Basal cell carcinoma - molecular biology and potential new therapies

Abstract

Basal cell carcinoma (BCC) of the skin, the most common malignancy in individuals of mixed European descent, is increasing in incidence due to an aging population and sun exposure habits. The realization that aberrant activation of Hedgehog signaling is a pathognomonic feature of BCC development has opened the way for exciting progress toward understanding BCC biology and translation of this knowledge to the clinic. Genetic mouse models closely mimicking human BCCs have provided answers about the tumor cell of origin, and inhibition of Hedgehog signaling is emerging as a potentially useful targeted therapy for patients with advanced or multiple BCCs that have hitherto lacked effective treatment.

Figure 1. Major subtypes of human BCC.

(A–E) Macroscopic (A, C, and E) and microscopic (B, D, and F) appearance of nodular (A and B), superficial (C and D), and sclerosing (E and F) human BCCs. Original magnification, ×100 (B, D, and F).

Figure 2. The Hh signaling pathway — a simplified model.

(A) In its “off” state, Ptch1 represses Smo activity. Gli2 and Gli3, effectors of the Hh pathway, are phosphorylated by a kinase cascade, which includes PKA, CK1, and GSK3β, and are directed to the proteasomal degradation pathway via the SPOP complex. A fraction of the Gli2/3 protein is processed into a repressor form, Gli-R, which inhibits Hh target gene transcription. (B) Hh ligand binding to Ptch1 abrogates its inhibitory effect on Smo, allowing Smo to translocate into the primary cilium and induce accumulation of the Gli-Sufu complex at the tip of the primary cilium. Activation of the Hh pathway results in accumulation of Gli-A and initiation of the transcription of Hh target genes such as PTCH1, GLI1, and HHIP.

Figure 3. The HF and its morphological units, stem cell compartments, and targeted cell populations.

The targeted cell populations are defined by endogenous or transgene promoter activities. K15* denotes a truncated version of the K15 promoter, restricted in its activity to the bulge area.