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Targeting tumor growth

Scientists identify novel anti-cancer target

Cold Spring Harbor Laboratory

Blood vessels nourish healthy tissues, but also provide a conduit for tumor growth and metastasis. A collaboration of researchers from the University of Michigan, NIH, and the University of Helsinki (Finland) has identified a novel, potential therapeutic target to prevent tumor vascularization.

In the April 15th cover story of Genes & Development, Dr. Stephen J. Weiss and colleagues demonstrate that "the recently characterized enzyme, termed the membrane-type 1 matrix metalloproteinase or MT1-MMP, controls the ability of new blood vessels to respond to a specific growth factor that plays a required role in maintaining the functional properties of the vasculature."

Mammalian vasculature is composed of two main cell types: endothelial cells (that line the blood vessels) and mural cells (that surround the endothelial tubules). Mural cells surrounding large vessels are known as vascular smooth muscle cells, while those on the surface of smaller vessels are called pericytes.

The platelet-derived growth factor-ß (PDGF-ß) intracellular signaling pathway has an established role in mediating cellular communication between endothelial and mural cells, which is essential for the normal formation of blood vessels. Dr. Weiss and colleagues have discovered that MT1-MMP, whose traditional role in endothelial and mural cells is to break down the proteins that reside in the spaces between cells, has an additional role in the regulation of PDGF-ß signaling.

To determine the effect of MT1-MMP on mural cell function, Dr. Weiss and colleagues used agenetically engineered a strain of mice that lacks MT1-MMP. Experimentation with these mice, and the MT1-MMP-null tissues derived from them, revealed that MT1-MMP helps propagate the PDGF-ß signal to direct mural cell investment in the microvasculature. MT1-MMP-null mice have severely compromised vascular architecture, with irregularly sized vessels and weakened vessel walls.

Dr. Weiss explains that "These findings, coupled with complementary reports from our group that cancer cells themselves use MT1-MMP to regulate their proliferative and metastatic properties, suggest that therapeutics directed against this single target could prove efficacious in controlling the ability of tumors to recruit new blood vessels, grow and spread to distant sites."

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