Feb. 19, 2004 A growing tumor needs an increased blood supply for its proliferating cells. But the implications of tumor-related angiogenesis – the growth of new blood vessels – are much more complex than many investigators have realized. Although these new vessels are required to nourish the tumor itself, they are disorganized and abnormal and can actually block therapeutic agents from reaching malignant cells.
In the Feb. 19 issue of Nature, researchers from Massachusetts General Hospital (MGH) describe how proliferating cancer cells compress both blood and lymphatic vessels within tumors. The findings suggest new strategies for improving the success of cancer treatment. Related studies in the February issue of Nature Medicine provide more information about improving the delivery of anticancer drugs to tumor cells.
"We've known for several years that internal pressure can make it difficult for many drugs to penetrate into a tumor," says Rakesh Jain, PhD, director of the Edwin Steele Laboratory in the MGH Department of Radiation Therapy, senior author of the Nature and Nature Medicine papers. "Much of our work has focused on fluid pressure within tumors, but this was the first look at solid pressure."
As described in the Nature study, fluid pressure had been assumed to be the force compressing vessels within tumors, but actual fluid pressures inside both tumors and their blood vessels are almost equal. The MGH team investigated whether solid pressure exerted by proliferating cancer cells could compromise blood supply in the same way that stepping on a hose cuts off the flow of water. Using human tumors implanted in mice, the researchers administered diphtheria toxin, which kills tissue from humans but not from mice, to selectively destroy cancer cells.
Analysis of the toxin-treated tumors found that both blood vessels and lymphatic vessels looked much more open than did vessels from untreated tumors, which were largely collapsed. However, although the treated blood vessels appeared to be functioning nearly normally, treated lymphatic vessels were not functional. "Some of the new questions we need to investigate are why decompressed lymphatics do not function, what role vessel decompression may play in tumor growth and metastasis, and how we can use vessel decompression to improve cancer treatment," say Jain, who is Cook Professor of Tumor Biology at Harvard Medical School.
One of the Nature Medicine papers may explain the mechanism of action behind the anti-angiogenesis drug Avastin (bevacizumab), which is currently in clinical trails for FDA approval. In a small group of patients with rectal cancer, the MGH researchers found that Avastin treatment reduces both the number and density of blood vessels within tumors, as well as reducing fluid pressures. Taken with the positive early results of the Avastin trials, this finding is the first clinical confirmation that normalizing the distorted blood supply within tumors could improve the results of therapy.
The second Nature Medicine report uses an advanced imaging technique to examine the structure of the tumor extracellular matrix, composed of connective tissues which block anticancer drugs from reaching tumor cells. The new imaging tool – two-photon fluorescence correlation microscopy – is a significantly better method of measuring the passage of molecules within the matrix. The MGH study revealed that the matrix actually has two components, one that is nearly liquid and a more viscous component that appears to be the most significant barrier to drug delivery. Targeting the viscous matrix component may also improve treatment results.
The Nature study was led by Timothy Padera of the Steele Laboratory. The Nature Medicine Avastin study was led by Christopher Willett, MD, of MGH Radiation Oncology, and the extracellular matrix study was led by George Alexandrakis, PhD, of the Steele Laboratory. All three studies were supported by the National Cancer Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
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