The role of the vitronectin receptor avb3, in melanoma invasion and metastasis

The incidence of melanoma worldwide has been increasing steadily in recent years with an associated rise in mortality rates. If detected early, melanoma lesions can be surgically removed with wide excisional margins resulting in high cure rates. However, as the melanoma invades the deep layers of the skin at the primary site and subsequently metastasizes to the regional and distant nodes, the prognosis for the patient becomes progressively worse. As the melanocytic lesion progresses from a benign nevus to a highly malignant metastatic melanoma, it undergoes changes in protein expression which may be relevant to melanoma development. Among the proteins found to be upregulated during melanoma progression are the vitronectin adhesion receptor $ alpha sb{ rm v} beta sb3$ and the receptor for the proteolytic enzyme urokinase plasminogen activator (uPAR). The present work describes our results with two new animal models of human melanoma which were developed to study the cellular and molecular mechanisms involved in lymphatic metastasis of this disease. Each model consisted of two cell lines with different metastatic abilities. Using these models, a correlation was found between the adhesion of the melanoma cells to cryostat sections of human lymph nodes and their metastatic ability in nude mice. When compared to the parent cells, the lymph-node metastasizing melanoma cells were found to express increased levels of the cell surface vitronectin receptor (VNR) $ alpha sb{ rm v} beta sb3$ which was utilized to mediate the increased adhesion to lymph node. In addition to the VNR, the metastatic cells also expressed increased levels of the uPAR. To study the relationship between expression of these two receptors, $ alpha sb{ rm v}$ expression was suppressed with $ alpha sb{ rm v}$ antisense phosphorothioate oligonucleotides. In the antisense-treated cells a 9-fold reduction in $ alpha sb{ rm v}$ mRNA was seen with a corresponding 2.8-fold decrease in adhesion to vitronectinIn a parallel study, a model of human breast carcinoma was used to study the role of cell adhesion in breast carcinoma metastasis. A correlation was observed between cell adhesion to frozen sections of human lymph modes and metastasis in vivo. However, unlike the melanoma cells, the metastatic breast carcinoma cells were found to utilize receptors $ alpha sb3 beta sb1$ and $ alpha sb5 beta sb1$ to adhere to lymph node fibronectin suggesting that different adhesion receptors may be involved in lymph node metastasis of different malignancies