The study provides the first genetic evidence that damage to the blood vessels that feed the tumor play a primary role in tumor regression. The blood vessel cells targeted by radiation are the endothelial cells, which are recruited by the tumor from the host to create the tumor microvasculature - a process called angiogenesis. Endothelial cells do not die in response to radiation due to DNA damage but rather by a specialized form of programmed cell death or apoptosis extensively studied at MSKCC. Understanding this form of radiation-induced cell death may ultimately have an effect on the treatment of cancer patients, approximately 50% of whom receive radiation therapy.
To study how endothelial cells within tumors respond to radiation, the researchers used a mouse model genetically engineered to be deficient in acid sphingomyelinase (asmase), an enzyme needed for endothelial cells to undergo apoptosis. When melanoma and fibro-sarcoma cells were implanted into mice, the tumors that developed in the acid sphingomyelinase deficient (asmase -/-) mice showed reduced endothelial apoptosis, had a tumor growth rate almost double that of the normal acid sphingomyelinase ( asmase +/+) mice, and were resistant to radiation-induced tumor regression.
"Our study confirmed that acid sphingomyelinase affects the endothelium and that in turn plays a role in a tumor's growth and its response to radiation," explained Monica Garcia-Barros, PhD, a member of Memorial Sloan-Kettering's Signal Transduction Laboratory and the study's first author.
Drs. Fuks and Kolesnick had published a study in Science in 2001 that also studied the role of endothelial cells in radiation. "Our earlier study showed that radiation damage to small blood vessels played a role in radiation injury to the gastrointestinal tract. It was unclear that this would also happen in tumors," said Richard Kolesnick, M.D., head of Memorial Sloan-Kettering's Signal Transduction Laboratory and one of the study's senior authors. "Our new study shows that damaging the angiogenic blood vessels of the tumor does indeed contribute to tumor regression."
With this new understanding of how radiation therapy destroys tumors, the next step is to translate the findings into patient care. "Our results suggest possible new clinical approaches," said radiation oncologist Zvi Fuks, M.D., senior co-author of the study and Deputy Physician in Chief for Planning at Memorial Sloan-Kettering. "Additional research is needed to look at several areas including radiation dose levels, timing of therapy, and possibly the combining of anti-angiogenic agents with radiation."
Dr. Steven Leibel, chairman of the Department of Radiation Oncology at Memorial Sloan-Kettering, who was not part of the study team, concurs. "While the results of radiation therapy are effective given our current knowledge, this landmark study will help to maximize and further increase the effects of radiation."
Other MSK researchers involved in the work are Carlos Cordon-Cardo, M.D., PhD; Adriana Haimovitz-Friedman, PhD; David Lyden, MD, PhD; and Shahin Rafii, M.D., Weill Cornell Medical College. The research was funded by the National Cancer Institute.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.
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