New insight into how tumors resist radiation

Scientists have uncovered new evidence about a critical cellular pathway that makes tumor blood vessels resistant to radiation therapy. The research, published in the May issue of Cancer Cell, may have significant clinical applications, as a better understanding of this mechanism may open new avenues for enhancing the effectiveness of radiation therapy.

Tumor growth and survival is completely dependant upon having an adequate blood supply. In fact, the sensitivity of a tumor's blood vessels to radiation therapy is a major determinant of how successful the treatment will be. Recent studies have shown, however, that tumors can respond to radiation by secreting factors that promote the survival of blood vessel cells. Dr. Mark W. Dewhirst and colleagues from Duke University Medical Center have investigated the activation of this protective response and whether the process can be successfully inhibited, thereby maximizing the effectiveness of radiation therapy. The investigators focused on a molecule called hypoxia inducible factor-1 (HIF-1) that is known to stimulate the production of factors called cytokines that are related to tumor metabolism, growth, and blood vessel formation.

They found that HIF-1 levels were increased in tumors after radiation treatment, and that HIF-1-regulated cytokines decreased the sensitivity of blood vessels to radiation. Based on this knowledge, the investigators demonstrated that administration of low doses of a HIF-1 inhibitor in tumor-bearing mice dramatically enhanced the effectiveness of radiation therapy by destroying tumor blood vessels without having an impact on normal vessels.

These results indicate that HIF-1 acts as a major factor directing resistance of tumor vasculature to radiation therapy. According to Dr. Dewhirst, "We believe that by understanding how this protective response is activated, we can discover an effective means of inhibiting it.

This work takes a major step toward achieving this understanding and might eventually translate into a significant clinical benefit by allowing optimal sensitization of tumor vasculature to conventional therapies including radiation."

Benjamin J. Moeller, Yiting Cao, Chuan Y. Li, and Mark W. Dewhirst: "Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules"

Published in Cancer Cell, Volume 5, Number 5, May 2004, pages 429-441.

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