Accelerated Induction of Bladder Cancer in Patched Heterozygous Mutant Mice

Abstract

The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a decreased PTC expression in superficial papillary bladder tumors led us to hypothesize that it could also be involved in this cancer. To further investigate this hypothesis, we submitted Ptc ϩ/Ϫ heterozygous mutant mice and their wild-type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl) nitrosamine to their drinking water. Preneoplastic and neoplastic changes were observed significantly earlier in the Ptc ؉/؊ than in the wild-type mice. Our data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder cancer.

Hyperplasia and Carcinomas in Pten-Deficient Mice and Reduced PTEN Protein in Human Bladder Cancer Patients

“…This hyperactivation might then accelerate the growth of a tumor initiated by a BBN-induced p53 mutation and influence CIS and nonpapillary TCC to become papillary. It should be noted that, compared with our observations, previous studies using the BBN-induced tumor model reported higher frequencies of bladder cancers at earlier times in WT mice (28,39). These differences may be due to the relatively low dose of BBN given in our study, the more advanced age of our mice, or the variations in genetic background.…”

“…FPten flox/flox (n = 35) and FPten flox/+ (n = 31) mice (8-10 weeks) and their WT littermates (n = 40) were fed drinking water containing freshly prepared 0.025% (v/v) BBN (TCI America, Portland, OR) as described (28). To analyze the onset of urothelial tumors, randomly selected mice were sacrificed at week 8 ( , and 6 FPten flox/flox ) after BBN treatment and examined histologically.…”

“…4B). However, the onset of bladder cancers in mice also involves p53, Rb (5), and PATCHED (28). Significantly, Pten directly affects p53 expression (13) and indirectly influences p53 (13) and Rb (32) expression.…”

Hedgehog: functions and mechanisms

“…Subsequently, it has taken its rightful place among the major signaling pathways controlling animal development, being found to regulate the morphogenesis of a variety of tissues and organs during the development of organisms ranging from Drosophila to human (McMahon et al 2003). In addition, the Hh pathway has been linked to multiple forms of human cancer, (Hahn et al 1996;Johnson et al 1996) Medulloblastoma (Goodrich et al 1997;Berman et al 2002) Rhabdomyosarcoma (Hahn et al 1996;Kappler et al 2004) Glioma (Kinzler et al 1987) Breast cancer (Kubo et al 2004) Esophageal cancer Watkins and Peacock 2004) Gastric cancer ) Pancreatic cancer (Thayer et al 2003) Prostate cancer Sanchez et al 2004) Small-cell lung cancer ) Biliary tract cancer ) Bladder cancer (Hamed et al 2004) Oral cancer (Nishimaki et al 2004) Mutations in Hh pathway components have been identified in BCC, medulloblastoma, rhabdomyosarcoma, and glioma (top).…”

Molecular pathogenesis of bladder cancer

“…13 In a mouse Table 2) model, it has been shown that Ptch −/− mice show increased susceptibility to carcinogen-induced bladder tumorigenesis, which provides additional support for a suppressor function in the bladder. 15 However, further studies are required to confi rm a role in human bladder cancer. Similarly, the DBC1 gene (9q33) has been implicated by mapping studies.…”