Also in the March 24 JNCI

Human Cytomegalovirus Stimulates Telomerase Activity in Tissue Culture Cells

Infection with human cytomegalovirus (HCMV) triggers expression of the telomerase reverse transcriptase (hTERT) gene in both normal human cells and tumor cells grown in culture.

HCMV has been suspected of causing or promoting cancer, but the mechanism by which the virus acts has been unclear. Several other cancer-related viruses stimulate telomerase activity, which promotes cell proliferation and immortalization.

To learn whether HCMV induces telomerase activity, Dawei Xu, M.D., Ph.D., of the Karolinska Institute in Stockholm, Sweden, and colleagues infected normal diploid fibroblasts and malignant glioma cells with HCMV or introduced a copy of the viral immediate early antigen 72 (IE-72) gene into the cells.

Infection with HCMV induced telomerase expression in both normal and malignant human cells. Introduction of the viral IE-72 gene also induced telomerase activity in both cell types.

"In this study, we reveal a novel mechanism through which HCMV may be linked to or modulate oncogenesis by demonstrating that HCMV stimulates hTERT transcription, thereby activating telomerase, which is essential for the immortalization and transformation of human cells," the authors write.

In an accompanying editorial, Jindrich Cinatl Jr., Ph.D., of the Universität Frankfurt in Germany and colleagues note that they hypothesized previously that HCMV may increase tumor malignancy rather than instigate malignancy. The results by Xu and colleagues may provide important mechanistic insight as to how such a modulatory role could occur.

"…HCMV-induced telomerase activation represents a mechanism that is of possible relevance for both (initiation of) malignant trans¬formation and oncomodulation by HCMV infection," the editorialists write.

Contacts:

• Article: Dawei Xu, dawei.xu@ki.se
• Editorial: Jindrich Cinatl, cinatl@em.uni-frankfurt.de, +49 (0)69 6301 6409

Reductions in Cancer and Overall Mortality Persist 10 Years After Vitamin and Mineral Supplementation

Individuals who took a dietary supplement called "factor D", which included selenium, vitamin E, and beta-carotene, continued to have lower gastric cancer and overall mortality 10 years after supplementation ceased compared with individuals who did not take the supplements, according to long-term follow-up data from the randomized, double-blind General Population Nutrition Intervention Trial in Linxian, China.

The trial tested the impact of four dietary supplement combinations on gastric and esophageal cancer incidence and overall mortality in a nutritionally-deprived population. The trial enrolled 29,584 adults between the ages of 40 and 69 years. Participants took dietary supplements from 1986 to 1991. The initial results from the study showed a significant reduction in risk of gastric cancer and overall mortality in individuals taking factor D.

In the current analysis, Philip R. Taylor, M.D., Sc.D., of the National Cancer Institute in Bethesda, Md., and colleagues at the Chinese Academy of Medical Sciences in China examined 10-year follow-up data.

Individuals who took factor D continued to show benefits, with a 5% reduction in overall mortality (from a cumulative mortality of 33.62% of participants not taking factor D to 32.19% of participants taking factor D) and an 11% reduction in gastric cancer mortality (from a cumulative gastric cancer mortality of 4.28% in the no-factor D group to 3.84% in the factor D group). Individuals who were under the age of 55 derived the majority of benefit from the supplement. Esophageal cancer incidence decreased by 17% in participants under the age of 55, but increased by 14% in those participants over age 55.

"The persistence of risk reduction for up to 10 years after treatment in this trial reinforces the validity of the original trial findings and is consistent with an emerging new paradigm in cancer prevention, namely, that prevention may be achievable with short-term as opposed to life-long treatment," the authors write. Contact: NCI Press Office, ncipressofficers@mail.nih.gov, 301-496-6641

Overexpression of Fatty Acid Synthase Promotes Prostate Cancer in Mouse Models

Fatty acid synthase (FASN) can act as a prostate cancer oncogene in mouse models.

FASN, a key enzyme in the synthesis of long-chain fatty acids, is overexpressed in prostate cancer, relative to its expression in adjacent normal tissue. Additionally, previous studies showed that inhibition of FASN activity promoted programmed cell death in prostate cancer cell lines.

In the current study, Massimo Loda, M.D., of the Dana-Farber Cancer Institute in Boston, and colleagues overexpressed FASN in a variety of prostate cancer and precancerous cell lines.

