Identification of a Population of Epidermal Squamous Cell Carcinoma Cells with Enhanced Potential for Tumor Formation

Abstract

Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation.

Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival

“…We recently characterized epidermal cancer stem cells (ECS cells) and showed that ECS cells express stem cell markers characteristic of normal epidermal stem cells and embryonic stem cells (9). These ECS cells are able to generate tumors in immune-compromised mice following subcutaneous injection of as few as 100 cells (9). ECS cells express pluripotent markers, which are also expressed in esophageal and head/neck cancer stem cells (6, 10, 11).…”

The role of oncogenic Ras in human skin tumorigenesis depends on the clonogenic potential of the founding keratinocytes

“…As the epidermis protects the body from environmental insults, keratinocytes have a high risk of acquiring oncogenic mutations and undergoing uncontrolled proliferation, which is one of the hallmarks of cancer. Many epithelial cancers, including squamous cell carcinomas (SCCs), contain a minor population of tumorinitiating cells named cancer stem cells (CSCs) that can reconstitute and maintain the tumor (Adhikary et al, 2013;Patel et al, 2012;Thieu et al, 2013). CSCs share some characteristics of normal stem cells, give rise to heterogeneous tumors and are the source of metastatic outgrowths.…”

Long-Lived Epidermal Cancer-Initiating Cells

“…). This suggests that SCC-forming populations arises from both HF SCs and IFE SCs, although the relationship between the two populations in the pathogenesis of SCC is not well understood [23]. To dissect the contributions of these two populations of SCs to tumourigenesis, removing the IFE SC compartment while maintaining the HF SC compartment led to a reduction in the number of papillomas and SCCs compared to wild type mice, following wounding and subsequent administration of the tumour promoter, TPA [31].…”