ENDOGENOUS INTERLEUKIN-6 CAN FUNCTION AS AN IN-VIVO GROWTH-STIMULATORY FACTOR FOR ADVANCED-STAGE HUMAN-MELANOMA CELLS

We have previously shown that a majority of human melanoma cell lines derived from early-stage lesions were growth inhibited by exogenous in terleukin 6 (IL-6) irt vitro, whereas cell lines from advanced-stage l esions were resistant to such IL-6-induced growth inhibition, Among th e resistant melanoma cell lines, 50-60% constitutively produced IL-6, which appeared to function as a growth stimulator irt vitro, based on the growth-suppressive effects of antisense oligonucleotides to the IL -6 gene, The present study was primarily aimed at evaluating whether e ndogenous IL-6 also functions in vivo as a growth modulator for IL-6-p roducing and -nonproducing melanoma cells, To do so, we first introduc ed an IL-6 expression vector into IL-6-nonproducing human melanoma cel ls using WM35, an early-stage (radial growth phase) cell line, the gro wth of which is normally inhibited by IL-6, and WM983A, an advanced-st age cell line, the growth of which in vitro is not affected by exogeno us IL-6. None of the IL-6-producing transfectants showed a significant alteration in tumor growth in nude mice, Next, two IL-6-producing mel anoma cell lines, both of which were derived from metastases, MeWo and WM9, and which are growth resistant to exogenously added IL-6, were t ransfected with an antisense IL-6 expression vector, Several transfect ant clones manifested a constitutive decrease in IL-6 gene expression and protein production, and they also gave rise to much smaller tumors with slower growth rates and longer latency periods, However, these I L-6 antisense transfectants were not growth suppressed in in vitro cel l cultures, relative to their respective parental controls, Taken toge ther, the results demonstrate that endogenous IL-6 can indeed function as a growth stimulator for human cutaneous melanomas in vivo. This gr owth-stimulatory or survival mechanism remains to be clarified but may be paracrine rather than autocrine in nature.