Growth inhibition of a human lymphoma cell line: induction of a transforming growth factor-beta-mediated autocrine negative loop by phorbol myristate acetate.

Abstract

Transforming growth factor-beta (TGF-beta) exerts profound inhibitory effects on a number of cell types, including normal B- and T-lymphocytes. In contrast, we have found a number of lymphoid tumor cell lines to be insensitive to the antiproliferative effects of TGF-beta 1 or TGF-beta 2. Binding and cross-linking with radioiodinated TGF-beta 1 demonstrated either low or absent expression of all three TGF-beta receptor species on three B-cell tumor lines, but T-cell and non-T, non-B tumors expressed large numbers of receptors. Treatment of the B-cell lines with phorbol 12-myristate 13-acetate (PMA) induced the expression of TGF-beta receptors and inhibited proliferation in all three lines in a dose- and time-dependent manner. The cell lines constitutively produced TGF-beta mRNA and released small amounts of latent TGF-beta; however, PMA induced the release of active TGF-beta. A neutralizing antibody to TGF-beta was able to reverse the PMA-induced growth inhibition of the malignant lymphoma cell line, RL, and addition of exogenous TGF-beta reversed the effect of the neutralizing antibody. Thus, TGF-beta can inhibit human lymphoma cell growth in vitro through an autocrine mechanism. Some lymphoma cells appear to have escaped from TGF-beta negative regulation by failing to express functional TGF-beta receptors and/or by failing to secrete active TGF-beta receptors and/or by failing to acts to inhibit lymphoma cell growth is by inducing the expression of TGF-beta receptors and the secretion of active TGF-beta, thereby reestablishing an autocrine growth-inhibitory loop.