July 6, 2001 BOSTON — A powerful new with high resolution, three-dimensional imaging tool is providing researchers with never-before-seen views of what goes on deep within a living tumor. Scientists at Massachusetts General Hospital (MGH) are using multiphoton laser scanning microscopy to visualize individual cells, where they can monitor gene expression, therapy effectiveness and tumor cells’ interactions with normal cells. The work published in this week’s Nature Medicine demonstrates that the technique could be adapted to measure a wide range of physiological parameters.
Since the researchers use a living mouse model, they can perform a variety of experiments and take numerous measurements over time. "We can figure out what’s going on under the surface of the tumor without disturbing the tumor itself," says principal investigator Rakesh Jain, PhD, of the MGH Department of Radiation Oncology.
Current imaging techniques do not have the same combination of depth or resolution. "This new technology gives us the ability to look deep inside the tissues of living animals," says lead author Edward Brown, PhD, also of the MGH Department of Radiation Oncology.
The MGH scientists first looked at gene expression at the tumor site, focusing on the angiogenesis-promoting gene, VEGF. Cancer cells can coax nearby normal cells to produce VEGF in order to recruit nourishing blood vessels to the tumor. By imaging individual cells in and around the tumor, the MGH team could see exactly which cells turned on the gene. They could also visualize blood vessels deep within a cancerous mass, and they hope this information will offer clues to the mechanism of tumor angiogenesis. "There’s a dance between the cancer cells and the host cells. We’ll now be able to see how that occurs," says Jain.
The scientists were also able to use their technique to track individual cell populations within a tumor. Some cancer cells develop a hardiness that allows them to survive in areas of very low oxygen. The MGH team could visualize these cells as they migrated to the center of the tumor mass, far away from oxygen-rich blood vessels. Since cancer therapies are generally administered through the blood stream, these cells might also be inaccessible to conventional treatments. Jain says that innovative strategies may need to be devised to target these cells.
The microscopic technique was also used by Jain and his team to monitor the delivery of cancer treatments. They saw that therapies tend to flow out of a blood vessel and into nearby tissues, but only at certain blood vessel locations. The scientists could see that there are regions of a tumor that may never be exposed to a drug that’s given systemically. This has important implications for developing strategies to target the whole tumor.
"In the future, this technology will apply to a lot of exciting areas," says Brown. "There’s three-dimensional resolution, a great depth of penetration, and you can look at individual cells." Brown and his colleagues are now focusing on understanding the detailed mechanisms behind their in-depth observations.
The 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 $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women’s Hospital 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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