations of normal cells,” Baylin wrote in an email to The News-Letter.
But in contrast to earlier studies, the degree of methylation observed in certain promoter genes in iPS cells was significantly less than in cancer cells.
Instead, cancerous characteristics and abnormal gene silencing in iPS seem to be due to factors that cause the reprogramming of the iPS cells themselves, particularly in the reactivation of pluripotency gene OCT4, which is thought to be responsible for the neoplastic phenotype in the skin and intestines of mice that overexpress OCT4.
Another significant finding notes the differences in responsiveness to various drugs: while silenced genes in embryonic stem cells (ESC) are maximally reactivated by one type of drug, TSA, cancer cells and iPS are only responsive to a much stronger drug, DAC.
Because the iPS cells respond similarly to cancer cells in this way, the researchers hypothesized that iPS cells and cancer cells share the common trait of having abnormally repressed genes. This repression may help to explain why reprogrammed stem cells oftentimes do not differentiate normally or go through the full progression.
These new findings will shed light on how cellular reprogramming may lead to the formation of populations of cancer cells.
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