Primordial biomarker

Galectin-3 discovery may lead to new cancer treatments

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DETROIT—Investigating a carbohydrate-binding protein that appeared in the plant kingdom before vertebrates existed, researchers at Wayne State University have determined that the protein, galectin-3, is a marker for prostate cancer progression that may one day lead to new treatments.

Galectin-3 belongs to a family of 14 galectin molecules, notes Dr. Avraham Raz, professor of pathology and radiation oncology in the School of Medicine at Wayne State University and the Karmanos Cancer Institute, "but only galectin-3 is a chimeric gene product that can cleave," he states. It is this cleaved form of the molecule that has been identified as a marker for prostate cancer progression.

Previous research indicated that decreased levels of galectin-3 are linked with neoplastic progression in prostate cancer. However, increased levels of galectin-3 are believed to be associated with tumorigenicity in other tumor types. Contributing to this apparent duality is the fact that galectin-3 is cleaved outside the cell in the tumor microenvironment, Raz says. "The scientific community has the tendency to focus solely on cancer cells," he states, "not the tumor microenvironment. We should be looking at both—the cell and what's happening around it. The last 20 years have seen very limited gains in prostate cancer therapy. We've been overlooking the 'neighborhood' around the cells." Resorting to metaphor, Dr. Raz adds, "It takes two to tango."

Galectin-3, a _-galactoside-binding protein, has been implicated in a variety of biological functions including cell proliferation, apoptosis, angiogenesis, tumor progression and metastasis. A study published in the April 2009 issue of The American Journal of Pathology authored by Raz and his team was undertaken to understand the role of galectin-3 in the progression of prostate cancer. Immunohistochemical analysis of galectin-3 expression revealed that the molecule was cleaved during the progression of prostate cancer. The study noted that galectin-3 knockdown by small interfering RNA (siRNA) was associated with reduced cell migration, invasion, cell proliferation, anchorage-independent colony formation, and tumor growth in the prostates of nude mice.

"Galectin-3 knockdown in human prostate cancer PC3 cells led to cell-cycle arrest at G1 phase, up-regulation of nuclear p21, and hypophosphorylation of the retinoblastoma tumor suppressor protein (pRb), with no effect on cyclin D1, cyclin E, cyclin-dependent kinases (CDK2 and CDK4) and p27 protein expression levels. The data obtained here implicate galectin-3 in prostate cancer progression and suggest that galectin-3 may serve as both a diagnostic marker and therapeutic target for future disease treatments," the authors stated.

Other Wayne State researchers involved in the study include Drs. Yi Wang, Pratima Nangia-Makker, Vitaly Balan, Victor Hogan and Larry Tait. Dr. Kenneth J. Pienta of the departments of internal medicine and urology at the University of Michigan also collaborated on this study.

The next step? Raz and his team will be collecting as many tumor samples from patients as possible to determine how effective galectin-3 may be as a marker and therapeutic target. In terms of any commercial development as a result of the work, Raz believes the answers will be in place in a year or two.

Prostate cancer, one of the most prevalent non-skin cancers in America, affects one in six men. In 2008, nearly two million Americans were being treated for prostate cancer; nearly 186,000 were newly diagnosed, and approximately 28,000 died from the disease.

Wayne State University is a quiet giant among the nation's public research universities in an urban setting, ranking in the top 50 in R&D expenditures of all public universities by the National Science Foundation.

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