Decreased expression of both the low-density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor and its receptor-associated protein in late stages of cutaneous melanocytic tumor progression.

ABSTRACT

We recently found that the proteins of the proteolytic system of plasminogen activation emerge in late stages of melanocytic tumor progression. A large body of evidence suggests a role for two proteins, the low-density lipoprotein receptor-related protein (LRP)/alpha(2)-macroglobulin receptor and its receptor-associated protein (RAP), in the internalization of components of the plasminogen activation system. Here, we present data on the presence of these two proteins in human melanoma cell lines which differ in metastatic capacity, their corresponding xenografts, and in cutaneous melanocytic lesions. With flow cytometry, we found surface expression of LRP to be restricted to urokinase plasminogen activator, producing highly metastatic cell lines. These cell lines also produce higher levels of LRP mRNA, whereas RAP mRNA and protein are expressed at equal levels in all cell lines and not expressed at the cell surface. Xenografts of cell lines producing high levels of LRP remarkably contain only a small fraction of LRP-positive tumor cells. Using immunohistochemistry on frozen sections of 107 human melanocytic lesions comprising the various stages of melanocytic tumor progression, we found that expression of both LRP and RAP decreased in tumor progression. Furthermore, we noted that LRP and RAP are coexpressed within the same lesion. Using immunofluorescence double staining, we found that LRP and RAP colocalize in the same cells in the lesions studied and in the same cell structures in the cell lines studied. In conclusion, our results indicate that LRP and RAP are coordinately expressed in a decreased fashion in melanocytic tumor progression. Based on the staining results in xenografts and in human melanocytic lesions, we conclude that a strong correlation between expression of LRP and urokinase-type plasminogen activator seems not to exist in in vivo melanomas.