Contribution of Keratinocytes in Skin Cancer Initiation and Progression

Abstract

Keratinocytes are major cellular components of the skin and are strongly involved in its homeostasis. Oncogenic events, starting mainly from excessive sun exposure, lead to the dysregulation of their proliferation and differentiation programs and promote the initiation and progression of non-melanoma skin cancers (NMSCs). Primary melanomas, which originate from melanocytes, initiate and develop in close interaction with keratinocytes, whose role in melanoma initiation, progression, and immune escape is currently being explored. Recent studies highlighted, in particular, unexpected modes of communication between melanocytic cells and keratinocytes, which may be of interest as sources of new biomarkers in melanomagenesis or potential therapeutic targets. This review aims at reporting the various contributions of keratinocytes in skin basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, with a greater focus on the latter in order to highlight some recent breakthrough findings. The readers are referred to recent reviews when contextual information is needed.

Keywords: keratinocyte; melanoma; microenvironment; skin carcinoma; tumor invasion.

Figure 2

Interactions of keratinocytes with adjacent keratinocytes and melanocytes. Epidermal keratinocytes interact with adjacent keratinocytes (left) and melanocytes (right) through adhesion-mediated interactions and paracrine signaling. These interactions trigger pathways modulating keratinocyte proliferation, differentiation, wound healing and inflammation, and control melanocyte proliferation and functions.

Figure 3

Main genetic deregulations in basal cell carcinoma and cutaneous squamous cell carcinoma. (Left) BCC is mostly driven by mutations leading to aberrant activation of the Hedgehog (Hh) pathway. Additional activating mutations in the EGFR and Hippo (Hpo) pathways contribute to the expression of growth and survival target genes. Inactivating TP53 mutation promotes resistance to senescence and cell death. (Right) cSCC presents mainly inactivating mutations in TP53 and CDKN2A promoting resistance to senescence and cell-death signals. Inactivating mutations in Notch1 and TGFBR1/2, activating mutations in HRAS, and increased expression of EGFR promote growth, survival, and migration. Inactivating or activating mutations are indicated with a red or green star, respectively. Increased expression is indicated with a green arrow.

Figure 4

Recent advances in the comprehension of keratinocyte contributions to melanoma initiation and progression. Molecular events attributed to keratinocytes and functional consequences are reported in red.

Figure 1

Skin architecture. (A) The skin is organized in three superposed layers: the epidermis, the dermis, and the hypo-dermis. (B) The epidermis cohesion is ensured by a large repertoire of adhesion molecules variously expressed among the epidermal layers (Stratum, S.) and forming different specialized adhesion structures, including adherens junctions (AJs), desmosomes (DSMs), tight junctions (TJs), and gap junctions (GJs). (C) Keratinocytes also communicate via Notch signaling.