For Immediate Release
March 16, 2007

 BUFFALO, NY – Researchers at Roswell Park Cancer Institute (RPCI) have identified a major mechanism to explain why endothelial cells (blood vessel lining cells) isolated from tumors are more sensitive to the antiproliferative effects of calcitriol – the most active form of vitamin D – than endothelial cells isolated from tissues. Results of their study are published in a recent issue of the Journal of Biological Chemistry.

Calcitriol has powerful growth inhibitory effects in preclinical cancer models and therapeutic efficacy in some patients with prostate cancer. However, its promise may be limited by the documented overexpression of 24-hydroxylase (CYP24) – the major enzyme which breaks down calcitriol – in prostate, colon, esophageal and breast cancers. This overexpression suggests a mechanism of resistance of these tumors to calcitriol treatment.

Using a model they established to obtain an enriched population of endothelial cells from tumors and proliferating normal tissues, the researchers demonstrated that calcitriol has selective growth inhibitory effects on endothelial cells derived from tumors, but not on those derived from environments in which healthy blood vessels are growing.

“When treated with calcitriol, only endothelial cells derived from tumors exhibited cell growth inhibition, cell cycle arrest and induction of cell death,” said Donald Trump, MD, Associate Director of Roswell Park and a pioneer in vitamin D research. “The tumor-derived endothelial cells ‘turn off’ expression of CYP24 and therefore are susceptible to calcitriol.”

Preliminary data from the study suggest that “epigenetic silencing” (a biological mechanism that affects how genes function) of CYP24 in endothelial cells isolated from the tumor microenvironment results in suppressed enzyme expression; however, further studies are needed to understand epigenetic defects in tumor microvasculature.

“The novel discovery not only identifies endothelial cells as possible targets in the tumor microenvironment for vitamin D therapy, but may help clarify the role of calcitriol in angiogenesis. Recent evidence suggests that vitamin D can act on the tumor vasculature,” notes Ivy Chung, PhD, RPCI’s Department of Pharmacology & Therapeutics.

Until this study, conventional wisdom held that endothelial cells recruited to form blood vessels in tumors were similar to those recruited for the same job in normal tissues, and thus, less likely to develop drug resistance to anti-angiogenic therapies. “However, our data indicate that the two differ and studies to compare the biological effects of calcitriol on tumor vasculature and normal proliferating vasculature are an important next step in vitamin D research,” continued to Dr. Trump.

Roswell Park Cancer Institute, founded in 1898, is the nation’s first cancer research, treatment and education center and is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers. Roswell Park has affiliate sites and collaborative programs in New York, Pennsylvania, and in China. For more information, visit RPCI’s website at www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or e-mail askrpci@roswellpark.org.

 

-30-