Understanding Tissue Invasion
The researchers found that a domain known as the hemopexin domain was important for tissue invasion events. During tissue invasion, cells from one tissue invade into and usually move through another tissue, sometimes ending up in a completely different part of the body from where the tissue was formed. This pathway is similar to metastasis, where cancer cells spread from the original tumor to other sites in the body.
Fly larvae missing the hemopexin domain of Mmp1 had highly distorted or absent head and wings. The growth of such body parts requires tissue invasion to move the cells to the right place in the animal. These abnormalities indicate that a hemopexin domain is needed for tissue invasion in fly development, and possibly in cancer metastasis, according to Page-McCaw.
Removing the Catalytic Domain
The other primary domain in MMPs, the catalytic domain, is considered the business part of the enzyme, as it is where MMPs break up or destroy other proteins. The catalytic domain was extensively targeted by pharmaceutical companies in efforts to block MMP function in cancer.
The researchers found that in flies, like in patients, blocking or removing the catalytic domain caused many different kinds of problems, beyond simply failures of tissue invasion. When the catalytic domain was removed, the larvae could not grow normally because they were unable to make necessary and basic developmental changes in their exoskeletons.
The findings shed light on why inhibiting the catalytic domain in the drug trials would have both the favorable impact of stopping tissue invasion and unfavorable impact of significant side effects. In the future, inhibiting only the hemopexin domain could be a method to inhibit tissue invasion without inhibiting all other necessary MMP functions, Page-McCaw said.
Publication and Funding
Their findings, which hold promise for improved cancer therapies, were published Feb. 5 in the online Early Edition of the Proceedings of the National Academy of Sciences (PNAS).