Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line.

Abstract

Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production of TNF-like protein in cell lysates and culture supernatants. Stable resistance to TNF-induced cytotoxicity develops when ZR-75-1 cells are exposed to increased concentrations of TNF. The TNF-resistant cells, designated ZR-75-1R, continuously express TNF transcripts and a TNF-like protein. Furthermore, ZR-75-1R cell supernatants contain cytotoxic activity that is abrogated by polyclonal antibody against TNF. The ZR-75-1R cells also possess TNF receptors that are occupied or down-regulated by the TNF-like protein. These findings thus suggest that (') TNF induces TNF transcripts and production of a TNF-like protein in ZR-75-1 cells and (it) resistance to TNF-induced cytotoxicity is associated with stable TNF expression.Tumor necrosis factor (TNF) is a polypeptide cytokine that exerts a wide variety of biological effects (1). TNF was originally identified by its ability to cause hemorrhagic necrosis in subcutaneous murine tumors (2). Subsequent studies showed that TNF is cytotoxic to certain murine and human tumors, both in vitro and in vivo (1-3).The cytotoxic effects of TNF appear to be cell cycledependent. TNF causes accumulation ofcells in G2 phase and cytolysis in late stages of mitosis (4). This cytolytic effect is enhanced by inhibitors of RNA and protein synthesis (5, 6). Tumor cells sensitive and resistant to TNF-induced cytotoxicity have similar numbers of cell surface receptors. Furthermore, both sensitive and resistant cells internalize and degrade TNF after receptor binding (7). Thus, cell surface receptors appear to be necessary but not sufficient for TNF cytotoxicity (8)(9)(10). The basis for the sensitivity or resistance of transformed cells to TNF remains unknown.Exposure of TNF-sensitive L-929 mouse fibroblasts to TNF results in the development of stable TNF resistance (11). Paradoxically, this TNF-resistant subline produces a TNF-like protein that is cytotoxic to the parent L929 cell line. We recently demonstrated that certain human epithelial tumor cell lines inherently resistant to TNF also produce both TNF mRNA and protein (unpublished work). These findings suggested that production of TNF may be associated with TNF resistance. The present studies investigated this relationship in human breast carcinoma cells sensitive to the cytotoxic effects of TNF in vitro. The results show that TNF treatment induces both TNF expression and resistance to TNF cytotoxicity. METHODSCell Culture. The ZR-75-1 human breast carcinoma cells were obtained from the American Type Culture Collection and grown in RPMI 1640 ...

Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression.

“…Moreover, cells transfected with TNF exhibited enhanced invasive capacity in nude mice, an effect that could be neutralized with antibodies to TNF (21 ). Other groups have shown that certain human tumor cell lines express TNF in vitro and that prolonged exposure to TNF led to the development of resistance to the cytotoxic effects ofTNF and induced constitutive secretion ofTNF by these cells (22).…”

Induced Autocrine Signaling through the Epidermal Growth Factor Receptor Contributes to the Response of Mammary Epithelial Cells to Tumor Necrosis Factor α

“…has been shown to mediate cleavage of both pro-TNF and pro-TGF␣ (40 -42). It has been reported that exposure of mammary cancer cells to TNF treatment stimulates the synthesis and release of soluble TNF and that this is associated with resistance to TNF cytotoxicity (43). The shedding of the p75 TNF receptor (TNFR2), which is also mediated by TNF-converting enzyme, is stimulated by TNF as well (44,45).…”

Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss

“…IL-1 and TNF, the prominent monocyte/macrophage products can be produced by a variety of tumour cell lines (Busson et al, 1987;Beutler & Cerami, 1986;Spriggs et al, 1987;Dinarello, 1988). Elevated circulating levels of TNF and IL-1 have been found in patients suffering chronic infection, parasitic and malignant diseases (Beutler & Cerami, 1986;Dinarello, 1988;Moldawer et al, 1988).…”