Patched1 Inhibits Epidermal Progenitor Cell Expansion and Basal Cell Carcinoma Formation by Limiting Igfbp2 Activity

Abstract

Basal cell carcinoma (BCC) of the skin is the most common form of cancer, with the majority being caused by mutations in the Patched1 (Ptch1) gene, leading to activation of the Hedgehog (Hh) signaling pathway. Hh signaling is implicated in many tumor types; thus, defining the mechanisms by which Ptch1 regulates tissue proliferation is of paramount importance. Here, we show that the key role of Ptch1 in the skin is to limit the size of the epidermal stem/progenitor compartment and allow hair follicle differentiation. Specifically, loss of Ptch1 leads to the promotion of progenitor cell fate by increasing basal cell proliferation and limiting the progression of basal cells into differentiated hair follicle cell types. Our data indicate that BCCs likely result from hair follicle progenitor cells that, due to Hh signal activation, cannot progress through normal hair follicle differentiation. These data confirm the role of Ptch1 as a negative regulator of epidermal progenitor turnover and also show for the first time that Ptch1 plays a role in the differentiation of the hair follicle lineage. In addition, we show that insulin-like growth factor binding protein 2 (Igfbp2) is upregulated in both murine and human BCCs and that blocking Igfbp2 activity reduces the Hh-mediated expansion of epidermal progenitor cells. We propose that Igfbp2 mediates epidermal progenitor cell expansion and therefore represents an epidermal progenitor cell-specific target of Hh signaling that promotes BCC development.

IGFBP-2 - taking the lead in growth, metabolism and cancer

“…These studies have shown that in the absence of Patched1 (Ptch1; trans-membrane receptor and negative regulator of Hh signalling), IGFBP-2 expression is enhanced and this led to the expansion of the epidermal basal cells in the proliferative layer of the skin, an event required to promote BCC development (Villani et al 2010).…”

“…Although synergism between the IGF1R and Hh signalling has been implicated in another cancer type (Rao et al 2004), the expression and action of IGFBP-2 in BCC appears to be IGF-independent in nature (Villani et al 2010) .…”

Patched Receptors Sense, Interpret, and Establish an Epidermal Hedgehog Signaling Gradient

“…Previous studies by Dlugosz and colleagues (Grachtchouk et al, 2003) have shown that the magnitude of Hh signalling activity defines the tumorigenic potential of the pathway. We have previously shown that loss of Ptch1 activity is sufficient to induce BCC formation across all epidermal locations (Villani et al, 2010). Thus the level of activity generated in Ptch1-deficient cells acts to define the tumorigenic threshold of Hh signalling in skin.…”

“…A number of studies have been directed at dissecting the cellular origin of BCC, whereby Hh signalling activity has been activated in specific epidermal and HF stem/progenitor cell compartments. Despite these studies, the BCCinitiating cell compartment remains controversial and consensus has been difficult to attain with some studies reporting BCC formation following Hh activation in a variety of HF stem cell compartments (Grachtchouk et al, 2011;Kasper et al, 2011;Peterson et al, 2015;Wang et al, 2011), and others indicating BCC potential from IFE structures (Adolphe et al, 2006;Grachtchouk et al, 2011;Villani et al, 2010;Wong and Reiter, 2011;Youssef et al, 2012;Youssef et al, 2010) M A N U S C R I P T…”

“…We have previously shown that loss of Ptch1 alone is necessary and sufficient to induce basal cell carcinoma (BCC) formation (Adolphe et al, 2006;Villani et al, 2010). Here we have quantitated the level of Hh pathway activity generated in the IFE of Ptch1-deficient cells It is predicted that Ptch1;Ptch2-deficient epidermis is not sensitive to Shh.…”