Abstract
Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-xL, demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic β-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-xL upon exogenous over-expression.
Highlights
For all cancerous lesions to increase in mass and malignant potential, cell proliferation must outstrip cell death [1]
The first direct genetic connection between modulation of apoptosis and tumor growth came from the discovery that expression of the Bcl-2 gene was dysregulated via chromosomal translocation in follicular lymphoma, and that this gene is homologous to the C. elegans regulator of cell death, ced-9 [6,7,8,9]
We demonstrate that Bcl-x is nonessential for RIP1-Tag2 tumorigenesis, and that cells harboring null alleles of Bcl-x do not have an inherent survival disadvantage to cells expressing wild type Bcl-x
Summary
For all cancerous lesions to increase in mass and malignant potential, cell proliferation must outstrip cell death [1]. Activation of apoptosis in response to oncogene-induced hyperproliferation has been described in a variety of genetically engineered mouse models of cancer, and in particular in two models of pancreatic neuroendocrine islet cell cancer In one such model, RIP1-Tag2 [13,14], SV40 T-antigens are constitutively expressed in the b-cells of the endocrine pancreas under control of the rat insulin promoter, resulting in a multistage pathway to invasive carcinoma that is stochastic in nature and temporally protracted. Genetic studies involving crosses to an IGFII null allele indicated that it largely functions as a survival factor in this model, in that absence of IGF-II evoked much increased (56) apoptotic rates in hyper-proliferative lesions, and the small tumors arising had a less malignant cellular phenotype; notably, the proliferation rate remained unchanged [18,19]
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