It has been proposed that benign
nevi that fail to differentiate normally may undergo stepwise growth and morphologic changes resulting in progression toward
dysplastic nevi, which in some cases progress into
malignant melanoma. In this study, we sought to determine the relationship between production of endogenous
growth factors and the appearance of
chromosomal abnormalities in cultured
nevi and melanomas. Newly established cultures from 8
nevi with benign histology and 6
malignant melanomas, and 2
malignant melanoma cell lines were studied. Assays for mitogenic
growth factors were based on stimulation of [3H]
thymidine incorporation into
DNA in Hs0294
malignant melanoma cells, produced by serum-free
conditioned medium from
nevus or
melanoma cultures. Karyotypes were examined in cultures of an equivalent passage. Three of the 8
nevus cultures were
mitogen-negative and displayed normal karyotypes; one
nevus culture was
mitogen-positive and had a normal karyotype, although the biopsied tissue demonstrated histologic evidence of benign melanocytic proliferation; one was
mitogen-negative initially, but had an extra chromosome 8 in 2 of 50 cells; 3 were
mitogen-positive and chromosomally abnormal. Each of the cultures in this latter group exhibited reciprocal translocation (rcpt) as the only identifiable abnormality [rcpt(6;15), rcpt(10;15), rcpt(15;20)], or a constitutional rcpt(4;5). Thus, there was direct correlation between
growth factor production and
chromosome abnormality in 6 of 8 benign
nevus cultures. In the newly established
melanoma cultures there was also concordance between
growth factor and chromosomal status;
conditioned media from 4 of 6 were
mitogen-positive by at least one assay, and all 4 of the
mitogen-positive cultures had chromosomally abnormal cell populations. Of the 2
melanoma cultures negative for
growth factors, one was also negative for
chromosome abnormality; the other had chromosomal change consisting of increased
polyploidy. Both
melanoma cell lines had
abnormal karyotypes and were
mitogen-positive. Though numerous chromosome changes were noted in the karyotypically abnormal
melanoma cells, 6 of the 8 cultures exhibited abnormalities in chromosomes 1, 6, and/or 7. These data suggest that steps in the progression from benign
nevi toward
dysplastic nevi or
malignant melanoma include: proliferation resulting from altered production of endogenous mitogenic
growth factors; and development of specific
chromosomal abnormalities.