LOSS OF RECEPTORS FOR TRANSFORMING GROWTH-FACTOR-BETA IN HUMAN T-CELLMALIGNANCIES

Ki-1 (CD30)(+) cutaneous T-cell lymphomas (CTCLs) are slowly progressi ve lymphomas in which initial spontaneous regression is often observed . To better understand the mechanisms of spontaneous regression and ev entual tumor progression in Ki-1(+) CTCLs, type beta transforming grow th factor (TGF-beta)-mediated growth inhibition of clonally related ce ll lines derived from two time paints, before and after tumor progress ion, was studied. TGF-beta 1 inhibited colony-forming efficiency (CFE) of a cell line (Mac-1) derived from clinically indolent Ki-1(+) CTCLs but failed to inhibit CFE of Mac-2A and -2B cell lines from advanced CTCLs. To determine the basis for TGF-beta 1 resistance in advanced CT CL cells, we looked for possible defects in the expression of cell sur face TGF-beta receptors. Mac-1 cells were found to express TGF-beta re ceptors I and II, which mediate growth inhibition, and the TGF-beta-bi nding proteoglycan betaglycan. In contrast, receptors I and II were no t detected in CTCL lines Mac-2A and -2B even though these cell lines d id express betaglycan. Various treatments that unmask or induce TGF-be ta receptors in other cells failed to show evidence for these receptor s in advanced CTCL cells. Loss of TGF-beta receptor expression in thes e cells correlated with a marked decrease in TGF-beta receptor II mRNA levels. Loss of cell surface TGF-beta receptors was also found in two of five other patients with T-cell lymphomas including the Sezary syn drome and a noncutaneous T-cell lymphoma, suggesting that loss of TGF- beta receptor expression may be a recurrent feature of human T-cell ma lignancies.