June 1 Cancer Research Highlights

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Selected Articles from the June 1, 2007 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the June 1 issue of Cancer Research.

Endothelial Akt Signaling Is an Important Target for Rapamycin

Treatment of mammary tumors in mice with the mTOR inhibitor rapamycin results in strong inhibition of tumor growth. However, the possible mechanisms for this are not well understood. Analysis of the effectors in the rapamycin pathway showed decreased phoshpo-Akt S⁴⁷³ in endothelial cells, yet increased phospho-Akt S⁴⁷³ in tumor cells following drug treatment. To understand the importance of the tumor vasculature in the antitumor effects of rapamycin, Phung et al. generated a mouse model of breast cancer with endothelial cell-specific expression of constitutively activated Akt. The antitumor efficacy of rapamycin was reduced in the setting of increased endothelial constitutive activation of Akt. These data suggest that the therapeutic effects of rapamycin are partially dependent on its ability to inhibit Akt signaling in the endothelium and have implications for further development of mTOR inhibitors.

Tobacco Smoke Mediates Heritable Mutations in the Germ-Line

There is currently no evidence to demonstrate that exposure to mainstream tobacco smoke (MTS) results in heritable DNA sequence mutation. Yauk et al. exposed mature male mice to MTS and measured tandem repeat DNA mutations arising in spermatogonial stem cells. The mutation frequency was 1.4 and 1.7 times higher than controls for mice exposed to MTS for 6 and 12 weeks, respectively, demonstrating the accumulation of mutations in spermatogonial stem cells. Mutations in sperm may be passed on to offspring, causing permanent changes in genetic composition. Therefore, the health consequences of smoking may extend beyond smokers to their nonsmoking descendents.

A Molecular Signature for Hormone-Refractory Prostate Cancers  

An important issue in prostate cancer research is the development of hormone-refractory prostate cancers (HRPCs), which show androgen-independent, aggressive behaviors and poor response to anticancer therapies. To characterize the molecular features of HRPCs, Tamura et al. generated the gene expression profiles of 25 clinical HRPCs and 10 hormone-naïve prostate cancers by genome-wide cDNA microarrays combined with microdissection, and compared their gene expression profiles. This analysis defined a novel molecular signature for clinically-derived HRPC tumors, which was verified using siRNA knockdown techniques in model systems. These results should provide information useful to understanding the molecular mechanism of HRPC progression and identifying novel molecular targets for HRPC treatment.

Host Perforin Expression Reduces Mammary Adenocarcinoma in a Mouse Model

The concept of tumor immune surveillance has long been supported by studies in mice that demonstrate that immune effector mechanisms suppress hematological malignancies; however, there is much less data supporting the immune surveillance of epithelial malignancies. Street et al. evaluated the role of perforin-mediated induced mammary cancer in the Her2/neu model. Perforin expression delayed both the onset and number of tumors, but did not affect survival. The effect of perforin is most evident during the earliest stages of carcinogenesis, and thus may mediate some suppression of epithelial carcinogenesis by intervening early in the tumor development process.

Nutrients from Food, but Not Supplements, Reduce Risk of Pancreatic Cancer