Cancer Biology

Protease Frees VEGF for Angiogenic Action

Science's STKE  24 Oct 2000:
Vol. 2000, Issue 55, pp. tw2
DOI: 10.1126/stke.2000.55.tw2

To become invasive (and thus really nasty), tumor cells need cooperation from other cells, particularly vascular endothelial cells that form new blood vessels in the tissues that the cancer cells invade. Bergers et al. used a transgenic mouse model of multistage carcinogenesis (RIP1-Tag2 mice expressing the SV40 T antigen) to analyze the onset of angiogenesis during development of tumors of the pancreatic islets. They unexpectedly found that vascular endothelial growth factor (VEGF)--an established inducer of angiogenesis--and its receptors were constitutively expressed in islets and did not increase in abundance when angiogenesis began. Nevertheless, an inhibitor of VEGF signaling did inhibit angiogenesis and tumor growth. What did correlate with angiogenesis was expression of matrix metalloproteinase-9. Furthermore, expression of MMP-9 promoted angiogenesis and release of VEGF from cultured islets. MMP-9 is not the whole story, however, because angiogenesis could still be observed when MMP-9 was absent or inhibited. Nevertheless, MMP-9 clearly participates in the "angiogenic switch" that leads to formation of pancreatic tumors in this model system. The results pose some new puzzles as well: MMP-9 appears not to be expressed by the cancer cells themselves, so what is the nature of the rare cells that appear to supply the enzyme and resemble infiltrating inflammatory cells? And what might the mechanism be by which VEGF is sequestered such that MMP-9 and other mechanisms can control its release and subsequent activity?

Bergers, G., Brekken, R., McMahon, G., Vu, T.H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z., and Hanahan, D. (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2: 737-744. [Online Journal]