The lymphatic system is an important part of the immune system, responsible for the production and circulation of certain immune cells, as well as the drainage of excess fluid from the body.
But the lymphatic vasculature also plays a role in the spread of cancer cells since many cancers metastasize through the lymph system. And it is metastases, rather than primary tumors, that ultimately kill most cancer patients. (See BioWorld Today, July 10, 2007, and July 11, 2007.)
Two recent papers described new findings that may be applied to foil cancer cells' use of the lymphatic system to spread.
In a paper that will be published in the January 2008 issue of Nature Medicine, now available online, researchers from the Mayo Clinic in Rochester, Minn., described the use of immature T cells to deliver an oncolytic virus to the lymph system.
The researchers removed the T cells from mice, loaded them with vesicular stomatitis virus (which replicates in and destroys cancer cells specifically), and injected them back into the animal. They found that the virus did not replicate in the T cells themselves, but was released and selectively destroyed metastatic tumor cells in the lymph nodes. The procedure also triggered a T-cell immune response to the tumor cells. Overall, the approach reduced or cleared metastases of melanoma cells, as well as lung and colorectal tumors from the lymph system. The primary tumor, though not the main target, also was reduced in size in the melanoma mice.
A number of researchers, both academic and industrial, are working on the use of antigen-specific T cells for cancer vaccines. But to date, the harnessing of T cell responses for cancer vaccines has a mixed track record at best. (See BioWorld Today, Nov. 5, 2007.)
The authors believe their approach may be more successful for two reasons. First, the researchers focused on using immature T cells to deliver a virus, rather than purifying specific antigen-bearing T cells.
"Although tumor antigen-specific T cells can now be efficiently recovered and expanded from cancer patients, this requires specific technical expertise," the authors explained in their paper. In contrast, they said, the purification of immature T cells is "relatively simple."
Also, their approach does not fight the tumor at home. Tumors suppress the immune system as part of their growth strategy. In their paper, the scientists noted the contrast between "the highly immune-stimulatory environment in the [draining lymph node] . . . and the highly immunosuppressive environment of a primary established tumor."
The second study, which appeared in the Dec. 20, 2007, issue of the Journal of Clinical Investigation, did not address the lymph system's role in cancer directly. But its discoveries theoretically could find applications in the treatment of cancer survivors whose lymph nodes have been removed surgically, as well as in the prevention of metastases.
In their JCI paper, the researchers used knockout mice to study the function of adrenomedullin, a hormone that also plays a role in blood vessel formation. Indeed, another paper in the same issue of JCI reported new findings on the role of adrenomedullin in that context.
The researchers studied knockout mice lacking the gene for adrenomedullin, its receptor calcrl or a separate protein called RAMP2 that is necessary for the receptor to function. Mice lacking any of the genes died before birth. The scientists showed that this early death most likely is due to the inadequate development of the lymph system - although notably, an independent paper in the same issue of JCI showed that adrenomedullin knockouts also have impaired blood vessel development.
The findings published in JCI have the most direct bearing on lymphedema, the inadequate drainage of the lymph system, which is caused most often by parasitic infections, but also can be the result of cancer treatments.
But in a prepared statement, senior author Kathleen Caron, an assistant professor of cell and molecular physiology and genetics at UNC Chapel Hill, said that the findings might point to a route toward preventing metastases as well. "In cancer treatments of the future, patients suffering from these aggressive cancers could be identified early and could be treated with a drug to inhibit the growth of the lymph vessels that transport the cancerous cells, thus keeping the cancer in check."