Research led by investigators at Beth Israel Deaconess Medical Center (BIDMC) helps explain how a group of angiogenesis inhibitor molecules serve as an important defense mechanism against the development and spread of cancer, offering key insights into why cancerous tumors grow at different rates among different individuals.
The findings, which could help lead to the development of new drug treatments to help keep existing tumors at bay, are reported in the early edition of the Proceedings of the National Academy of Sciences (PNAS) and in the Feb. 22 edition of the publication.
Angiogenesis, the process by which new blood vessels are derived from preexisting capillaries, is considered essential for tumor growth. The "angiogenic switch" is turned on when levels of angiogenesis stimulator molecules (VEGF, bFGF) exceed those of angiogenesis inhibitor molecules. These proteins – which include tumstatin, endostatin and thrombospondin-1 – are naturally present in body fluids or tissues, providing a counterbalance to the stimulator molecules.
Earlier studies by the paper's senior author Raghu Kalluri, PhD, published in Science and Cancer Cell in 2002 and 2003, respectively, helped to explain the mechanisms by which tumstatin and endostatin prevent the growth of new blood vessels.
Based on these earlier findings, and coupled with two separate clinical observations – that Down syndrome patients have a significantly smaller incidence of cancer than the population-at-large and that nonsymptomatic microscopic tumors exist in the organs of healthy individuals – Kalluri hypothesized that angiogenic inhibitor molecules were acting as tumor suppressors to control the rate of cancer progression.
"For several decades now, autopsies have shown that many people [between ages 40 and 50] who have died of trauma [i.e. automobile accidents, suicide] have tiny dormant tumors in one or more of their organs, though only one percent have been diagnosed with cancer," explains Kalluri, who is the director of the Center for Matrix Biology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "Our goal in this research was to find out if naturally occurring proteins were preventing the recruitment of new blood vessels into the tumors, and thereby keeping the tiny dormant tumors from developing into large malignant tumors. We wanted to better understand the important guards and checkpoints that our bodies possess."
To test the hypothesis that angiogenesis inhibitor molecules were responsible for reining in tumor growth, Kalluri and his colleagues studied the proteins tumstatin, endostatin and thrombospondin-1, natural inhibitors of angiogenesis found in blood, urine and tissues throughout the body. The authors created mice genetically deleted in each of these proteins to help ascertain their normal function in tumor growth.
Their results showed when any one of these inhibitors was removed from the mice, tumors grew at a rate two to three times faster when compared with normal mice. "But even more significant," notes Kalluri, "we found that when two of the inhibitor proteins were simultaneously removed, the tumors grew faster still, suggesting that the body's own natural capacity to guard against cancer progression plays a role equally as important as genetic defects of cancer cells in whether or not tumors grow and spread."
To demonstrate therapeutic possibilities, the researchers then developed a transgenic mouse that overproduced the endostatin protein in quantities that mimicked Down syndrome patients (a 1.6-fold increase over normal) who, due to an extra copy of chromosome 21, have elevated levels of the protein. As predicted, tumors in this group of mice grew three times more slowly than did tumors in normal mice.