Japanese researchers for the first time isolated and characterized so-called induced pluripotent cancer stem-like cells (iCSCs). These cells have properties of cancer stem cells – ability to self-renew coupled with tumorigenicity in vivo. This new type of cells could serve as a good model for carcinogenesis and safety of iPS cell-based therapeutics.
To isolate iCSCs, the following scheme was applied:
fetal lung fibroblasts (TIG1) + 4 Yamanaka’s factors –>
iPS cells (iPSC) + unstable induced epithelial stem cell (iESC) –>
iESC –> re-plating –> 30 passages –> emryoid body (EB) –> iESC EB
primary iCSCs –> 20 passages –> primary teratomas in mice –>
secondary iCSCs –> secondary teratomas
The authors compared gene expression profile of fibroblasts, iESCs, iPSCs and iCSCs based on core modules, identified by Orkin’s group in 2010:
Notably, acquisition of self-renewal and pluripotency was linked with up-regulation of the Core and Myc, but not PRC, modules (Fig. 4). These data indicated that the property of self-renewal and pluripotency could be conferred on somatic nuclei prior to full reprogramming into iPSCs.
To reprogram somatic cells to iCSCs, up-regulation of the Myc module is a key event.
(Properties of self-renewal and pluripotency are linked with transient or continuous up-regulation of the Core and Myc modules, but not PRC module. C, Core module; P, PRC module; M, Myc module. doi:10.1371/journal.pone.0048699.g004)
So, iCSCs could be isolated by simple picking up unstable induced epithelial stem cell clones in mixed iPS cell culture and passaging them. Identification of gene expression modules allows to determine and dissect conditions and factors, essential for reprogramming, self-renewal and carcingenesis.