June 5, 2003 Many types of cancer--like those of the breast and prostate--would not be nearly as deadly if it weren't for their ability to spread to vital organs. Still, scientists don't yet fully understand the way in which cancer spreads, or metastasizes, or how to prevent the process.
Now, researchers at the San Francisco VA Medical Center (SFVAMC) have used a modified version of a naturally occurring human protein to decrease the spread of human breast cancer implanted in mice.
"We were able to significantly reduce the spread of the disease and decrease tumor growth without any evidence of toxicity," said senior author Gary Jarvis, PhD, a SFVAMC microbiologist and UCSF associate professor of laboratory medicine.
The current findings appear in the June issue of Clinical Cancer Research, with figures from the paper appearing on its cover.
Jarvis credits first author Constance John, PhD, a research chemist in his lab at the time, with coming up with the idea of interfering with the ability of cancer cells to stick to one another as a way of attacking metastasis. The ability to adhere to other cells is what allows a cell that breaks away from a primary tumor to lodge in other parts of the body.
"It's when tumors spread to essential organs, such as the liver or lung, that they become fatal. There is nothing to date that has been approved by the FDA for treatment of cancer that works on that process," said John.
John, who is no longer affiliated with SFVAMC, is currently the president of MandalMed, Inc., a San Francisco-based company working to develop a drug that inhibits metastasis based on these findings. (Jarvis, of SFVAMC/UCSF, has no financial stake in MandalMed.)
A drug that could reduce metastasis would greatly improve upon the beneficial outcomes already achieved with chemotherapy, surgery and radiation, John said. "We're not trying to develop a cure for cancer. What we're trying to do is make cancer a disease that one can live with," she said.
As a way of targeting metastasis, John proposed modifying a human protein known as galectin-3, a member of the family of proteins called lectins that bind to sugar molecules on the surfaces of cells. Galectin-3 is known to play multiple roles in cancer formation, including the promotion of cell-to-cell adhesion, or sticking. "The idea was to break that contact and inhibit secondary cancer formation," Jarvis said.
The researchers left the sugar-binding region of galectin-3 intact, but removed the part of the protein that normally allows cells to stick to one another. They then implanted portions of human-derived breast cancer tumors into the chest pads of nude mice, mice having a low-functioning immune system. Once the tumors were established, they injected the experimental animals with truncated galectin-3. The control mice were given sham injections.
By the end of the experiment, the team found that cancer had spread to lymph nodes or other organs in four out of 20 experimental mice versus 11 of 20 control mice. In addition, the post-treatment growth of the implanted tumor fragments was significantly less than in the control animals. Monitoring the animals during this and additional experiments showed that the modified protein did not cause any apparent adverse effects or death in the mice.
Jarvis believes that the modified version of galectin-3 was able to interfere with the breast cancer cells' ability to stick to one another and to the healthy cells of other organs. "The data supports the hypotheses that truncated galectin-3 inhibits the process of metastasis," he said.
Jarvis and his colleagues at the SFVAMC are currently working on the functional studies that would determine the mechanism behind the reduction in metastasis they observed.
Jarvis said a drug therapy targeting galectin-3 activity might someday be effectively used in combination with currently available cancer medications. "If we can stop metastasis in humans, we will have gone a long way towards successfully treating cancer," he said.
Jarvis and his colleagues at the SFVAMC have since repeated these results and plan to extend the current study by looking at different types of cancer and different truncated versions of galectin-3 in combination with currently available anticancer medications.
Additional authors on the paper include Hakon Leffler, MD, PhD, Barbro Kahl-Knutsson and Inga Svensson of the Institute of Laboratory Medicine at Lund University in Lund, Sweden.
This research was supported by a grant to the Northern California Institute for Research and Education (NCIRE) from the U.S. Department of the Army Breast Cancer Research Program. Based at the SFVAMC, NCIRE is the largest congressionally sanctioned research foundation. The Swedish Medical Research Council also provided support.
Statement of financial disclosure: Neither UCSF, SFVAMC nor Gary Jarvis, PhD, has a financial stake in MandalMed, Inc. Constance John, PhD, serves as president of MandalMed, Inc., but was employed as a research chemist in Jarvis' laboratory at the time this research was conducted.
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