BioWorld International Correspondent

LONDON - New cancer therapies that focus on preventing the spread of tumor cells through the lymphatic system could arise from a flurry of studies examining vascular growth factors. The research holds out the prospect of developing new drugs to reduce the risk of cancer metastasis, as well as those to encourage lymph vessel growth where needed.

The studies have also provided an animal model for lymphedema in humans. Its availability is likely to speed the development of therapies to treat lymphedema, which may be hereditary, or follow damage to the lymphatic vessels by, for example, surgery. Lymphedema is also a common complication of the worm infection, filariasis.

The vascular growth factors under scrutiny are those belonging to the vascular endothelial growth factor (VEGF) family. VEGF, first identified in 1989, plays a role in the growth of new blood vessels (angiogenesis). In 1997, Kari Alitalo, research professor at the Finnish Academy of Sciences, together with colleagues in Finland and the U.S., reported in Science that a related molecule, VEGF-C, helps the endothelial cells lining the lymphatic vessels grow (a process called lymphangiogenesis).

VEGF-C and another member of the family, VEGF-D, are known to bind to VEGFR-3, a tyrosine kinase receptor. The following year, Alitalo and colleagues published a paper demonstrating that VEGFR-3 is essential for the normal development of the cardiovascular system in mice. More recently, Alitalo's team, in collaboration with Robert Ferrell and David Finegold at the University of Pittsburgh, discovered that humans with hereditary lymphedema have mutations in the gene that encodes VEGFR-3.

Now a further batch of papers, including three in the February edition of Nature Medicine, examines the role of VEGFR-3 and its ligands, VEGF-C and VEGF-D, in lymphangiogenesis. The report from Alitalo's group is titled "Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3."

Alitalo told BioWorld International, "When we did our earlier experiments in which we knocked out the VEGFR-3 gene, the mice died very young, so we were unable to find out very much about its role in lymphangiogenesis. So we decided to construct transgenic mice that would secrete the soluble extracellular domain of the receptor in their skin. We hoped that we would get live mice and perhaps a phenotype where the receptor was compromised in the skin; maybe the lymphatic vessels would be affected because such a receptor would mop up VEGF-C and VEGF-D."

In the event, the receptor circulated in the serum of the mice and was fairly stable in body fluids. Its effect was "quite unexpected," Alitalo said. "The mice were born without lymphatic vessels in the skin. We were surprised because the receptor had also abolished the development of most of the lymphatic vessels in the internal organs. Yet the mice were alive and seemed well. Their only symptom was swelling of the skin and paws."

These results showed, Alitalo said, that lymphangiogenesis requires a signal from growth factors in order to occur. "If you block that, the vessels self-destruct," he added.

A further surprise was that even in the adult transgenic mice, where levels of the receptor remained at inhibitory concentrations, the lymphatic vessels started to grow back once the mice reached about 4 weeks of age. "This means," Alitalo explained, "that the vessels when they start to develop in young animals are totally dependent on a survival signal, which is mediated by this receptor, but that later some other mechanism takes over. We are now studying what that other mechanism could be."

The finding fits with other work carried out by the Finnish-led team in collaboration with Michael Pepper from Geneva, Switzerland, and Gerhard Christofori from Vienna, Austria, soon to be published in EMBO Journal, which shows that overexpression of VEGF-C in tumor cells promotes tumor lymphangiogenesis and metastasis.

Alitalo's group will also report in the March 1 issue of the journal Cancer Research, that in an animal model, VEGF-C acted to promote the growth of lymphatic vessels around tumors, which often contained tumor cells. But adding the soluble extracellular domain of VEGFR-3 abolished this effect.

Alitalo is supported by the Finnish Academy of Sciences and the State Technology Development Centre in Helsinki. To protect the intellectual property rights of the team's findings, the university set up a company called Licentia Ltd., which is in partnership with the Ludwig Institute for Cancer Research.

Alitalo speculates that tumors probably secrete endothelial growth factors in order to promote lymph vessel growth around themselves and thus increase the probably of metastasis. In terms of new cancer treatments, he said, "If we can block the lymphangiogenesis, then we should be downregulating the probability of metastasis." A handful of reports already have suggested that there may be a positive correlation between overexpression of VEGF-C in human tumors, and metastasis via the lymphatic system, he added.

If further studies confirm these early reports, then it would certainly be possible to target drugs at this process, Alitalo said. "The fact that our soluble receptor blocks tumor lymphangiogenesis means that there are a variety of drugs that could be developed to inhibit this receptor, using strategies such as monoclonal antibodies, peptide inhibitors, or small molecules. Our transgenic mouse model has already shown that inhibition of this receptor has no other deleterious effects in adult animals," he concluded.