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View the Table of Contents for the August 1 issue of Cancer Research.
Wei et al. Page 77429
Activating mutations of epidermal growth factor receptor (EGFR) vIII and aberrant signaling through the PI3Kinase pathway from loss of PTEN/MMAC1 expression are the most common genetic alterations of human malignant astrocytomas. Using a transgenic murine astrocytoma model, Wei et al. demonstrate that somatic expression of EGFRvIII or loss of PTEN expression in the brain cannot induce astrocytomas by themselves. However, both can potentiate progression with the resulting malignant astrocytomas harboring concordant loss of PTEN and EGFR overexpression. This novel murine model, involving the two most common genetic alterations of human high-grade astrocytomas, can be utilized for preclinical evaluation of therapies targeting pathways specifically dysregulated by EGFR expression or PTEN loss.
Charest et al. Page 7473
Ectopic expression of the orphan receptor tyrosine kinase ROS is an event associated with malignant primary brain cancer, an insidious disease which claims the lives of most patients within a few years of diagnosis. Charest et al., have created a mouse strain that can be triggered to express a constitutively activated form of ROS in brain cells of adult animals that consequently develop malignant brain cancers. Through state-of-the-art biochemical and genetic approaches, they have studied in detail the mechanisms of tumor initiation in this model system which is now poised for preclinical testing of targeted therapeutics.
Yanagihara et al. Page 7532
Recent progress in the optical imaging of cancers in animal models presents many potential advantages for preclinical study. To monitor the dissemination of gastric cancer cell lines with high metastatic potential, Yanagihara et al. engineered the cells to express luciferase so that tumor growth and spread can be followed noninvasively by in vivo imaging analysis. This system successfully monitored peritoneal dissemination following orthotopic cell injection; thereby allowing quantitative evaluation of the following in living animals: peritoneal dissemination processes, metastasis detection, diagnosis, drug screening and development, and treatment responses of gastric cancer.
Gizatullin et al. Page 7668
VX-680 is a potent inhibitor of Aurora kinases that induces aberrant mitosis and defective cytokinesis. Gizatullin et al. treated a panel of solid tumor cell lines and demonstrated that integrity of the p53-p21Waf1/Cip1–dependent post-mitotic checkpoint governed the response to VX-680. Cells with intact checkpoint function were arrested in pseudo-G1. In contrast, cells with compromised checkpoint function, including both p53-deficient cells and some wild-type– expressing cell lines, underwent endoreduplication followed by apoptotic cell death due to the absence or delayed induction of p21Waf1/Cip1 and incomplete inhibition of cyclin E-cdk2 activity. This work begins to define tumor cell populations most likely to undergo apoptosis in response to Aurora kinase inhibition.
Walser et al. Page 7701
There is considerable evidence that the cytokine receptor CXCR4 contributes to malignant and metastatic behavior in a wide range of tumors. The receptor CXCR3 is expressed on malignant breast, melanoma, prostate, neuroblastoma and B cell lymphomas, but less is known about its role in malignant behavior. Using a murine model of metastatic breast cancer, Walser et al. examined the ability of a small molecule antagonist of CXCR3 to modify tumor behavior. These studies show that this antagonist inhibits tumor cell migration in vitro and metastasis in vivo. Local tumor growth was unaffected by systemic receptor antagonism. These studies support the further examination of CXCR3 as a potential target to prevent metastatic dissemination.