For 20 years, Wistar scientist, Meenhard Herlyn, D.V.M., and his research team have been studying the evolution of melanoma, a potentially deadly skin cancer that is expected to strike 40 300 and kill 17 400 Americans this year. Dr. Herlyn's most recent studies focus on the "switch" that turns benign lesions into malignancies. "This change," says Dr. Herlyn, "determines the outcome of disease. By identifying the genes that turn the switch on, we can design new therapies to keep it turned off."
Thus far, two genes, the Alphav and Beta3, which are found in the vitronectin receptor (a cell surface glycoprotein that promotes the spread of cells and often is found at sites of skin repair), appear to be involved in melanoma development. "Of the two," says Dr. Herlyn, "we believe the Beta3 subunit is most critical." Supporting documentation for this hypothesis appears in yesterday's American Journal of Pathology.
During their early stage of development, melanoma cells remain in the epidermis, which is the upper layer of the skin, and do not infiltrate the dermis, or lower layer. As soon as these cells begin to express the Beta3 subunit of the vitronectin receptor, however, they become highly aggressive, continuously proliferating and deeply invading, which results in high levels of vascular infiltration and an increased rate of metastasis.
As a result of these findings, Dr. Herlyn's group is developing new inhibitors to block the activity of the vitronectin receptor, one of the most interesting and promising targets for the prevention of angiogenesis.
There are five types of lesions that indicate the level of severity in human melanoma: common acquired nevus, dysplastic nevus, radial growth phase (RGP) primary melanoma, vertical growth phase (VGP) primary melanoma, and metastatic melanoma.
The switch from a benign lesion to a malignancy occurs during the RGP primary melanoma stage, though even then, malignant cells grow only within or in close proximity to the epidermis. It is not until the VGP primary melanoma stage that these same cells gain the ability to invade deeply into the dermis. Consequently, it appears that the most critical step in the progression of melanoma occurs between the RGP and VGP stages, when Beta3 is expressed.
