Through allele-segregation and loss-of-heterozygosity analyses, we demonstrated loss of the translocation-derivative chromosome 3 in five independent renal cell tumors of the clear-cell type, obtained from three members of a family in which a constitutional t(2;3)(q35;q21) was encountered. In addition, analysis of the von Hippel-Lindau gene, VHL, revealed distinct insertion, deletion, and substitution mutations in four of the five tumors tested. On the basis of these results, we conclude that, in this familial case, an alternative route for renal cell carcinoma development is implied. In contrast to the first hit in the generally accepted two-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harboring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.
The induction of expression of the components of the proteolytic plasminogen activation system in cutaneous melanocytic tumour progression has previously been reported. Plasminogen activators, their inhibitors, and the receptor for urokinase were present only in advanced primary melanomas and melanoma metastases. The present study reports on the presence of tetranectin and plasmin/plasminogen, two proteins connected with plasminogen activation, in cutaneous melanocytic lesions. The distribution of tetranectin and plasminogen was studied by immunohistochemistry in 105 freshly frozen melanocytic lesions of common naevocellular naevi (n=24), atypical naevi (n=14), early (n=12) and advanced (n=20) primary melanomas, and melanoma metastases (n=35). Both tetranectin and plasminogen were detected in a variety of tissue components. In all stages of melanocytic tumour progression, tetranectin was found in endothelium, perivascular dendritic cells, and leukocytes. Plasminogen was present in endothelium and in the basal layer of the normal skin. Tetranectin and plasminogen staining of fibroblastic cells at the invasive front and of extracellular matrix was, however, restricted to malignant lesions. Co‐localization of tetranectin and plasminogen was found in 50 per cent of the early primary melanomas and in more than 75 per cent of the advanced melanomas and melanoma metastases. These results suggest a coordinated role for tetranectin and plasminogen at the invasive front of melanomas. Tetranectin‐bound plasminogen may facilitate the migration of tumour cells.
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