For the first time, researchers have identified epidermal stem cells as the “cell of origin” of basal cell carcinoma (BCC) in a mouse model, and mapped the cellular dynamics that lead to tumor initiation in these cells.1
Dying epidermal cells are constantly replaced by progenitor cells, which are more differentiated than the stem cells from which they develop. It was not clear, however, whether stem cells or progenitor cells could give rise to invasive tumors.
“We consider the identification of the stem cells as the cells of origin of basal cell carcinoma [to be] a key finding, and that the understanding of the cellular dynamics leading to tumor initiation will allow us to better design new treatments for basal cell carcinoma,” said study co-author Cedric Blanpain, MD, PhD, of the Universite libre de Bruxelles in Belgium, in an email to Cancer Therapy Advisor.
“Our study suggests that strategies that favor differentiation or promote cell death…specifically in the cells that activate the oncogene, would potentially be good candidates to be administrated together with vismodegib,” said Dr Blanpain. “Targeting resistance to apoptosis and stimulating differentiation are 2 therapeutic approaches that emerge from this study.”
Vismodegib inhibits the hedgehog cell signaling pathway, the activation of which has been implicated in the development of BCC.2
Researchers used mice with genetically altered stem and progenitor cells in which SmoM2, an oncogene in the hedgehog pathway, had been activated to induce BCC. In stem cells, activation of SmoM2 expression led to invasive tumors that were resistant to apoptosis. In progenitor cells, however, activating the oncogene resulted in benign lesions that did not resist cell death.
“Following SmoM2 activation, both progenitors and stem cells acquire a persistent and constant fate bias towards cell duplication, leading to clonal expansion at the expense of neighboring normal cells,” said study co-author Benjamin Simons, PhD, of the University of Cambridge in the United Kingdom, in an email to Cancer Therapy Advisor. “A gradual reduction in the proliferation rate allied with an increase in the apoptosis rate, however, leads to an arrest of progenitor cell-derived lesions in a dysplastic state.”
The researchers also found that cell location affected the fate of oncogenic activation. Mouse tail epidermis has 2 cellular regions: scale and interscale. Stem cells in the interscale region of the tail epidermis gave rise to BCC, while those in the scale region did not.
“We believe that insights into early diagnosis and novel treatment strategies may be found by targeting the earliest phase of disease initiation and progression,” said Dr Simons.
“Already, there has been significant progress in tracing the early phases of tumor growth in the intestine, using clonal lineage tracing approaches. We believe that the current study may provide a model of how analyses of clonal evolution can provide quantitative insights into disease progression in other tissue types, particularly where tumors are maintained by a minority population of equipotent tumor-maintaining cells.”
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The research group is focused on studying the cellular dynamics that lead specifically to basal cell carcinoma, though they plan to perform similar experiments in other skin and breast cancers, in an effort to look for similarities in the clonal dynamics that lead to tumor initiation in different solid cancers.
- Sanchez-Danes A, Hannezo E, Larismont JC, Liagre M, Youssef KK, Simons B, Blanpain C. 2016. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature. 08 Jul 2016. doi: 10.1038/nature19069 [Epub ahead of print]
- Basset-Seguin N, Hauschild A, Grob JJ, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 13 May 2015. doi: 10.1016/S1470-2045(15)70198-1 [Epub ahead of print]