Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness

Abstract

Cancer stem cells have been described in various cancers including squamous tumours of the skin by their ability to reform secondary tumours upon transplantation into immunodeficient mice. Here, we used transplantation of limiting dilution of different populations of FACS-isolated tumour cells from four distinct mouse models of squamous skin tumours to investigate the frequency of tumour propagating cells (TPCs) at different stages of tumour progression. We found that benign papillomas, despite growing rapidly in vivo and being clonogenic in vitro, reformed secondary tumours upon transplantation at very low frequency and only when tumour cells were co-transplanted together with tumour-associated fibroblasts or endothelial cells. In two models of skin squamous cell carcinoma (SCC), TPCs increased with tumour invasiveness. Interestingly, the frequency of TPCs increased in CD34 HI but not in CD34 LO SCC cells with serial transplantations, while the two populations initially gave rise to secondary tumours with the same frequency. Our results illustrate the progressive increase of squamous skin TPCs with tumour progression and invasiveness and reveal that serial transplantation may be required to define the long-term renewal potential of TPCs.

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression

“…1B), suggesting that tumor-initiating cells of WDSCCs, but not those of PD/S-SCCs, retained the ability to differentiate into an epithelial shape. As reported in other mouse models (11,12), a6-integrin It is important to highlight that the tumors that did not progress to PD/S-SCC during serial engraftment did not exhibit an expansion of CSCs or further induction of EMT (OT9 in Supplementary Fig. S2F), indicating that these events are not a consequence of long-term growth in immunodeficient mice.…”

“…Wnt/b-catenin, TGFb, and VEGF signaling pathways regulate CD34 þ -CSC features at early stages of progression (11,15,16). Moreover, skin SCC progression is associated with an expansion of the CD34 þ -CSC population (12,16). However, it is not known whether signaling pathways regulating CSC function switch during progression.…”

“…CSCs are also the most likely candidates for metastasis-initiating activities, as they may induce epithelial-tomesenchymal transition (EMT), which promotes tumor cell migration (9,10). Mouse skin SCC cells expressing CD34 and a6-integrin are enriched in tumor-initiating and long-term tumor-propagating cells compared with the bulk of tumor cells, and they are able to recapitulate the phenotypic cell diversity of parental tumors in engraftment assays (11,12). Sox2 expression is induced in CSCs of SCCs to promote CSC self-renewal and skin SCC growth (13,14).…”

miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival

“…Once formed, the growth of SCC is fueled by CSCs (Malanchi et al 2008;Lapouge et al 2011;White et al 2011;Driessens et al 2012) that share several key features of stemness: They can self-renew long-term and differentiate into lineage-restricted progenies of their tissuein this case, the SCC. At the transcriptional level, however, SCC-CSCs differ dramatically from normal skin stem cells, with >700 mRNAs changed by two times or more in CSCs relative to stem cells of either the epidermis or HF (Schober and Fuchs 2011;Lapouge et al 2012).…”

“…Quantitative PCR (qPCR) analysis of normal skin stem cells and SCC-CSCs purified by fluorescence-activated cell sorting (FACS) (Schober and Fuchs 2011;Lapouge et al 2012) revealed that miR-125b levels in SCC-CSCs were intermediate between epidermal basal progenitors and HFSCs isolated from the bulge niche (Fig. 1B;Schober and Fuchs 2011).…”