Active transforming growth factor-β in human melanoma cell lines: No evidence for plasmin-related activation of latent TGF-β

Abstract

Cultured human melanoma cells were found to secrete TGF-P mostly in latent biologically inactive form but in addition five of six melanoma cell lines studied produced in conditioned culture medium active TGF-p in the range from 370 to 61 0 pg per 1 O6 cells per 24 h. A distinct characteristic of these melanoma cell lines is that they form active surface-bound plasmin by the activation of plasminogen with surface-bound tissue-type plasminogen activator. The present study was performed to assess the role of plasmin in the process of latent TGF-P activation in the melanoma cell lines. No direct correlation was found between cell-associated plasmin activity and the amount of active TGF-P present in the conditioned medium of individual cell lines. The melanoma cell lines exhibited diverse responses to exogenous active TGF-PI; three cell lines were growth-stimulated, two were growth-inhibited, and one had a very low sensitivity to the growth factor. The active TGF-P produced by the melanoma cells was found to inhibit the natural killer cell function of peripheral blood lymphocytes, suggesting that it may have an immunosuppressive effect and a role in the development of melanomas. o 1996 Wiley-Liss, Inc.

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

“…For example, mechanical forces such as tension and compression can induce conformational changes in a latent TGF-β complex, freeing an active TGF-β ligand [117,118]. A non-enzymatic activation of TGF-β may occur through interactions with thrombospondin-1 (TSP-1), the integrin αvβ6, reactive oxygen species (ROS) [119], heat, low pH [120][121][122][123], and ionizing radiation (Figure 2) [124]. The glycoprotein A repetitions predominant (GARP) localized on the surface of T cells and platelets also non-enzymatically activates TGF-βs from their latent forms [125,126], with a greater activation of TGF- Initially synthesized as homodimers with pro-peptides, mature TGF-βs are cleaved from latency-associated proteins (LAPs) by furin-like enzymes in the trans-Golgi.…”