Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer Export

@article{citeulike:4037246, abstract = {<p>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-x_L, 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 <italic>Bcl-x</italic> 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 <italic>Bcl-x</italic> knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the <italic>Bcl-x</italic>-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-x_L upon exogenous over-expression.</p>}, author = {Hager, Jeffrey H. and Ulanet, Danielle B. and Hennighausen, Lothar and Hanahan, Douglas}, citeulike-article-id = {4037246}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pone.0004455}, day = {11}, doi = {10.1371/journal.pone.0004455}, journal = {PLoS ONE}, keywords = {ablation, bcl-x, cell, death, hager09pdf, tumor}, month = {February}, number = {2}, pages = {e4455+}, posted-at = {2009-02-12 00:09:24}, priority = {2}, publisher = {Public Library of Science}, title = {Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer}, url = {http://dx.doi.org/10.1371/journal.pone.0004455}, volume = {4}, year = {2009} }

TY - JOUR ID - citeulike:4037246 L3 - citeulike-article-id:4037246 N2 - <p>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-x_L, 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 <italic>Bcl-x</italic> 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 <italic>Bcl-x</italic> knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the <italic>Bcl-x</italic>-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-x_L upon exogenous over-expression.</p> IS - 2 JF - PLoS ONE TI - Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer PB - Public Library of Science VL - 4 SP - e4455 KW - ablation KW - bcl-x KW - cell KW - death KW - hager09pdf KW - tumor AU - Hager, Jeffrey AU - Ulanet, Danielle AU - Hennighausen, Lothar AU - Hanahan, Douglas PY - 2009/02/11/ UR - http://dx.doi.org/10.1371/journal.pone.0004455 ER -