BioWorld International Correspondent

LONDON - New treatments for inherited lymphedema - which can cause severe swelling of the limbs - and for the swelling of the tissues that follows some types of surgery might result from the discovery of a growth factor that can stimulate new lymph vessels to grow.

Clinical trials to establish the safety of the molecule will begin soon in Finland. Additional studies are examining whether the same molecule has a role in helping tumors metastasize via the lymphatic vessels.

Kari Alitalo, research professor of the Finnish Academy of Sciences in Helsinki, told BioWorld International: "Our findings have important implications for the treatment of many diseases involving the lymphatic system, because this growth factor now becomes a prime candidate for various types of therapeutic approaches."

The growth factor concerned is called VEGF-C, a member of the family of vascular endothelial growth factors. VEGF itself is essential for the generation of blood vessels in the embryo.

Alitalo and his colleagues knocked out the gene for VEGF-C in mice.

"We found that the VEGF-C gene is absolutely essential for the first lymphatic vessels to develop from the blood vessels, which happens normally around mid-gestation," he said.

None of the mice lacking both copies of the gene for VEGF-C were born live. Those embryos were notably edematous.

Mice with only one copy of the VEGF-C gene were slightly abnormal. Their lymphatic systems were not fully developed, with fewer lymph vessels than normal at birth. Although lymph vessels eventually grew into most organs within a few weeks of birth in those animals, adults had swollen paws. Analysis showed that although the blood vessels of the animals were normal, the lymphatic vessels in the skin remained underdeveloped.

Alitalo said: "What this shows is that even if the animal has only one copy of the gene, it does not suffice - levels of VEGF-C are critical in normal development. In these animals, the skin was the organ that suffered most severely, with absent or remnant lymphatic vessels. This is what happens in patients with hereditary lymphedema - the skin vessels are the most severely affected. On the other hand, it is good news because the skin is a very accessible target for therapy, much more so than the internal organs or even the muscles."

Further studies showed that the gene for VEGF-C was expressed during gestation in an area where the first components of the lymphatic system form.

The work is reported in the January 2004 issue of Nature Immunology in a paper titled "Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins."

The authors write: "Our results indicate that mutations that inactivate VEGF-C could predispose a person to primary lymphedema, which is a disabling swelling of the extremities due to poorly functional and/or hypoplastic cutaneous lymphatic vasculature. The VEGF-C+/- mice described here provide a preclinical model for the development of therapies aimed at regenerating damaged or hypoplastic lymphatic vessels."

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, Helsinki University set up a company called Licentia Ltd., which is in partnership with the Ludwig Institute for Cancer Research. In addition, a second company called Lymphatix Ltd. has been founded. Its goal is to develop therapies for various lymphatic and vascular disorders.

The team also is exploring the role of VEGF-C and other members of the family in cancer. Alitalo said: "The results concerning normal development do not exclude the possibility that there could be an additional function for these factors in tumors. There is already evidence that tumor metastasis is associated with overexpression of VEGF-C."

Several groups have already shown, he added, that overexpression of factors such as VEGF-C is associated with a higher likelihood of metastasis via the lymphatic system, both in patients and in tumor-bearing mice.

"The problem is that metastasis has already happened in most patients by the time they are diagnosed," Alitalo said. "So we are trying to imagine how you could design a clinical trial to interfere with this process."