Transforming growth factor-beta protection of cancer cells against tumor necrosis factor cytotoxicity is counteracted by hyaluronidase (Review)

Numerous cancer cells, when exposed to transforming growth factor beta (TGF -beta), become resistant to tumor necrosis factor (TNF) cytotoxicity. Pretr eatment of L929 fibroblasts, for example, with TGF-beta isoforms (beta 1, b eta 2 and beta 3) for at least 0.5-1 h results in resistance to TNF killing . TGF-beta 1 mediates the following sequential events in L929 cells: i) rap id induction of protein tyrosine-phosphorylation (<30 min), ii) stimulation of protective protein synthesis and acquisition of TNF resistance (similar to 0.5-1 h), and iii) suppression of I kappa B-alpha expression(1-2 h). Tw o protective proteins induced by TGF-beta 1 are a 46 kDa extracellular matr ix TNF-resistance triggering (TRT) protein and a putative transmembrane ant i-apoptotic adhesion protein TIF2 (containing an RGD motif in the extracell ular region). Both proteins enable L929 cells to resist TNF killing. Notabl y, testicular hyaluronidase increases TNF sensitivity in several types of c ancer cells, counteracts TGF-beta-mediated TNF-resistance, and suppresses T GF-beta 1 gene expression in L929 cells in a serum-dependent manner. Moreov er, hyaluronidase antagonizes TGF-beta-mediated inhibition of epithelial ce ll growth. Both TGF-beta and hyaluronidase are essential for the progressio n and invasiveness of breast, prostate and other cancers. Conceivably, a st age-dependent expression, as well as a balanced production, of these protei ns is essential for cancer development and self protection against TNF cyto toxicity.