Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

Abstract

The human epidermal clonal evolution, i.e. the transition from stem cells (SCs) to transient amplifying (TA)-cells and post-mitotic cells, is a continuous and tightly regulated process that ensures physiologic tissue homeostasis. The Ras family of small GTPases has a key role in skin homeostasis and tumorigenesis. Indeed, activating mutations in Ras genes have been found in human cutaneous squamous cell carcinomas (cSCCs) and in experimentally-induced murine cSCCs. In mouse models, the Ras signaling might lead to hyperproliferative phenotypes, including the development of cSCCs, depending on the nature of the founding cells. Tumor-initiating cells or Cancer Stem Cells (CSCs) have been demonstrated in murine and human cSCCs even if the mechanism of their development from normal SCs or TA-cells is not completely elucidated. Here, the relation between the Ras expression outcome and the clonogenic potential of the target keratinocyte is discussed.

The Protein Tyrosine Phosphatase H1 PTPH1 Supports Proliferation of Keratinocytes and is a Target of the Human Papillomavirus Type 8 E6 Oncogene

“…The PTPH1/p38γ kinase/phosphatase signaling network was found to be important for oncogenic Ras activity in colon cancer cells [56,57]. Constitutive active Ras signaling appears to be frequent in cSCC [37].…”

“…Activating mutations in codons 12, 13 or 61 of Ras genes have been detected in at least 22% of human SCCs, and in experimentally induced cSCC in mouse models. However, the number of human tumors with a constitutively active Ras pathway might be significantly higher (reviewed in [37]). Ras signaling is essential for proper development of the epidermis and hair follicles.…”

“…However, activation of Ras by mutations or upstream signaling pathways is regarded as an early event in skin tumor formation. Two genetic events, i.e., K- Ras induction followed by TP53 inactivation, as consequence of UV irradiation [39] are necessary for progression from papilloma to SCC [37].…”

Transit Amplifying Cells (TACs): a still not fully understood cell population

“…Indeed, activating mutations in Ras genes have been found in human cutaneous squamous cell carcinomas. Dellambra has suggested, although not completely proven, that Ras family members can play a role also in normal transition from epithelial SCs to TACs (Dellambra, 2016). Interestingly, the identification and an initial characterization of "early" and "late" TACs in the human epidermis was recently reported (Lotti et al, 2022).…”

Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?

“…While differentiating, keratinocytes acquire a defined gene expression signature that includes cell cycle regulators and tumor suppressor genes [3]. Specifically, acquired mutations in the Ras or p53 genes in skin cells lead to altered response to growth factors and environmental insults, and consequently to keratinocyte hyperproliferation and neoplastic transformation [4,5]. However, the exact mechanism perturbing epidermal homeostasis and tipping the balance towards the development of cSCC, in contrast to other epidermal dysplasias, remains unclear.…”