HPV Co-Infections May Increase Risk of Precancerous Lesions

Simultaneous infection with multiple types of human papillomavirus (HPV) significantly increases the risk of developing abnormal lesions that can lead to cervical cancer, researchers reported last week. Co-infections that include two HPV types in particular, HPV 16 and HPV 58, seemed to confer the greatest risk of developing these lesions.

"Women who harbor multiple infections are at higher risk for cervical lesions than those ever infected with one type only and should be followed more closely," said the study's lead investigator, Dr. Eduardo L. Franco, director of the Division of Cancer Epidemiology at McGill University in Montreal.

The epidemiologic study, partly funded by NCI and published in the July Cancer Epidemiology, Biomarkers, and Prevention, involved more than 2,400 Brazilian women participating in a long-term HPV cohort study. Participants were seen once every 4 months for the first year, and then two times a year for the next 3 years, with cervical specimens collected at each visit.

Previous studies have not found an increased risk associated with co-infections with multiple HPV types, the authors noted. In their study, however, the greater the number of HPV types involved in the co-infection, the greater the risk of the precancerous lesions, suggesting that the different types "seem to act synergistically in cervical carcinogenesis."

While HPV 16 alone increased the risk for developing the lesions by nearly 25 times compared with women who were HPV-negative, an additional threefold increased risk was associated with co-infection of HPV 16 and at least one other HPV type, whether the infections were simultaneous or were detected concurrently during follow-up visits. Co-infections that included HPV 58 also significantly increased risk, regardless of whether the infection included HPV 16.

There is a need for more research to determine whether the elevated risk represents true synergy or the combination of independent viral risks, noted Dr. Mark Schiffman of NCI's Division of Cancer Epidemiology and Genetics.

Test for Bladder Cancer Analyzes DNA in Urine

Researchers have developed an experimental test for detecting bladder cancer that screens urine for DNA changes associated with the disease. The noninvasive test, which needs more study before entering the clinic, detects DNA methylation, a chemical change that can alter the activity of genes, including those associated with cancer. Many researchers are investigating whether abnormal methylation can be a biological marker for cancer.

To develop the test, Dr. David Sidransky of Johns Hopkins School of Medicine and colleagues profiled the methylation patterns of nine key genes that are altered in various cancers, including bladder cancer. They then analyzed the genes in urine from 15 bladder cancer patients and 25 healthy individuals. For all 15 patients, the methylation pattern in urine matched that in the primary tumors.

"All of the 15 primary tumors tested in this study harbored at least one methylated marker," the researchers wrote in the July 19 Journal of the National Cancer Institute (JNCI). "Moreover, the methylation status of the urine sample always matched that of the tumor sample from the same patient."

Among a larger group of 175 bladder cancer patients, 121 showed methylation in at least 1 of 4 genes, whereas none of the nearly 95 healthy individuals did.

The detection method, quantitative methylation-specific PCR assay, is sensitive enough to identify 1 methylated gene among more than 1,000 unmethylated genes, the researchers say. The gold standard for diagnosing bladder cancer is cystoscopy, but the procedure has limitations, is expensive, and is uncomfortable for the patient.

Tissue Growth Factor Inhibits Metastatic Activity in Lung Cancer

Scientists showed that connective tissue growth factor (CTGF) inhibits metastatic activity of human lung cancer cells in mice by inhibiting angiogenesis, according to a study in the July 19 JNCI.

The researchers, led by Dr. Cheng-Chi Chang at National Taiwan University, transfected the lung cancer cells with either CTGF or hypoxia-inducible factor 1α (HIF-1α), a protein associated with metastatic activity and angiogenesis. The cells were then injected into mice to form xenograft tumors. Tumors that grew from the CTGF-transfected cells grew more slowly and the mice survived longer, the investigators reported.

"We have shown that CTGF expression can inhibit tumor growth in primary or metastatic sites by reducing VEGF-A gene expression and its subsequent angiogenic effects in tumor cells," they explain. "Most importantly, we have provided functional evidence that CTGF acts as an angiogenesis suppressor, inhibiting tumor growth and metastasis in mouse models of human lung adenocarcinoma."

A JNCI editorial noted that "the elucidation of the interplay between central and tributary pathways in tumor progression, such as those highlighted here for the putative metastasis suppressor gene CTGF, will help in deciding which molecular target in the network will more specifically affect aberrant tumor angiogenesis without compromising the physiological process." Targeting the tumor microenvironment, in addition to attacking tumor cells, "may permit important improvements to clinical outcomes in the future."

Smoking Blamed for Half of Difference in Death Rates

Numerous research studies have documented that men and women from lower socioeconomic backgrounds have a higher mortality risk than those from higher socioeconomic backgrounds. Now a new study from researchers at the University of Toronto and the University of Oxford attributes more than half of this difference, in middle-aged men at least, to smoking.

Regardless of whether this discrepancy is due to factors such as smoking prevalence, smoking intensity, or lung cancer treatment, the authors concluded, "a substantial increase in cessation could approximately halve these…social inequalities in adult male mortality."

Released early online on July 15 by the Lancet, the study team, led by Drs. Prabhat Jha and Richard Peto, used what they describe as an "indirect method" to estimate the contribution of smoking to the mortality difference between these two groups of men, "based solely on the national age-specific death rates for lung cancer and for various other [smoking-related] diseases."

They looked at nearly 600,000 deaths that occurred in 1996 in men aged 35 to 69 years in the United Kingdom, Canada, the United States, and Poland. They used different measures of "social strata" for each country. For men in the United Kingdom, for example, they used a national social classification system based on occupation, whereas for men in the United States they used completed years of education.

Although they admitted that the estimation method they used was "crude," they argued that the "major pattern in these populations is clear."

The study results confirm the role of smoking in health disparities worldwide, Dr. Michael Marmot from the University College London noted in an accompanying editorial. It also highlights the need to answer important questions about how to reduce smoking rates in lower income populations, as well as address "the other major social causes of inequalities in health."

SPORE Investigators' Workshop Held July 16-19

The goal of NCI's Specialized Programs of Research Excellence (SPORE) program is to conduct translational research to rapidly move promising laboratory results into early-phase clinical trials. The 14th SPORE Investigators' Workshop, held in Baltimore, July 16-19, drew researchers from 58 SPOREs representing 14 individual organ sites.

NCI is increasing its focus on translational research, explained Dr. Ernie Hawk, director of the Office of Centers, Training and Resources, in the conference's opening session, because "advances in cancer biology offer enormous opportunities to improve cancer treatment and prevention. Translation of these new concepts into drugs, devices, and interventions that can be tested in the clinic or population has not kept pace with advances in fundamental research. Expanding opportunities and high expectations coupled with limited resources require a translational research system that can identify and pursue the most promising opportunities efficiently and productively."

A day of breakout sessions allowed organ-site programs to discuss the most important recent scientific advancements within their SPOREs and in their fields, and explore opportunities for future collaborations. Mini-symposia and working groups gave investigators the chance to discuss new findings and identify new research challenges.

The conference closed with a morning of plenary sessions, highlighting the best efforts of each SPORE to achieve a human application or intervention from its basic research. Investigators presented promising new research and novel uses for established drugs and techniques.

Dr. John Park, of the University of California, San Francisco, Brain SPORE, stressed the contribution of this cutting-edge translational drug development in his plenary session remarks: "I think that the development of new therapeutics…within the SPOREs and within academic centers is a critical part of global oncology drug development and the cancer therapeutics enterprise. I think that it represents a sorely needed and very complementary process to…industry and biotechnology."