Also in the Feb. 24 JNCI

February 24, 2009

Prostate Biopsy Samples Show Evidence of Differential Gene Expression in Patients After Supplement Use

Researchers have shown that prostate biopsy samples taken from surgically removed prostate (prostatectomy specimens) after preoperative treatment with vitamin supplements can be used to investigate their effects on gene expression. Gene expression profiles differed between tumor samples from patients who had taken vitamin E, selenium, both supplements, or placebo.

Earlier observational studies had reported that selenium, vitamin E, or both, might reduce the risk of prostate cancer.

To determine whether gene expression patterns change in patients after supplement use, Jeri Kim, M.D., of the University of Texas MD Anderson Cancer Center in Houston, and colleagues enrolled 39 patients in a phase IIA trial and randomly assigned them to receive selenium, vitamin E, both supplements, or placebo for three to six weeks before prostatectomy. Researchers then isolated and studied tumor cells, stromal cells, and normal cells from biopsy samples removed from the prostatectomy specimens.

The investigators found that gene expression patterns differed between the treatment groups. Expression of several molecular pathways associated with cancer were altered in the supplement groups compared with the placebo group.

"We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis generating engine," the authors conclude.

In an accompanying editorial, Eric A. Klein, M.D., of the Glickman Urological and Kidney Institute in Ohio, reviewed the history of selenium and vitamin E in prostate cancer chemoprevention efforts and put the new data into context. "...the study is noteworthy for demonstrating that even short-term exposure (i.e., 3 - 6 weeks) to these agents can affect expression of a majority of the genes interrogated and, in the robust demonstration of the utility of the preprostatectomy model, for deriving information on modulation of biomarkers..."

These data are consistent with data from past observational studies. However, two large randomized trials failed to show statistically significant benefit from the use of vitamin E and/or selenium in the prevention of prostate or other cancers or cardiovascular disease. The lack of consistency between epidemiological and in vitro studies and randomized trials suggest that randomized controlled trials "do not always validate what we believe biology indicates and that our model systems are imperfect measures of clinical outcomes in the real world," the editorialist concludes.

Contacts:


Model May Predict Lynch Syndrome in Colon Cancer Patients

A model called 'MMRpredict' showed the best discriminating ability of four models evaluated to help identify colorectal cancer patients who should be screened for Lynch syndrome, an inherited cancer condition that accounts for about 3% of all colorectal cancers. Its use could substantially reduce the proportion of colorectal cancer patients who are unnecessarily referred for genetic testing.

Inherited mutations in genes that repair DNA are the cause of Lynch syndrome. It is important to identify mutation carriers because their treatment will be different and because members of their extended families must also be screened. However, the models to help identify Lynch syndrome patients were designed for use in high-risk patient populations and their value in the general patient population was unknown.

In the current study, Roger C. Green, Ph.D., of Memorial University, St. John's, Newfoundland, and colleagues tested the ability of four models to distinguish between individuals who did and did not carry mutations in DNA mismatch repair genes. They examined a series of 725 colorectal cancer patients whose mutation status was known.

By analyzing such factors as the age of the patient, the type of cancer, and the number of affected relatives, a model called 'MMRpredict' was the best of the four in predicting which patients carried a Lynch syndrome mutation. If the model were used in the clinic, it would reduce the percentage of Newfoundland patients selected for genetic testing from 50%, with the currently used criteria, to 11%.

"We conclude that for colorectal cancer patients who were younger than 75 years at diagnosis, MMRpredict appears to be an excellent screening tool that identifies an at-risk group that should undergo further diagnostic workup," the authors write.

Contact: Sharon A. Gray, sgray@mun.ca, 709-777-8397




Novel Imaging Marker Allows Tracking of Putative Cancer Initiating Cells in Mice

A fluorescent fusion protein can be used to identify cancer-initiating cells in vitro and in mouse models of breast and brain cancer.

Some researchers hypothesize that a subset of cells in a tumor, called cancer-initiating cells (CICs), are capable of regenerating a tumor or forming metastases. Investigators have identified several cell surface markers that detect CICs in vitro, but markers that can be used in vivo are lacking.

In the current study, Frank Pajonk, M.D., Ph.D. of the David Geffen School of Medicine at the University of California, Los Angeles and colleagues engineered breast and glioma cell lines to express a fluorescent protein that was a target for degradation by the 26S proteasome, which normally disposes of unwanted cellular proteins.

Under normal growth conditions, the level of fluorescence was low, indicating high proteasome activity. But when cells were grown in conditions that favor the growth of CICs, the level of cell fluorescence increased, suggesting that reduced proteasome activity was a characteristic of CICs. The highly fluorescent cells had greatly increased ability to form tumors in animals compared to cells that did not accumulate the fusion protein, and were verified to have a number of markers specific to CICs. Using this system, they demonstrate for the first time that specific elimination of CICs is sufficient to cause regression of solid cancers.

"Our results demonstrate that reduced 26S proteasome activity is a general feature of CICs that can easily be exploited to identify, track, and target them in vitro and in vivo," the authors conclude.

Contact: Frank Pajonk, FPajonk@mednet.ucla.edu, 310-206-8733
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Also in the February 24 JNCI: Note to Reporters:

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