Human genes MAGE-1 and MAGE-3 code for antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. These antigens may constitute useful targets for specific anti-tumor immunization of cancer patients, since genes MAGE-1 and MAGE-3 are expressed in a number of tumors of different histological types, but are not expressed in normal adult tissues other than testis. This also applies to genes MAGE-2 and MAGE-4, which are closely related to MAGE-1 and MAGE-3. We have analyzed the expression of these 4 MAGE genes in cutaneous melanoma. Sixteen of 100 primary tumors vs. 69 (48%) of 145 metastases from individual patients expressed MAGE-1. Similar differences in the frequency of gene expression between primary and metastatic tumor samples were observed for MAGE-2, MAGE-3, and MAGE-4. MAGE expression in primary tumors was correlated with tumor thickness: there was a significantly increased frequency in the expression of MAGE-1, -2 and -3 in tumors of greater thickness. Benign and dysplastic nevi, as well as in situ melanomas, did not express any of the 4 MAGE genes.

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In order to evaluate the significance of adhesion molecules expressed on melanocytic tumours for progression and prognosis in vivo, we studied integrin expression (VLA-1 to VLA-6, CD18, CD51, CD61) on 10 naevi, 40 primary malignant melanomas, and 11 metastases by immunohistology using the APAAP technique. Evaluation was done by grouping the percentage of positive tumour cells in six categories. Statistical analysis (Wilcoxon rank test, Scheffe test) revealed significant differences in the expression of VLA-1 (P < 0.0001), VLA-2 (P = 0.0001), VLA-5 (P = 0.0093), VLA-6 (P = 0.0232), and CD61 (P = 0.0002) between naevi and primary melanomas. Comparing primary melanomas with metastases, a statistically significant decrease in the expression of VLA-1, VLA-2, and VLA-6 was detectable, as well as a significant increase in VLA-4 and VLA-5. There was no correlation between integrin expression and tumour type (superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma), regression and ulceration. Changes of VLA-1, VLA-4, and VLA-6 expression correlated with the tumour thickness of the primary melanoma, but only VLA-4 and VLA-6 expression on primary melanomas correlated significantly with the development of metastases (P = 0.024 and P = 0.001). These changes of integrin expression during tumour progression particularly, the data showing an increase of VLA-4, and a decrease of VLA-6 expression support the concept that integrins are a new additional set of prognostic markers which indicate predisposition to the development of metastases.

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The phenotypic changes in human melanoma cells during the course of tumor progression were studied with monoclonal antibodies (MAbs) against the melanoma-associated antigens (MAA) M.2.2.4, H.2.8.10, K.1.2, A.1.43, and A.10.33, and HLA-(A,B,C and D). Cryostat sections of 172 primary melanomas of the skin, 157 melanoma metastases and 56 nevi were investigated with an indirect immunoperoxidase method. Phenotypic heterogeneity was observed within lesions at all stages, and also within different tumors of the same patients. Despite this heterogeneity, principles of antigen expression were found. From the reaction pattern of MAbs, the following classifications of antigens were derived: "constitutive" markers of nevomelanocytic cells (M.2.2.4 and H.2.8.10) were found expressed over a wide range of local and systemic tumors. One MAA, K.1.2 (Suter et al., 1985), that declines with progression of melanoma, was classified as an "early" antigen, whereas MAA that appear in primary melanoma in proportion to invasiveness, and which are expressed in metastases of lymph nodes and visceral organs (A.1.43, and A.10.33), were classified as "late" markers of tumor progression. HLA-antigens were classified as "intermediate" markers, HLA-A,B,C, as an "early-intermediate", and HLA-DR as a "late-intermediate" marker. The occurrence of class II HLA, A.1.43-, and A.10.33-positive tumor cells in primary melanoma indicates a high metastatic potential of tumors, independent of tumor thickness. The data show that local and systemic progression of melanoma is associated with qualitative changes in tumor cells which can be recognized by MAbs.