PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

Abstract

Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1+/− genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis

“…Using a cutoff of p<0.05 and neglecting genes with less than 100 reads, 609 genes were identified. To enrich for likely Hh targets, these 609 genes were cross-referenced against five known Hh target lists (Table S1) (Falkenstein and Vokes, 2014; Hsu et al, 2014; Ingram et al, 2002; Valin et al, 2009; Yu et al, 2009). …”

Hedgehog signaling in skin cancers

“…However, autocrine and paracrine Hh signaling cannot be excluded in BCC[183,184]. Recent data indicatet that the surrounding PTCH1+/− stroma may affect BCC development in the NBCCS patients [185]. Therefore, it is very important to understand the signaling mechanisms by which Hh signaling mediates carcinogenesis.…”

Hedgehog signaling and gastrointestinal cancer

“…The specificity of Ptch1 is somewhat controversial since its function depends on the cell type, and protein domain involved [47,48]. Hematopoietic cell-specific deletion of Ptch1 does not result in constitutively active Hh signaling [49], as Hh signaling has recently been shown to be dispensable for hematopoiesis [50,51], whereas in skin, brain and colon, mutations in Ptch1 result in unregulated Hh signaling causing basal cell carcinoma of the skin [52,53], medulloblastoma of the brain [54,55], and Gorlin syndrome [56,57], an autosomal dominant disorder characterized by the early appearance of basal cell carcinomas and cancers in other organs, e.g., brain, colon and ovary.…”