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Enhanced Hepatic Amino Acid Transport in Tumor-bearing Rats Is Partially Blocked by Antibody to Tumor Necrosis Factor¹

Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [B. P. B., W. W. S.], and Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610 [Y. I., E. M. C.]

The liver of the host with cancer exhibits an enhanced requirement for amino acids to support tumor-induced increases in hepatic protein synthesis and gluconeogenesis. To address the mechanism by which the liver ensures adequate delivery of these substrates for intracellular utilization during cancer, we studied the activities of several amino acid transporters in hepatic plasma membrane vesicles prepared from rats implanted with a rapidly growing s.c. fibrosarcoma. The presence of the tumor resulted in a generalized stimulation of concentrative (Na⁺-dependent) 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 enhancement 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- to tumor-bearing rats attenuated the increase in hepatic amino acid transport activity by 60–100%. Treatment of nontumor-bearing control rats with tumor necrosis factor- mAb did not alter basal 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 tumor necrosis factor.

¹ Supported by NIH Grant R01 CA57690 (to W. W. S.).

² To whom requests for reprints should be addressed, Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Cox Building, 100 Blossom Street, Boston, MA 02114.

Received 3/ 7/95. Accepted 6/19/95.

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