ENHANCED HEPATIC AMINO-ACID-TRANSPORT IN TUMOR-BEARING RATS IS PARTIALLY BLOCKED BY ANTIBODY TO TUMOR-NECROSIS-FACTOR

The liver of the host with cancer exhibits an enhanced requirement for amino acids to support tumor-induced increases in hepatic protein syn thesis and gluconeogenesis. To address the mechanism by which the live r ensures adequate delivery of these substrates for intracellular util ization during cancer, we studied the activities of several amino acid transporters in hepatic plasma membrane vesicles prepared from rats i mplanted with a rapidly growing s.c. fibrosarcoma. The presence of the tumor resulted in a generalized stimulation of concentrative (Na+-dep endent) glucogenic (small neutral) amino acid uptake via System A (3.4 -fold), System N (2.3-fold), and System ASC (1.7-fold), as well as in the facilitative (Na+-independent) uptake of arginine via System y(+) (1.7-fold). Kinetic analysis revealed that the tumor-induced enhanceme nt of transport activity was due to increases in the maximum transport velocity (V-max), whereas transporter substrate affinities (K-m) did not change significantly. Administration of antibody to tumor necrosis factor-alpha to tumor-bearing rats attenuated the increase in hepatic amino acid transport activity by 60-100%, Treatment of nontumor-beari ng control rats with tumor necrosis factor-alpha mAb did not alter bas al transport activity. The results from these studies suggest that the tumor elicits a generalized increase in hepatic plasma membrane amino acid transport activity via a pathway that involves the cytokine tumo r necrosis factor.