IDENTIFICATION OF TISSUE SITES FOR INCREASED ALBUMIN DEGRADATION IN SARCOMA-BEARING MICE

Plasma albumin concentration declines in both experimental and clinical cancer. Previous investigations have demonstrated that this is partly explained by increased breakdown of albumin. The present study has identified the tissue sites for increased albumin degradation in a nonmetastasizing sarcoma mouse (C57/BL6J) model. Results have been compared to non-tumor-bearing animals either freely fed or food restricted (pair-weighed) so that their body composition was similar to tumor-bearing animals. Tumor-bearing mice had increased albumin degradation (0.13 ± 0.02 mg/hr/g bw) compared to both freely fed (0.09 ± 0.007) and pair-weighed control animals (0.05 ± 0.008). Radioactivity from circulating [3H]raffine aldehyde labeled albumin appeared with maximum peak values in lysosomes isolated from both tumor and nontumor tissues at 48 hr following iv injection. The intralysosomal accumulation of radioactivity was two- to threefold higher in tumor tissue compared to liver tissue, although the specific activity of protease(s) for albumin degradation measured in vitro was not higher in tumor tissue (30.4 ± 3.6 mg/hr/g tissue) compared to normal liver tissue (36.9 ± 1.7). Accounting for the entire tumor the proteolytic capacity for albumin breakdown was however much larger in the tumor (161.6 ± 32.6 mg/organ) compared to both normal liver (37.5 ± 2.3) and tumor-host liver (56.4 ± 2.8). Pepstatin inhibited 78 ± 6% of the proteolytic activity in the tumor measured by 125I-labeled undernatured mouse albumin as the substrate. Leupeptin inhibited 49 ± 6%. There was a significantly decreased breakdown of albumin in both skeletal muscles and the gastrointestinal tract from tumor-bearing animals. This decrease was probably explained by the adaptation to anorexia and malnutrition, since the same phenomenon was seen in pair-weighed controls. The results demonstrate that hypoalbuminemia in experimental cancer is in part explained by increased albumin breakdown, which takes place within the tumor lysosomal system. Increased albumin breakdown is primarily due to the expanding tumor compartment and perhaps also to an increased tumor lysosomal uptake of circulating albumin compared to normal tissues. © 1991.