Abstract
Human sarcomas arise suddenly, thus preempting the study of preneoplastic and early neoplastic lesions. To explore the natural history of these tumors we studied male mice carrying a heterozygous deletion of p53 and an activated HER-2/neu transgene (BALB-p53Neu mice), that develop urethral rhabdomyosarcomas with nearly full penetrance and early onset (4 months of age). Among genes prominently upregulated in preneoplastic tissue, and more highly expressed in tumors, we found the insulin-like growth factor 2 (Igf2) and tumor suppressors, p19Arf and p21Cip1. In urethral tissues of male mice p53 was less expressed than in female mice, whereas HER-2/neu was more expressed, a combination not found in other skeletal muscles of the same mice that could contribute to the anatomic and sexual specificity of BALB-p53Neu rhabdomyosarcoma. Upregulation of p19Arf and p21Cip1 was additively determined by HER-2/neu activation and by p53 inactivation. Silencing of p19Arf or p21Cip1 in rhabdomyosarcoma cell lines can inhibit cell growth and motility, thus suggesting that these genes can contribute to growth autonomy and malignancy of tumor cells. In vivo injection of gene-silenced cells highlighted selective variations in organ-specific metastatic ability, indicating that overexpression of p19Arf and p21Cip1 controlled both tumor cell-intrinsic properties and microenvironmental interactions. The onset of pelvic rhabdomyosarcoma in BALB-p53Neu male mice is triggered by the coincidental overexpression of HER-2/neu and hypoexpression of the residual p53 allele, that foster p53 loss, Igf2 autocriny and overexpression of p19Arf and p21Cip1, a phenotype that could provide novel potential targets for cancer prevention and therapy.
Highlights
Alterations of tumor suppressor genes play a prominent role in cancer development, alone or in combination with activated oncogenes
Here we found that some tumor suppressor genes were upregulated, in particular cyclin-dependent kinase inhibitor 1A (CDKN1A/p21Cip1) and cyclin-dependent kinase inhibitor 2A (CDKN2A/p19Arf)
Twenty genes showed a >2-fold change expression in the preneoplastic urethra of male BALB-p53Neu mice, and even higher levels of expression were found in tumors, than in urethral tissues of BALB/c mice (Table 1), suggesting an early involvement in the genesis of rhabdomyosarcoma
Summary
Alterations of tumor suppressor genes play a prominent role in cancer development, alone or in combination with activated oncogenes. From a therapeutic perspective, inactivated tumor suppressor genes are problematic targets, especially when inactivation results from the lack of a tumor suppressor protein, rather than from a mutant with dominant negative activity. Overexpression of tumor suppressors might be either an irrelevant, “passenger” phenomenon, or a driving event in the genesis of specific tumor types. In the latter case, such “reactive”, hyperexpressed tumor suppressor genes might provide new therapeutic targets, to develop an anticompensatory therapy to inhibit cancer progression
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