An international research group including scientists from Finland and from the Massachusetts General Hospital (MGH) may have found the first factor regulating growth of lymphatic vessels. The discovery, which appears in the May 30 issue of Science, could lead to ways of repairing damage to lymphatic vessels and to better understanding of certain types of cancer.
The lymphatic system, the body's secondary circulatory system, is a network of fine vessels and nodes that collect a milky fluid called lymph from throughout the body and return it to the bloodstream near the heart. The fluid -- containing white blood cells, proteins and fats -- passes through lymph nodes, which filter out infectious bacteria, viruses and other foreign bodies. While the lymphatic system plays an important role in the body's immune function, many investigators believe it may be a conduit through which cancer spreads in the process called metastasis.
In recent years, scientists have identified several factors -- including vascular endothelial growth factors (VEGFs) -- that control the growth and proliferation of blood vessels, but until now no such factor controlling lymphatic vessels has been identified. The current article reports that a factor called VEGF-C, originally identified by researchers in the laboratory of Kari Alitalo, MD, PhD, at the University of Helsinki, appears to induce the enlargement of lymphatic vessels.
"This new factor eventually could make it feasible to program the behavior of cells lining the lymphatic vessels, possibly accelerating or inhibiting their growth," says Alitalo. "Applications could include improving healing after lymph nodes are removed in breast cancer surgery, preventing some tumors affecting the lymphatic system, or developing novel imaging methods to detect cancer in the lymphatic system."
The Finnish team created a group of transgenic mice that over-expressed the human gene for VEGF-C. Researchers in the laboratory of Rakesh Jain, PhD, at the MGH, found that the skin of these mice contained many unusually large vessels that functioned just like lymphatic vessels do.
The MGH researchers also found abundant messenger RNA for VEGF-C in the skin of the transgenic mice and located RNA for VEGF-C receptors in cells lining the abnormal vessels, observations which supported the relationship between the growth factor and the unusual vessels. The investigators also showed that the factor acted only on lymphatic vessels, having no effect on blood vessels, and that it induced vessels to grow larger -- up to twice the diameter of normal vessels -- but did not cause additional vessels to form.
Jain, whose research focuses on the physiology of tumors, notes: "A major problem in treating many solid tumors is that they have very high internal pressures, which makes it difficult to get drugs inside to kill the cancerous cells. This pressure may be related to the fact that, while tumors do grow new blood vessels, they do not develop functional lymphatic vessels, which normally drain fluids from the body's organs. One of our next steps will be to look at whether this new factor may be involved with the absence of functional lymphatics in tumors. The answer to that question could lead to better treatment methods."
Jain adds that VEGF-C may be only the first of a number of lymphatic growth factors to be discovered. "There may be additional factors involved in migration and growth of new vessels, activities not affected by VEGF-C. This is just the tip of the iceberg."
Jain is A.W. Cook Professor of Tumor Biology at Harvard Medical School and professor of Health Sciences and Technology at Massachusetts Institute of Technology. Alitalo also is a research professor at the Finnish Academy of Sciences.
The first authors of the Science paper are Michael Jeltsch, MSc, and Arja Kaipainen, MD, PhD, of Alitalo's lab in the Haartman Institute at University of Helsinki. Other coauthors at Helsinki are Vladimir Joukov, PhD, Xiaojuan Meng, MSc, Merja Lakso, PhD, and Heikki Rauvala, MD, PhD. Coauthors from the Steele Laboratory in the MGH Department of Radiation Oncology are Melody Swartz and Dai Fukumura, MD, PhD.
Contacts for Finnish researchers:
Kari Alitalo, MD, PhD
telephone: 011-358-9-191-26434
e-mail: kari.alitalo@helsinki.fi
Martti Turtola, Public Affairs
e-mail: martti.turtola@helsinki.fi
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