A cryptic collagen epitope (green) is exposed on some tumor blood vessels.

Inject monoclonal antibodies into an animal with a tumor, the treatment inhibits angiogenesis, and tumor growth stops. Sound familiar?

This time, however, there is a twist: the antibodies described by Xu et al. (page 1069) target a cryptic epitope in the extracellular matrix rather than a cellular growth factor, and the results suggest an important activity for collagen type IV in directing the growth of new blood vessels.

Recent work has shown that proteolytic enzymes like the matrix metalloproteinases are required for normal angiogenesis, but the significance of these findings remained unclear. In the new work, the authors analyzed a monoclonal antibody that binds to proteolyzed collagen-IV, but not to the intact triple helical form of the protein. The cryptic epitope, HUIV26, is not seen in the basement membranes of normal blood vessels, but becomes exposed in angiogenic and tumor-associated blood vessels. HUIV26 epitope exposure correlates with a loss of α1β1 integrin binding and a gain of αvβ3 binding, and the monoclonal antibody can strongly inhibit angiogenesis and tumor growth in several animal models.

The collagen epitope (green) is associated with matrix metalloproteinase-2 (red).

The new results suggest that proteolysis of the extracellular matrix exposes cryptic sites, which then transduce signals required for angiogenesis. The authors are now searching for additional cryptic signaling sites in other extracellular matrix proteins, and have already found additional monoclonal antibodies that inhibit angiogenesis and tumor growth. They have also discovered that the HUIV26 epitope may be able to regulate other types of behavior in neuronal, epithelial, and tumor cells. ▪