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Cutaneous melanoma progression in an ink4a-null, tyrosinase-RAS transgenic mouse. Shown here are photomicrographs of normal tissue (left) and its progression to early neoplastic changes (middle), invasive disease (upper right), to a highly destructive, metastatic tumor (lower right). The cartilage layer is clearly seen in the top panels and bottom right; as the disease advances, tumor cells acquire a highly invasive phenotype manifest here by their penetration through the cartilage layer (arrow). Background shows an immunohistochemistry analysis of cultured melanoma cells using an anti-RAS antibody. (For details, see Chin et al., p. 2822.)