VEGF receptor-3 implicated in lymphangiogenesis and cancer metastasis

Last Updated: 2001-01-31 17:02:37 EST (Reuters Health) - Vascular endothelial growth factors (VEGFs), working through VEGF receptor-3 (VEGFR-3), promote lymphangiogenesis and the metastatic spread of cancer cells, according to three related reports in the February issue of Nature Medicine.

Dr. Kari Alitalo from University of Helsinki in Finland and colleagues examined the role of VEGFR-3 in lymphangiogenesis using a soluble form of VEGFR-3 coupled to the Fc domain of IgG and expressed in transgenic mice.

By blocking native VEGFR-3, soluble VEGFR-3-Ig induced total lymphatic vessel regression during embryonic development, the authors report. By several weeks of age, however, lymphatic vessels began to regrow, reaching normal levels in many organs by adulthood.

"The data demonstrates that soluble VEGFR-3 is a potent and specific inhibitor of lymphangiogenesis in vivo. But more broadly, it shows that compounds that can block ligand-mediated VEGFR-3 signaling can modulate the growth of vessels that express VEGFR-3," Dr. Alitalo told Reuters Health.

Dr. Steven A. Stacker from Royal Melbourne Hospital in Victoria, Australia and associates investigated the role of VEGF-D, a VEGFR-3 ligand, in lymphangiogenesis and tumor spread in a mouse tumor model.

Besides promoting tumor angiogenesis and tumor growth in this model, VEGF-D expression was "clearly required for the growth and establishment of lymphatic vessels in the tumor mass," the investigators write. Moreover, VEGF-D-expressing tumors developed metastasis to local lymph nodes in 14 of 23 animals, whereas tumors without VEGF-D metastasized in none of 30 animals.

These findings "demonstrate the existence of molecules (such as VEGF-D) capable of inducing formation of new tumor lymphatic vessels, and show that such molecules promote the spread of tumor cells from the primary tumor to local lymph nodes," Dr. Stacker told Reuters Health. "The new lymphatic vessels provide a 'route of escape' for the tumor cells."

In a third report, Dr. Michael Detmar from Massachusetts General Hospital and Harvard Medical School in Charlestown and co-researchers studied the effects of overexpression of VEGF-C, another VEGRF-3 ligand, by human breast cancer cells transplanted into nude mice.

Like VEGF-D in the other study, VEGF-C promoted lymphatic vessel proliferation throughout the central tumor areas and at their peripheries, the report indicates. This enhanced lymphangiogenesis also brought a 60% increase in tumor metastases to regional lymph nodes and a sixfold increase in lung metastasis volume.

"These studies provide the first direct experimental evidence that tumors are able to activate tumor lymphangiogenesis," remarks Dr. Karl H. Plate from the University of Erlangen in Germany in a related editorial. "If human tumors that express high levels of VEGF-C and VEGF-D show a consistently high incidence of lymphatic metastasis, inhibition of VEGFR-3 function may be a novel approach to inhibit lymphatic metastasis in patients."

"The most important question is whether these observations are of any relevance for human cancer," Dr. Plate cautioned in an interview with Reuters Health. "Now it is necessary to generate exact data on VEGF-C and VEGF-D expression in human cancer to determine whether the expression levels correlate with lymph metastasis and whether tumor lymphangiogenesis indeed occurs in human cancer as well."

Reference

Nature Medicine 2001;7:151-152,186-205. (Abstract not available online at time of posting.)