I believe that this paper is highly cited because it shows for the first time that matrix metalloproteinases (MMPs) can play opposite effects on tumor growth and vascularization. On one hand increased MMP synthesis may promote invasion and metastasis by facilitating extracellular matrix degradation and cell migration. On the other hand, MMP synthesis may prevent primary tumor growth and consequent vascularization by generating inhibitors of endothelial cell proliferation, including angiostatin. Integrin alpha1-null mice offer a genetic model of increased MMP/angiostatin synthesis and they can be used to study in vivo the role of MMP inhibitors in the prophylaxis of tumor growth. Based on the observation that MMPs can be indeed anti-angiogenic, it is conceivable that the use of MMP inhibitors as anti-tumor agents might have the unwanted effect of increasing tumor angiogenesis and development by preventing the generation of inhibitors of EC growth.

In order to grow and spread within an organism, tumors need nutrients and blood supply, which usually derive from the host in which tumors develop. Thus, blocking blood supply might represent a valid tool to prevent and reduce tumor growth. We have found that some enzymes, called matrix metalloproteinases (MMPs), are beneficial to the hosts as they produce molecule/s able to inhibit the growth of blood vessels, thus preventing blood supply to the tumors with consequent reduction in tumor growth and development. We have generated a mouse that produces high levels of MMPs and show reduced tumor growth and development.

I have been always interested in angiogenesis and host-tumor interactions. When I was a graduate student I was interested in how particular growth proteins (i.e. bFGF or gap junctions gene products) control endothelial cell communication, proliferation and migration both in vitro and in vivo. When I moved to The Scripps Research Institute in La Jolla I had the fortune and pleasure to work with Dr. Humphrey Gardner who let me explore the complicated and fascinating world of integrins, matrix metalloproteinases, angiostatin and tumor angiogenesis. Now, that I am at Vanderbilt University I am still working on metalloproteinases and tumor angiogenesis and one of our goals is to determine how stimulation of the MMP/angiostatin axis can be used as a tool to inhibit specifically tumor vascularization and growth.