Basal cell carcinomas: attack of the hedgehog

Abstract

Basal cell carcinomas (BCCs) were essentially a molecular 'black box' until some 12 years ago, when identification of a genetic flaw in a rare subset of patients who have a great propensity to develop BCCs pointed to aberrant Hedgehog signalling as the pivotal defect leading to formation of these tumours. This discovery has facilitated a remarkable increase in our understanding of BCC carcinogenesis and has highlighted the carcinogenic role of this developmental pathway when aberrantly activated in adulthood. Importantly, a phase 1 first-in-human trial of a Hedgehog inhibitor has shown real progress in halting and even reversing the growth of these tumours.

Figure 1. Histological sections of basal cell carcinoma and squamous cell carcinoma of the skin

a | Basal cell carcinomas (BCCs) are keratinocyte tumours that are so named because of their histological resemblance to the cells along the basement membrane — the ‘basal’ layer of the epidermis. b | Often BCCs are grouped as non-malignant skin cancer together with squamous cell carcinomas of the skin (shown) and several other less common tumours.

Figure 2. The cutaneous appearance of basal cell carcinoma

BCCs classically appear as slow-growing, translucent, elevated lesions on the sun-exposed skin of persons with ‘fair’ skin and occur more commonly in men than in women.

Figure 3. A basic schematic of the Hedgehog (HH) signalling pathway

a | The family of extracellular HH ligands, of which there are three in mammals (sonic hedgehog (SHH), Indian hedgehog (IHH) and desert hedgehog (DHH)) bind to the patched 1 (PTCH1) receptor. This relieves the inhibition of smoothened (SMO) by PTCH1, and SMO sends signals through a series of interacting proteins, including suppressor of fused (SUFU), resulting in activation of the downstream Gli family of transcription factors: GLI1, GLI2 and GLI3. b| Loss of PTCH1 in patients with basal cell nevus syndrome predisposes them to basal cell carcinoma (BCC) development. Sporadic BCCs routinely carry mutations in PTCH1 and TP53, consistent with their having been produced by ultraviolet radiation and, in 10% of instances, in SMO. Other mutations have been implicated in BCC development, including genes that regulate skin colour, DNA damage repair genes, members of the phosphoinositide 3-kinase (PI3K)–Akt and the Wnt pathways and FOXM1.