From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. In this Review we discuss clinical and molecular parameters used to define this range of cutaneous neoplasia and integrate these with the multiple experimental approaches used to study this disease. Insights gained from modeling cSCCs have suggested innovative therapeutic targets for treating these lesions.

Figure 1. Probability that human cutaneous neoplastic lesions will progress to invasive carcinoma.

The likelihood of AKs in patients with fewer than 5 or more than 20 lesions progressing to cSCC is shown (9, 10).

Figure 2. A clinical, histologic, and molecular comparison of AKs, cSCC, and metastatic cSCC.

The common clinical, histologic, and molecular features of human cutaneous neoplasia are shown.

Figure 3. Key signaling pathways involved in the formation of cSCC.

Mutations induced by UVB exposure can perturb multiple cellular pathways leading contribute to the formation of cSCC. Thick arrows signify an increase or decrease of signaling in SCC. Red T-bars indicate inhibitory relationships.

Figure 4. Comparative analysis of models used to study cSCC.

The commonly used models for studying cSCC are listed with corresponding strengths and weaknesses.

Figure 5. Potential pathways that may be targeted by small molecules to treat AKs and cSCCs.

Key signaling pathways driving cutaneous neoplasia are shown. Small molecules that can permeate the epidermis and target these signaling deficits may have therapeutic potential. Arrows denote stimulatory relationships and T-bars denote inhibitory relationships.