German researchers have found that high circulating levels of angiopoietin-2 (Ang-2), a naturally occurring angiogenesis stimulator, correlates with tumor progression and reduced survival in patients with advanced (stage III and IV) melanoma. The findings were published in the February 15, 2009 issue of the journal Clinical Cancer Research.

The docking station of Ang-2 is the receptor Tie2 on the surface of endothelial cells, which form the inner lining of blood vessels. The angiopoietin/Tie system regulates the later stages of angiogenesis by controlling endothelial cell survival and vessel maturation.

Researchers, led by Dr. Hellmut Augustin and Prof. Dirk Schadendorf of DKFZ and Mannheim Medical Faculty of the University of Heidelberg, measured Ang-2 concentrations in blood samples of melanoma patients. They discovered that larger tumors and more advanced disease stages correlate with high levels of Ang-2; if one tracks the Ang-2 levels of individual patients over time, an increases occurs in parallel to disease progression. In contrast, patients who have lived with the disease for a long time, i.e., whose disease was not, or only slightly progressive, had lower Ang-2 levels. The researchers found that Ang-2 concentration in blood serum is a more precise indicator of the progression and stage of the disease than previously used biomarkers.

This close association between melanoma progression and Ang-2 levels prompted the question of whether Ang-2 only stimulates vascularization in the tumor or whether it has additional influence on the behavior of the actual cancer cells. Such an effect had not yet been proposed for any one of the various growth factors that act on the cells of the vascular walls. In this study, melanoma cells were found to produce both soluble Ang-2 and the matching receptor, Tie2, on their own cell membranes, which meant they were theoretically capable of self-activation.

To test this hypothesis, researchers genetically silenced the Ang-2 expression in some of the melanoma cells and compared them against control cells. Test systems in the culture dish subsequently revealed that the melanoma cells had lost their ability to migrate—the migration tendency of cancer cells is regarded as important information about their ability to invade other tissue in the body and metastasize.

Advanced melanoma therefore appears to use the Ang-2/Tie2 signaling system to strengthen its malignant properties. "Ang-2 is a very promising therapeutic candidate, both as a biomarker for better monitoring disease progression and as a target structure for therapy," said lead author Hellmut Augustin. “Therapies that block Ang2 might not only attack the tumor's blood supply, but also reduce its malignant growth.”

By Roderick Smith, M.S.

References: Helfrich I, Edler L. Sucker A, et al. Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin Cancer Res 2009;15(4):1384-1392.