Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice

Abstract

Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations. We report here that Ptch+/- mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription. The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.

Enhanced expression of hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions

“…23 It was reported that PTCH þ /À mice have a higher incidence of squamous cell carcinomas after ultraviolet (UV) exposure, and the size of the tumor is also greatly increased. 24 Therefore, it is possible to postulate that genetic alteration or deregulation of the expression of PTCH superimposed with another genetic alteration such as UV exposure or p53 alteration by HPV may play a role in the development of squamous cell carcinoma of uterine cervix.…”

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

“…Doxycycline (Dox)‐inducible GLI1‐expressing HaCaT keratinocytes and mouse BCC cell line ASZ00122 were grown as described previously 23, 24. Induction of GLI1 expression in HaCaT keratinocytes was done as reported in Refs.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Su(Fu) null mouse mutants not only fail to repress the pathway (Svard et al, 2006), but have some phenotypes similar to inactivation of Ptch1. Although Ptch1 þ /À mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, and basal cell carcinomas following irradiation (Goodrich et al, 1997;Hahn et al, 1998;Aszterbaum et al, 1999b), Su(fu) þ /À mice mainly develop a skin phenotype characterized by basaloid epidermal proliferations. Moreover, Su(Fu) null MEFs and wild-type cells treated with Su(Fu) siRNAs display Hh pathway activation, supporting a central role in pathway repression (Svard et al, 2006).…”