Altered macrophage activity and tumor necrosis factor: Tumor necrosis and host cachexia

Abstract

Tumor necrosis factor (TNF) may be a mediator of cancer cachexia. This study evaluates the activity of macrophages from non-tumor-bearing (NTB) and tumor-bearing (TB) rats by measuring TNF production in response to endotoxin (LPS), both in vitro and in vivo, and correlates macrophage activity with tumor burden and parameters of host cachexia. Isolated macrophages from rats with small tumors, normal food intake, and weight gain secreted more TNF in response to 10 μg/ml LPS than macrophages from control NTB rats and behaved similar to activated macrophages from rats previously treated with thioglycollate. Heightened macrophage activity (increased production of TNF in response to LPS) in TB rats increased further as tumor burden increased ( r = 0.889, P < 0.001). Tumor resection reversed the heightened macrophage activity as LPS-induced levels of TNF secreted by macrophages from resected TB rats were not different from those of sham-operated NTB control rats. TB rats had serum levels of TNF activity following an iv bolus of 10 mg/kg LPS greater than those of NTB rats ( P < 0.05). In addition, peak serum TNF activity levels following iv LPS increased directly as tumor burden increased ( r = 0.91, P < 0.001). Supernatants from tissue cultures of the tumor (MCA sarcoma) failed to have any detectable TNF activity. However, large tumors in vivo had increased amounts of necrosis (78 ± 8%), increased numbers of infiltrating macrophages, and increased levels of TNF (480 ± 68 U/ml) compared to small tumors. Rats with large tumors also had detectable TNF activity in serum (28 ± 13 U/ml), as well as reduced food intake and body weight loss, while STB animals did not. The results suggest that host macrophages are activated in response to a malignant tumor prior to clinical signs of cachexia. As tumor progresses macrophage activity further increases and elevated levels of TNF production are associated with both tumor necrosis and host cachexia.