The hemolytic component of cancer anemia: effects of osmotic and metabolic stress on the erythrocytes of rats bearing multifocal inoculations of the Walker 256 tumor

Abstract

Cancer anemia is classified as an anemia of chronic diseases, although it is sometimes the first symptom of cancer. Cancer anemia includes a hemolytic component, important in the terminal stage when even transfused cells are rapidly destroyed. The presence of a chronic component and the terminal complications of the illness limit studies of the hemolytic component. A multifocal model of tumor growth was used here to simulate the terminal metastatic dissemination stage (several simultaneous inoculations of Walker 256 cells). The hemolytic component of anemia began 3-4 days after inoculation in 100% of the rats and progressed rapidly thereafter: Hb levels dropped from 14.9 ± 0.02 to 8.7 ± 0.06 from days 7 to 11 (~5 times the physiologically normal rate in rats) in the absence of bleeding. The development of anemia was correlated (r 2 = 0.86) with the development of other systemic effects such as anorexia. There was a significant decrease in the osmotic fragility of circulating erythrocytes: the NaCl concentration causing 50% lysis was reduced from 4.52 ± 0.06 to 4.10 ± 0.01 (P<0.01) on day 7, indicating a reduction in erythrocyte volume. However, with mild metabolic stress (4-h incubation at 37 o C), the erythrocytes showed a greater increase in osmotic fragility than the controls, suggesting marked alteration of erythrocyte homeostasis. These effects may be due to primary plasma membrane alterations (transport and/or permeability) and/or may be secondary to metabolic changes. This multifocal model is adequate for studying the hemolytic component of cancer anemia since it is rapid, highly reproducible and causes minimal animal suffering.

Modelo experimental do carcinossarcoma 256 de Walker em bexiga de ratos

“…Desde então ele vem sendo mantido em diversos laboratórios no mundo inteiro como um recurso valioso no auxílio à pesquisa básica em oncologia. São numerosos os trabalhos sobre o tumor de Walker, seu comportamento biológico, suas alterações bioquímicas e efeitos metabólicos 2,3 , e sua utilização em modelos experimentais no pulmão 4 , estômago 5 , rim 6 , cavidade oral 7 e fígado 8 . Nosso objetivo é o estudo de um modelo experimental para Walker em bexiga.…”

Changes in red blood cell osmotic fragility induced by total plasma and plasma fractions obtained from rats bearing progressive and regressive variants of the Walker 256 tumor

“…We had previously reported that in intact rats bearing the progressive A variant of the W256 cancer the rapid terminal destruction of RBC was associated with a decrease or no change in RBC osmotic fragility (8). In contrast, rats inoculated with the AR tumor variant systematically developed a temporary anemia associated with a marked increase in RBC osmotic fragility at the beginning of tumor regression.…”

“…Macro-and/or microscopic alterations of bone marrow have long been ruled out as factors involved in cancer anemia in humans (23) and rats (4). In the terminal stage of cancer, RBC are rapidly destroyed, even transfused ones, at a rate of up to five times the physiological rate, without an increase in RBC osmotic fragility (8). This terminal anemia is not temporary but continues to increase with a very high correlation (r 2 = 0.86) with the other severe systemic effects involved in terminal general failure (8).…”

“…In the terminal stage of cancer, RBC are rapidly destroyed, even transfused ones, at a rate of up to five times the physiological rate, without an increase in RBC osmotic fragility (8). This terminal anemia is not temporary but continues to increase with a very high correlation (r 2 = 0.86) with the other severe systemic effects involved in terminal general failure (8). Development of hemolytic anemia associated with increased RBC osmotic fragility is not frequent in cancer and has been associated with a) autoimmune antibodies, b) microangiopathic alterations, and c) chemotherapy (24,25).…”

Tumor growth characteristics of the Walker 256 AR tumor, a regressive variant of the rat Walker 256 A tumor

“…Two variants of this tumor have been previously reported as W256 A and B (Guaitani et al, 1982), which are currently known by their growth capacity and lethality after subcutaneous (sc) injection in Wistar rats. This lethality is associated to the severe homeostatic disturbances induced by the W256 tumor, which includes anorexia (Rettori et al, 1995;Guaitani et al, 1982), anemia (Zucker et al, 1977;Vido et al, 2000), thymus atrophy (Rettori et al, 1995) and hydro electrolyte disturbances with glomerular filtration and tubular function alterations (Toal et al, 1960;Morrison, 1971;Rettori et al, 1995;Guimarães et al, 1999;Rettori et al, 2000). Nevertheless, spontaneous W256 tumor regression can occur.…”