Cancer-related anemia in a rat model: a 2 -macroglobulin from Yoshida sarcoma shortens erythrocyte survival Bhanushali AA, Raghunathan R, Kalraiya RD, Mehta NG. Cancer-related anemia in a rat model: a 2 -macroglobulin from Yoshida sarcoma shortens erythrocyte survival. Eur J Haematol 2002: 68: 42–48. # Blackwell Munksgaard 2002. Abstract: Implantation of Yoshida ascites sarcoma in rats was found to lead to a reduction in the hemoglobin content, the erythrocyte count and the packed cell volume of blood to 30% of normal in 4 d; however, there was no decrease in the mean cell hemoglobin, the mean cell volume and the mean corpuscular hemoglobin concentration, or suppression of erythropoiesis. The red cells from the circulation of tumor-bearing animals, tagged with 51 Cr and injected intravenously in normal rats, showed significantly faster clearance than normal. The erythrocytes contaminating the tumor ascites exhibited extremely short survival, suggesting that one or more secreted tumor product(s) may be responsible for the effect. Incubation of red cells from normal rats in the cell-free ascites fluid, or with an isoform of a 2 -macroglobulin purified from it, also led to reduction in the survival; but the ascites fluid depleted specifically of a 2 -macroglobulin was without any effect. The erythrocytes exhibiting reduced survival showed a proportionate decrease in their cellular deformability. The study identifies a tumor product that is directly responsible for the causation of anemia in the host, and the mechanism by which it does so. Aparna A. Bhanushali, R. Raghunathan, Rajiv D. Kalraiya, Narendra G. Mehta Biochemistry and Molecular Biology Division, Cancer Research Institute, Tata Memorial Centre, Parel, Mumbai, India Key words: cancer-associated anemia; paraneoplastic syndrome; survival of red cells; deformability; a 2 -macroglobulin; oncofetal protein Correspondence: Dr Rajiv D. Kalraiya, Biochemistry and Molecular Biology Division, Cancer Research Institute, Tata Memorial Centre, Parel, Mumbai 400 012, India Tel: +91–22–412 3803 Fax: +91–22–414 6089 e-mail: cri3@soochak.ncst.ernet.in Accepted for publication 3 December 2001 Anemia occurs in nearly all cancer patients (1), but its mechanism is poorly understood. It may be due either to suppression of erythropoiesis or to accelerated destruction of circulating erythrocytes (1–4). The inflammatory cytokines interleukin-1, tumor necrosis factor-a and interferon-c are increased in cancer, and may suppress production of erythropoietin, thereby reducing erythropoiesis (2, 3). They may also impair iron utilization. An ‘anemia-inducing substance’ is believed to be responsible for reduced erythrocyte survival (3). Cancer-associated anemia is a paraneoplastic syndrome (5, 6). Paraneoplastic syndromes arise due to the effects of tumor cells on the structure and function of host cells not in contact with them (6, 7). Tumor products released into the circulation probably bring about these distant effects (8, 9). Earlier we investigated the mechanism by which Yoshida ascites sarcoma in the peritoneal cavity enhances the concanavalin A (Con A)-mediated agglutinability of erythrocytes in the circulation of rats (10). We found that a 170-kDa subunit glyco- protein, secreted by the tumor cells, enters the circulation, binds to erythrocytes (11) and increases their agglutinability by reducing the charge on the cell surface (12). The protein was identified as an oncofetal variant of the rat acute-phase plasma protein, a 2 -macroglobulin (13). During these studies it was repeatedly observed that, following transplantation of the tumor, the yield of erythro- cytes from the blood of the rats decreased pro- gressively. After 4 d the cell number was found to be only about a third of normal. We have used this system to investigate the mechanism by which the tumor causes anemia in the animals. Material and methods Material The sources of reagents and other material used in the study have been described earlier (13, 14) except Eur J Haematol 2002: 68: 42–48 Printed in UK. All rights reserved Copyright # Blackwell Munksgaard 2002 EUROPEAN JOURNAL OF HAEMATOLOGY ISSN 0902-4441 42