Murine basal cell carcinoma leads to tumor-mediated alterations in endocrine Igf1 signaling

Abstract

The intrinsic properties underlying cancer development are extensively studied while the effect of a cancer on the host is often overlooked. Activation of the Hedgehog (Hh) signaling pathway underlies a number of types of common human cancers, yet little is known concerning endocrine signaling in such tumors. Here, we investigated endocrine signaling in a murine model of basal cell carcinoma (BCC) of the skin, the most common cancer. BCCs were generated by the activation of Hh signaling resulting from the specific deletion of the Ptch1 gene in the developing epidermis. Subsequently, a severe growth deficiency was observed in the murine BCC model, and we identified a deficiency of circulating IGF1 (Igf1). We demonstrate that Hh pathway activation in murine BCC induces IGF binding proteins, thereby regulating Igf1 sequestration into the skin and skewing Igf endocrine signaling. Significantly, these results show that Hh-induced tumors can have endocrine effects on normal tissues that in turn can greatly impact the host. This study not only identifies that Igf is important in Hh-associated skin tumors but also exemplifies the need to consider endocrine signaling when interpreting complex in vivo tumor models.

The role of insulin-like growth factor-1 in the pathogenesis of cancer and inflammatory skin diseases

“…Researchers indicate a relationship between the increase in the tissue expression of this protein with development and progression of BCC. In another study by the same author it was proved that blocking IGFBP-2 activity reduced proliferation of epidermal cells mediated by sonic hedgehog signalling pathway [46,47]. A similar correlation was observed in cancers of other organs induced by the sonic hedgehog signalling pathway, such as medulloblastoma, glioma, pancreatic, breast, prostate, ovarian, lung and colon cancer [48].…”

“…Additionally, it was hypothesized that recruitment of free IGF-1 to the skin was increased, which stimulated development of BCC and explained the decrease in the free serum IGF-1 level. This hypothesis seems to be confirmed by the fact that decreased IGF-1 concentration was not associated with increase in serum IGFBP level [46]. In contrast, deletion of the Ptch subunit led to increased concentration of IGFBP-2, IGFBP-4 and IGFBP-5 binding proteins in epidermal cells.…”

“…In a study by Villani et al conducted in mice, it was observed that the loss of the Ptch subunit at the epidermal level was associated with development of BCC and growth disturbance in mice (3-4 weeks after deletion). These phenomena were accompanied by decreased expression of circulating IGF-1 in the serum, which was considered to be the direct cause of growth inhibition [46]. Additionally, it was hypothesized that recruitment of free IGF-1 to the skin was increased, which stimulated development of BCC and explained the decrease in the free serum IGF-1 level.…”

“…przeprowadzonym na myszach zaobserwowano, że utrata podjednostki Ptch na poziomie naskórka wiązała się z rozwojem BCC i zaburzeniem wzrostu badanych myszy (po 3-4 tygodniach po delecji). Zjawiskom tym towarzyszył spadek ekspresji krążącego IGF-1 w surowicy, co uznano za bezpośrednią przyczynę zahamowania wzrostu [46]. Dodatkowo wysnuto hipotezę wzmożonej rekrutacji wolnego IGF-1 do skóry, co pobudzało rozwój BCC i tłumaczyło zmniejszenie stężenia wolnego IGF-1 w surowicy.…”

“…Dodatkowo wysnuto hipotezę wzmożonej rekrutacji wolnego IGF-1 do skóry, co pobudzało rozwój BCC i tłumaczyło zmniejszenie stężenia wolnego IGF-1 w surowicy. Hipotezę tę wydaje się potwierdzać fakt, że zmniejszone stężenie IGF-1 nie wiązało się ze zwiększeniem stężenia IGFBP w surowicy [46]. Delecja podjednostki Ptch prowadziła do zwiększonego stężenia białek wiążących IGFBP-2, IGFBP-4 i IGFBP-5 w komórkach naskórka.…”