Tufts-NEMC researchers identify enzyme that activates cancer cell growth and invasion

Boston, Mass. – Researchers from Tufts-New England Medical Center have identified a long-sought-after enzyme that interacts with a specific protease-activated receptor, PAR1, on breast cancer cells. The study authors identified metalloprotease-1 as the molecular scissors that activates PAR1 resulting in cancer cell invasion and tumor growth. They were able to block the spread of the breast cancer in animals using novel compounds called pepducins that act on the inside surface of the cell downstream of the enzyme and receptor. Their study appears in the February 11 edition of the journal Cell.

PARs are a unique class of receptors that have long been known to play critical roles in blood clotting, inflammation and growth of blood vessels. More recently, PAR1 has been linked with the invasive and metastatic properties of many different kinds of cancers, however, it was not known how the receptor was being activated in tumors.

"We were surprised to find that the cancer cell itself did not provide the missing protease. We found that the protease was being secreted by the surrounding host cells. This is an example of a cancer cell manipulating the host to provide the key missing ingredient, namely the protease," said Athan Kuliopulos, MD, PhD, of Tufts-NEMC's Molecular Oncology Research Institute and Hematology-Oncology Division, and the study's lead author. "The MMP-1 protease was thought to be mainly involved in cleavage of collagen. This means that MMP-1 is not only cutting up the tough collagen matrix that surrounds cancer cells, it is also activating PAR1 to enable the cancer to invade into other tissues."

The researchers identified several cell-penetrating compounds called pepducins that block activated PAR1 from triggering cancer invasion and angiogenesis. Tufts-NEMC has filed patent applications for these pepducins and will be exploring further research in this area.

"We believe that blocking the MMP-1/PAR1 pathway with the pepducins described in our study could provide a novel therapeutic approach for treating invasive cancers and possibly other tissue remodeling processes such as inflammation and atherosclerosis," said Kuliopulos.

The other scientist-researchers on the study were Adrienne Boire, PhD, of Tufts-NEMC's MORI and Tufts University School of Medicine's Department of Biochemistry, Lidija Covic, PhD, of MORI and the Medical Center's Division of Hematology-Oncology, Anika Agarwal, MD, and Susanne Jacques, PhD, of MORI, and Sheida Sherifi, MD, formerly at NEMC, now in the Department of Pathology at Mt. Auburn Hospital.

Published in Cell, Volume 120, Number 3, February 11, 2005, pages 303-313.
http://www.cell.com/content/article/abstract?uid=PIIS0092867404012103

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