Feb. 23, 2005 BOSTON – 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.
"The evidence that tumor angiogenesis is controlled by endogenous proteins has been accumulating over the past decade, but has depended largely on the use of these molecules that are introduced into tumor-bearing mice," notes Robert Weinberg, PhD, of the Whitehead Institute for Biomedical Research and the Department of Biology at the Massachusetts Institute of Technology (MIT). "The real question has been, however, whether the tissues of the tumor-bearing mouse [and by extension, a human] produce these agents in quantities that truly affect tumor growth. With this paper, we have compelling evidence that a number of these molecules, when produced by the mouse's own tissues, are able to act to constrain blood vessel growth in the tumors – the final piece of proof needed to demonstrate their importance in preventing the outgrowth of tumors."
"These mice [in the Kalluri study] are the first animals to mimic the protection against cancer which is afforded individuals with Down syndrome who also have a similar increase in endostatin in their blood, and are the most protected against cancer of all humans," adds Judah Folkman, MD, Director of the Vascular Biology Program at Children's Hospital Boston whose laboratory first proposed the angiogenesis paradigm more than 30 years ago.
"This is a landmark paper because it provides genetic proof that endogenous inhibitors of angiogenesis circulating in the blood may protect us from the disease of cancer and is the first demonstration that a mild increase in one of the circulating angiogenesis inhibitors, endostatin, confers protection against cancer in mice, i.e. reduces the growth rate of tumors by 300 percent," Folkman adds.
"Between nine and 10 million people worldwide die of cancer each year," says Kalluri. "While a lot has been learned of how genetic defects convert normal cells into cancerous cells, much less is known about how the body defends itself against the growth of cancer. Our study helps provide a glimpse into what may be happening. The hope is that this new understanding of cancer growth can eventually lead to the use of these natural proteins as therapies to treat cancer at an early stage, before it becomes a devastating disease."
Coauthors include BIDMC investigators Malin Sund, MD, PhD, Yuki Hamano, MD, PhD, Hikaru Sugimoto, MD, PhD, Akulapalli Sudhakar, PhD, Mary Soubasakos, BS, Udaya Yerramalla, PhD, Laura Benjamin, PhD, Jack Lawler, PhD, and Amish Shah, BS, and Mark Kieran, MD, PhD, of the Dana-Farber Cancer Institute.
This study was funded by the Ann L. and Herbert J. Siegel Philanthropic Jewish Communal Fund; the National Institutes of Health; the Stop and Shop Pediatric Brain Tumor Foundation; the Sigrid Juselius Fellowship and Foundation; the Maud Kuistila Foundation; the Finnish Medical Society Duodecim; and the Emil Aaltonen Foundation; and a Joseph Lubrano Memorial Goldfield Family Trust Donation to the Center for Matrix Biology at BIDMC and Harvard Medical School.
BIDMC has licensed certain intellectual property surrounding tumstatin to Ilex Oncology, Inc. (Boston) BIDMC and Raghu Kalluri are equity owners in Ilex Oncology, Inc.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
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