Overexpression of FASN increased cell proliferation and substrate-independent growth. When immortalized prostate epithelial cells that expressed both FASN and the androgen receptor were injected into immunodeficient mice, the cells gave rise to invasive cancer. Inhibition of FASN gene expression led to programmed cell death in a prostate cancer cell line grown in culture. FASN expression showed an inverse correlation with the rate of programmed cell death in prostate cancer biopsy samples.

"The experimental evidence we provide on the oncogenic role of FASN in the prostate suggests that pharmacological targeting of FASN might represent an effective treatment for prostate cancer," the authors write.

Contact: Bill Schaller, william_schaller@dfci.harvard.edu, 617-632-5357

Analysis Identifies Possible Prognostic Markers in Melanoma and Need for Better Methodology

A systematic literature review and meta-analysis of published studies found several promising markers associated with clinical outcome in early-stage melanoma patients. However, the review also revealed that numerous published reports did not meet the minimum guidelines established in 2005 for biomarker studies.

Some patients with early stage melanoma can be treated with surgery alone. However, biomarkers that distinguish these patients from patients who will have recurrent disease have not emerged, despite numerous reports of putative markers in the literature.

To better understand why this disconnect exists, Bonnie Gould Rothberg, M.D., of the Yale University School of Medicine in New Haven, Conn., and colleagues performed a systematic literature review and meta-analysis of studies that reported on putative protein biomarkers associated with clinical outcome in patients with early melanoma. The investigators restricted their analysis to studies that used immunohistochemistry-based biomarker detection.

The team initially identified 102 cohort studies in the literature, but only 37 met all of their inclusion criteria. Twenty-seven studies were excluded by the investigators because they lacked adequate methodological information, despite having been published after 2005, when the medical research community established minimum guidelines for publication of biomarker studies, called REMARK.

The thirty-seven studies that met the inclusion criteria for the meta-analysis evaluated 62 protein markers. Several promising markers emerged, including MCAM/MUC18, matrix metalloproteinase-2, Ki-67, PCNA, and p16/INK4A.

"This systematic review…supports involvement of cyclin-dependent kinase inhibitors, effectors of DNA replication and cell proliferation, growth-promoting transcription factors, and multiple regulators of tissue invasion and metastasis (the latter including cell-adhesion molecules, matricellular proteins, and selected matrix metalloproteinases) in modulating melanoma outcomes," the authors conclude. "These results, however, need to be validated in adequately powered prospective studies."

Contact: Renee Gaudette, renee.gaudette@yale.edu, 203-436-8533

Underreporting of Cancer Cases from Veterans Affairs Facilities Led to Lower Apparent Cancer Incidence Trends

Underreporting of cancer cases from Veterans Affairs (VA) hospitals reduced the apparent overall burden of cancer in the United States in 2005 by 1.6 percent for males and 0.05 percent for females.

A policy change at the VA resulted in underreporting of newly diagnosed cancer cases in some of the Surveillance, Epidemiology and End Results (SEER) population-based cancer registries.

To quantify the impact of the underreporting on the 2005 cancer incidence rates and long term trends, Nadia Howlader and colleagues of the National Cancer Institute in Bethesda, Md., estimated the number of missing VA cancer cases in 2005 based on a variety of factors.

Among the top ten cancers, the proportion of cancers missing in the 2005 SEER database ranged from 2.5 percent for liver cancer to 0.4 percent for melanoma. The missing data had a modest impact on long-term incidence trends with the largest impact among black males.

"Adjusting the data to include estimates of missing VA cancer cases may lead to more accurate assessment of current SEER incidence trends," according to the authors. "In reporting cancer trends, a change of as little as 1 percent per year demonstrates improvements or causes alerts in cancer control efforts," the authors write. "Such changes could easily be obscured by incomplete reporting of VA hospital data. Trends for black males in particular could be underestimated severely in the future."

Contact: NCI Press Office, ncipressofficers@mail.nih.gov, 301-496-6641

Also in the March 24 JNCI:

• http://www.eurekalert.org/emb_releases/2009-03/jotn-hpg031909.php
• http://www.eurekalert.org/emb_releases/2009-03/jotn-tcc031909.php

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