November 1 Cancer Research Highlights

AACR Journal Highlights features summaries of up to six articles that the Editor-in-Chief of each journal has selected from each issue. The summaries, which are also published in the print versions of each journal, cover why the study was done, what was found, and why it is important.

The articles referenced in the current Highlights sections will be available online in HTML and PDF formats at no charge until the next issues of each journal are published.

The AACR welcomes your pubs{at}aacr.org on this new feature.

Diabetes Drug Found to be Growth Inhibitor 

Metformin is widely used in the treatment of type 2 diabetes. It recently was shown to activate AMP kinase in hepatocytes, which leads to a decrease in glucose output by the liver, improving the hyperglycemia and hyperinsulinemia of type 2 diabetes. Zakikhani et al. report that metformin also activates AMP kinase in cancer cells, where it activates signaling pathways that inhibit cell growth. Thus metformin or similar agents may act to restrain cancer growth both by systemic effects in reducing high insulin levels that may stimulate proliferation of some cancers, and also by direct growth inhibitory action on neoplastic cells. These mechanisms are of particular interest in the context of cited population studies which provide clues that diabetics treated with metformin may have unexpectedly low cancer rates. 

Genetic Grading of Breast Cancers Improves Prognosis 

Histological grading of breast cancer defines morphological subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity, particularly among the moderately differentiated grade 2 (G2) tumors. Ivshina et al. posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. Their findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low- and high-grade diseases, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression. 

Dysfunctional Mitochondria Yield Unstable Clones 

Radiation-induced genomic instability (RIGI) manifests as a heritable increased rate of genetic alterations in the progeny of irradiated cells generations after the initial insult. The progeny can show an increased frequency of chromosomal translocations, deletions, mutations, micronuclei, and decreased plating efficiency. What perpetuates RIGI is unclear; however, persistently increased levels of reactive oxygen species (ROS) are frequently associated with genomically unstable clones. Because mitochondria are a major natural cellular source of ROS, Kim et al. tested the hypothesis that mitochondrial dysfunction has a role in maintaining the elevated ROS levels in irradiated, genetically unstable GM10115 Chinese hamster ovary cells. These studies demonstrate that mitochondria from unstable cells are abnormal and likely contribute to the persistent oxidative stress in the unstable clones. 

HPV Testing May Find What Cytological Tests Miss 

In spite of the success of cervical cytology as a cancer-screening tool, it has important limitations; human papillomavirus (HPV) testing may be more valuable in future screening. The majority of women in screened populations who test HPV positive will have a concurrent normal smear, and more information is needed about the risk for subsequent high-grade cervical lesions in these women. Kjaer et al. examined more than 10,000 women who were followed for development of cervical neoplasia through the Danish Pathology Data Bank. The results indicated that even a single positive HPV test in cytologically negative women is substantially predictive of high-grade CIN and suggest that HC2 testing can help stratify women into different risk categories. 

New Models for Human Esophageal Cancer 

There are currently no good animal models for human esophageal cancers. To investigate pathways of human esophageal squamous cell transformation, S-H. Kim et al. generated esophageal tumor cells using human telomerase- and SV40-immortalized primary esophageal epithelial cells (EPC2) by overexpression of selected combinations of oncogenes and compared their kinetics of growth to each other and their gene expression profiles with human tumors. Surprisingly, some gene expression profiles matched better with adenocarcinoma whereas others matched better with squamous cancer. These genetically engineered models may provide new platforms for understanding human esophageal cancer and may assist in the evaluation of new therapies. 

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