Melanoma-inhibiting activity (MIA) was isolated previously as a small soluble protein secreted from malignant melanoma cell lines in vitro. In vivo, highly restricted expression patterns in melanocytic tumors were identified. We therefore quantitated serum levels of MIA protein by means of a nonradioactive ELISa and investigated whether MIA provides a clinically useful parameter in patients with malignant melanomas. Here, we report enhanced MIA serum levels in 13 and 23% of patients with stage I and II disease, respectively, and in 100% with stage III or IV disease. Compared with S-100 and soluble intercellular adhesion molecule 1 serum levels in these patients, MIA was the most sensitive marker. Response to therapy in stage IV disease correlated with changes in MIA serum levels. Measuring repeatedly sera of 350 patients with a history of stage I or II melanoma during follow-up, we detected 32 patients developing positive MIA values. At the time of serum analysis, 15 of them had developed metastases, and one presented with metastatic disease 6 months later. In contrast, none of the patients with normal MIA serum levels developed metastases during the follow-up period of 6–12 months. In conclusion, MIA represents a novel serum marker for systemic malignant melanoma revealing the highest sensitivity and specificity among currently available markers. Useful clinical applications include staging of primary melanomas, detection of progression from localized to metastatic disease during follow-up, and monitoring therapy of advanced melanomas.
This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Krebshilfe (to R. B. and R. H.) and by Boehringer Mannheim.