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Using B16 F10 murine melanoma cells and sublines generated from the JB/MS melanoma which exhibit various degrees of melanogenesis, the relationships among differentiation, tumorigenicity, and metastatic potential were examined. The effect of melanocyte-stimulating hormone (MSH), which specifically stimulates differentiation of melanocytes, was also studied. All melanoma lines tested were capable of growing as experimental pulmonary metastases but, surprisingly, the undifferentiated and amelanotic JB/MS-w cells failed to grow as primary subcutaneous tumors. JB/MS-w cells, which had few surface MSH receptors, did not respond to MSH with an increase in melanin production, unlike the other cell lines. Although in vitro treatment with MSH did not change the rates of growth of primary tumors by these cell lines, such treatment decreased the number of pulmonary metastases from B16 F10, JB/MS cells, JB/MS-b1 cells and JB/MS-w cells. Conversely, MSH treatment significantly increased the rates of pulmonary metastases from JB/MS-p cells. The expression of surface melanoma antigens, urokinase-type plasminogen activity and susceptibility to natural killer cells were examined. MSH did not significantly alter surface melanoma antigen expression, but increased the natural killer cell susceptibility of B16 F10, JB/MS and JB/MS-b1 cells, cells which possess abundant surface MSH receptors. There was an inverse correlation between differentiation (pigmentation) and proliferation in vitro, and the more pigmented melanoma cells (B16 F10, JB/MS and JB/MS-b1) expressed relatively lower levels of class-I MHC, relatively higher levels of class-II MHC and the highest metastatic capacity. These results demonstrate that MSH possesses the capacity to regulate not only melanogenesis, but also other factors critical to the metastatic growth of the cells.

The recently obtained JB/MS melanoma (induced by DMBA in C57Bl/6 mice) has been successfully established in culture, and characterization of various parameters of these cells, as they have been serially passaged in vivo and in vitro, has begun. The culture lines were initially highly dendritic and melanotic, growing slowly in vitro and extremely slowly in vivo. During serial passage in vivo and in vitro the cell lines have gradually evolved into less melanotic, but more proliferative, tumorigenic and metastatic cells. We have been able to demonstrate that the JB/MS melanoma shares the common melanoma TSTA previously reported for B16, K1735 and JB/RH melanomas, but does not cross-react with the S91 melanoma or with other non-melanoma cell lines used as specificity controls. The JB/MS cells can be induced to differentiate in vitro by alpha-melanocyte stimulating hormone, a physiologically relevant agent, and studies have been initiated to detail the level at which this induction occurs. These sublines should prove to be excellent models for study of the progression of transformed cells from non-tumorigenic to tumorigenic phenotypes, and for progression through stages of varying metastatic potential, immunogenicity and differentiation.