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American Journal of Pathology, Vol 144, 776-786, Copyright © 1994 by American Society for Investigative Pathology

REGULAR ARTICLES

Variant sublines of early-stage human melanomas selected for tumorigenicity in nude mice express a multicytokine-resistant phenotype

H Kobayashi, S Man, JR MacDougall, CH Graham, C Lu and RS Kerbel
Division of Cancer Research, Sunnybrook Health Science Centre, Ontario, Canada.

Surgical removal of early-stage radial growth phase or vertical growth phase primary cutaneous human melanomas usually results in cure of the disease. Hence there are few examples of genetically-related paired human melanoma cell lines for study in which one member of the pair is from a curable early-stage lesion and the partner is a more aggressive malignant variant. A rapid method of obtaining such variants is described. It consists of injecting cells from established early-stage radial growth phase or vertical growth phase melanoma cell lines--which are normally non- or poorly tumorigenic in nude mice--into such hosts, where the cell inoculum is co-mixed with Matrigel, a reconstituted basement membrane extract. This resulted in the rapid formation of progressively growing solid tumors from which permanent cell lines were established. Subsequently, the sublines were found to be frankly tumorigenic upon retransplantation into new nude mouse hosts in the absence of Matrigel co-injection. This process was repeated a second time, resulting in the isolation of secondary sublines, manifesting a stepwise increase in tumorigenic properties. The tumorigenic variant sublines were examined for their relative sensitivity to a panel of different cytokines that are normally growth inhibitory for melanoma cells from early-stage primary lesions. All the sublines were found to express an increased resistance to the cytokines transforming growth factor-beta, interleukin-6, interleukin-1 and tumor necrosis factor- alpha, and did so in a stable manner. Thus the results support the hypothesis that a progressive multicytokine resistance accompanies the progression of human melanoma. The availability of such related sublines should provide a valuable resource to help study the changes associated with, and perhaps causative of, disease progression in human malignant melanomas.

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