Obesity and Weight Gain Linked to Prostate Cancer Mortality

The impact of excess weight on prostate cancer has been studied extensively without consistent findings. Now, a prospective study in the February 15 Cancer shows clearly that obese men are more likely to die from prostate cancer than men of normal weight, though no more likely to actually develop the disease.

Dr. Margaret E. Wright from NCI's Division of Cancer Epidemiology and Genetics (DCEG) and colleagues said their finding confirms earlier reports of an obesity-prostate cancer mortality link, but is the first to show that weight gain after age 18 also increases the risk of dying from prostate cancer.

"This is a large study that shows a convincing dose-response association between obesity and adult weight gain and death from prostate cancer," said Dr. Wright. Nearly 287,000 male AARP members aged 50 to 71 years self-reported their height and weight at enrollment into the NIH-AARP Diet and Health Study, begun in 1995. During the next 5 to 6 years, 9,986 developed prostate cancer and 173 died of the disease.

Compared with men with a body-mass index (BMI) of less than 25 kg/m², those who were overweight (BMI 25-29.9) had a 25 percent increased risk of death, mildly obese men (BMI 30-34.9) had a 46 percent higher risk, and severely obese men (BMI greater than 35) doubled their risk.

"The growing prevalence of obesity in Western countries is alarming, and reducing the risk of prostate cancer death is only one among many health reasons to maintain a healthy weight through diet and exercise," said Dr. Wright.

Molecular Switch Controls Cancer-Implicated "Chaperone"

NCI researchers have discovered a molecular modification at a specific site on a protein implicated in tumor development that directly affects its activity. The protein, heat shock protein 90 (Hsp90), is called a "chaperone" because it aids other proteins - its so-called clients - in performing essential functions, such as helping them fold properly and escorting them to their proper place in a cell.

Published in the January 12 Molecular Cell, the study demonstrated that the addition of an acetyl group to Hsp90 at a specific site affects its ability to perform its chaperoning activity. When this acetylation was interfered with in both human cell and yeast cultures, Hsp90's ability to bind to its client proteins was strengthened; conversely, when the acetyl group was added to the site, its chaperoning activity was weakened.

Cancer cells use Hsp90 to, among other things, sustain cancer-causing mutations in certain client proteins, allowing the cells to escape growth regulation and develop into tumors. The study leader, Dr. Len Neckers from NCI's Center for Cancer Research (CCR), has been leading the effort to develop and test Hsp90 inhibitors in cancer treatment clinical trials.

In this current study, Dr. Neckers and colleagues also showed that when cells were treated with another class of anticancer drugs under development, inhibitors of the enzyme histone deacetylase (HDAC), which removes acetyl groups from a wide range of proteins, Hsp90 was acetylated and chaperone activity was inhibited.

"These results give us a better understanding of why promoting Hsp90 acetylation, by inhibiting deacetylation, might be a good approach to inhibiting cancer cell growth," said Dr. Neckers. "Now we can start thinking about combining HDAC inhibitors with Hsp90 chemical inhibitors for the treatment of cancer."

New Nanoparticles Form Promising Clots in Tumors

An interdisciplinary team of researchers has developed a nanoparticle system that mimics the clotting action of platelets by sticking to tumor vasculature and connective tissue and then recruiting more clotting elements and nanoparticles to that site. Study results were published online January 8 in the Proceedings of the National Academy of Sciences.

The team targeted its nanoparticles using a short peptide (cys-arg-glu-lys-ala, or CREKA) that binds to clotted plasma proteins in tumor blood vessels and stroma. They attached a fluorescent dye to one end of the CREKA peptide for imaging, and then coupled the peptides to 50 nm superparamagnetic, amino dextran-coated iron oxide particles (SPIO), which have been used as contrast agents for magnetic resonance imaging.

SPIO enhanced the fluorescence of the CREKA peptide conjugates, allowing clear imaging of the plasma protein meshwork in vivo in mouse tumors. By injecting decoy particles that slowed the clearance of CREKA-SPIO, the researchers were able to amplify the intensity and duration of the clotting, and hence the imaging effect.

"Some nanomaterials are capable of triggering system thrombosis," the authors wrote, "but here the thrombosis induced by the CREKA particles was confined to tumor vessels." They noted that the mechanism by which CREKA-SPIO induced clotting requires further study, and that other nanoparticles could be coupled with CREKA for similar imaging effects or other purposes. This indicates that the CREKA nanoparticle system has potential not only for imaging, but also for starving tumors of their blood supply by blocking vessels through local embolism or for slowly releasing drug payloads while blocking blood vessels in tumors.

The team, led by Dr. Erkki Ruoslahti of the Burnham Institute, initiated the research under NCI's Unconventional Innovations Program. They will continue their efforts with support from the NCI Alliance for Nanotechnology in Cancer program.

Availability of Radiation Services May Influence Use

Whether a hospital has onsite radiation services may influence its use in the treatment of pancreatic cancer, according to a new study. Patients undergoing surgery to treat pancreatic cancer at facilities with onsite radiation services were almost twice as likely to receive adjuvant radiotherapy, for which a benefit has not been established, as those treated at a facility without such services (42.9 percent vs. 26.1 percent), the study revealed.

In contrast, whether a hospital had onsite radiation services had no influence on its use for patients being treated for rectal cancer, for which adjuvant radiation therapy is often recommended. The rates of adjuvant radiotherapy were nearly identical in patients being treated for rectal cancer at hospitals with and without onsite radiation services (29.4 percent vs. 29.1 percent). The study was released early online January 8 by the journal Cancer.

"Our findings suggest that adjuvant radiotherapy for pancreatic cancer is either being over-utilized at hospitals with radiation facilities, or under-utilized at centers without them," wrote lead author Dr. Sandra L. Wong, from the University of Michigan Department of Surgery, and colleagues.

The researchers used NCI's SEER-Medicare registry to review records from 10,198 patients who underwent major resection for rectal or pancreatic cancer between 1992 and 1999. Radiation service availability was culled from the American Hospital Association's 2000 survey of U.S. hospitals. The researchers noted a limitation in their ability to definitively confirm the presence or absence of radiation services at 27 percent of the treating hospitals. These hospitals were excluded from the analysis.

Emissions from Household Coal Combustion Cause Cancer

An International Agency for Research on Cancer (IARC) monograph working group has concluded that indoor emissions from household combustion of coal are carcinogenic in the Group 1 category to humans, and are associated primarily with an increased risk of lung cancer. Dr. Qing Lan of NCI's DCEG was a member of the working group and her research in this area, conducted in Xuan Wei county in China, served as the primary evidence of carcinogenesis.

The working group also concluded that indoor emissions from household combustion of biomass fuel (mostly wood) and from high-temperature frying are probably carcinogenic (Group 2A category) to humans. DCEG scientists contributed to the research leading to these conclusions.

Exposure to environmental carcinogens varies widely around the world, but the use of solid fuels for cooking and heating is most common in low- and medium-resource countries, where about half of the world's population lives. "This provides a warning that exposure to indoor combustion products of coal and other biomass is hazardous, and that steps need to be taken to reduce exposure, such as improving indoor ventilation," said Dr. Lan, who pointed out that many millions of people are at increased risk from such indoor air pollution around the world. In fact, a study by Dr. Lan showed that improved venting of indoor combustion products resulted in a drop in lung cancer rates.

The working group was convened by the IARC Monographs Programme, the cancer research agency of the World Health Organization. A summary of the IARC evaluation was published in the December 2006 issue of The Lancet Oncology.