Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis.
Although ras is a potent mitogenic oncogene, its tumorigenicity depends on cellular context and cooperative events. Here we show that low-level expression of a constitutively active Ha-ras in mouse urothelium induces simple urothelial hyperplasia that is resistant to progression to full-fledged bladder tumors even in the absence of Ink4a/Arf. In stark contrast, doubling of the gene dosage of the activated Ha-ras triggered early-onset, rapidly growing, and 100% penetrant tumors throughout the urinary tract. Tumor initiation required superseding a rate-limiting step between simple and nodular hyperplasia, the latter of which is marked by the emergence of mesenchymal components and the coactivation of AKT and STAT pathways as well as PTEN inactivation. These results indicate that overactivation of Ha-ras is both necessary and sufficient to induce bladder tumors along a low-grade, noninvasive papillary pathway, and they shed light on the recent findings that ras activation, via point mutation, overexpression, or intensified signaling from FGF receptor 3, occurs in 70%-90% of these tumors in humans. Our results highlight the critical importance of the dosage/strength of Ha-ras activation in dictating its tumorigenicity--a mechanism of oncogene activation not fully appreciated to date. Finally, our results have clinical implications, as inhibiting ras and/or its downstream effectors, such as AKT and STAT3/5, could provide alternative means to treat low-grade, superficial papillary bladder tumors, the most common tumor in the urinary system.
Mo
Lan
L
Department of Urology, New York University Cancer Institute, New York University School of Medicine, New York, New York, USA.
Zheng
Xiaoyong
X
Huang
Hong-Ying
HY
Shapiro
Ellen
E
Lepor
Herbert
H
Cordon-Cardo
Carlos
C
Sun
Tung-Tien
TT
Wu
Xue-Ru
XR
D000818:Animals; D001483:Base Sequence; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D018628:Gene Dosage; D005786:Gene Expression Regulation; D019942:Genes, p16; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D050791:STAT Transcription Factors; D051057:Proto-Oncogene Proteins c-akt