Currently, the scale and consistency of changes of gene expression profiles in models of melanoma progression are largely unknown. Therefore, we investigated siblings of cell lines or malignant melanomas (MM), which have been selected by nude mouse passages for (a). increased tumorigenicity (local ECM-independent growth), (b). metastatic potential, or (c). selected for increase invasiveness using the Boyden chamber. cDNA array analysis surveying more than 27.000 transcripts per cell line showed that 1.5-2.8% of all detectable transcripts were consistently differentially regulated during selection process in those models. Using array analysis, we identified 33 individual transcripts that exhibited significant differential hybridization paralleling the increased aggressiveness of the selected progeny. Because some of those genes could play a significant functional role in the progression of MM, we additionally proved their regulative pattern using Northern blotting. Among others, progressive overexpression of osteonectin/SPARC, a angiogenesis, was found in the selected offspring from all three experimental models and may therefore be considered as a potential marker for aggressive MM as well a promising therapeutic target. We further show that the selection of MM cells for increased ECM-independent local growth was accompanied by overexpresssion of macrophage migration inhibiting factor (MIF), an important modulator of both cell cycle progression and angiogenesis, and cathepsin Z, a novel member of the family of matrix degrading proteinases.