A considerable number of patients with cancer suffer from anemia, which has detrimental effects on quality of life and survival. The mechanisms underlying tumor-associated anemia are multifactorial and poorly understood. Aimed at systematically assessing the patho-etiology of tumor-associated anemia in mice, scientists from University of Basel demonstrate reduced red blood cell (RBC) survival rather than altered erythropoiesis is driving the development of anemia. The tumor-induced inflammatory and metabolic remodeling affect RBC integrity and augment splenic phagocyte activity promoting erythrophagocytosis.
Exercise training normalizes these tumor-associated abnormal metabolic profiles and inflammation and thereby ameliorates anemia, in part, by promoting RBC survival. Fatigue was prevented in exercising tumor-bearing mice. Thus, exercise has the unique potential to substantially modulate metabolism and inflammation and thereby counteracts pathological remodeling of these parameters by the tumor microenvironment. Translation of this finding to patients with cancer could have a major impact on quality of life and potentially survival.
To investigate the systemic alterations responsible for the anemia caused by the tumor rather than metastasis, blood loss, or chemotherapy, they used a well-established primary cancer model and injected Lewis lung cancer (LLC) cells subcutaneously into the flank of C57BL/6J mice. LLC tumors induce severe anemia within 3.5 weeks.
Next, they tested whether the removal of RBCs is elevated in TB animals and could contribute to the severe reduction in Hb. Mirroring anemia, RBC elimination was accelerated in TB mice throughout tumor development . Thus, to investigate whether RBCs of TB mice are more stressed and show abnormalities, they assessed phosphatidylserine externalization, a cellular marker of enhanced eryptosis. In TB mice, a fivefold increase in the number of phosphatidylserine-exposing RBCs was found as measured by annexin V binding, implying an inherent predisposition for phagocytosis.
To investigate how the tumor contributes to RBC abnormalities such as phosphatidylserine externalization, systemic factors that could affect the RBC niche were assessed. The cytokines TNFα and IL-1β that are suggested to reduce RBC survival were measured in plasma of Ctrl and TB mice. At this time point, only IL-1β was elevated in plasma of TB mice compared to Ctrl (Fig. 4A). Since the tumor induces major metabolic remodeling that could alter RBC environment, blood lactate levels and plasma levels of free fatty acids and triglycerides were determined and were shown to be substantially elevated. Our data demonstrate that these metabolites and IL-1β promote eryptosis and might thereby contribute to the reduced RBC survival observed in TB mice.
To shed light on the causes of the altered metabolic profile, they assessed body composition of Ctrl and TB mice using EchoMRI. Our findings suggest that the reduced oxidative metabolism and fatty acid oxidation in the liver could contribute to the accumulation of acylcarnitines and triglycerides in plasma of TB mice and thereby affect RBC environment.
As tumor-induced metabolic remodeling leading to substantial elevation of acylcarnitines and triglycerides potentially contributes to the reduced RBC survival and thereby anemia, we investigated whether normalizing the lipid profile by pharmacological or physiological interventions could ameliorate the development of anemia. They found that a targeted lowering of triglyceride levels is not sufficient to improve RBC life span, but that other factors that are affected by exercise are essential for RBC survival and thereby important to slow down the development of anemia.
As exercise does not only normalize the lipid profile in blood but also elicits a variety of systemic effects such as an anti-inflammatory response, they assessed IL-1β levels in the plasma. The significant elevation of IL-1β in TB mice was blunted by the training intervention. Similarly, exercise could also prevent the rise in blood lactate in rest and after exercise, most likely due to a substantial elevation of the lactate importer monocarboxylate transporter 1 (MCT1; encoded by Slc16a1) and lactate dehydrogenase B (Ldhb), converting lactate to pyruvate, in skeletal muscle. Exercise also elicited effects on tumor lactate handling. However, despite the reduction in circulating IL-1β in TB-ex animals, only minimal changes in the expression of a selection of cytokines and chemokines were found in the liver and tumor of TB and TB-ex animals.
As they have observed that IL-1β but not lactate promotes phosphatidylserine externalization on RBCs and thereby could contribute to reduced RBC survival, they next studied whether IL-1β or lactate could directly affect the phagocytic activity of splenocytes. Our data therefore suggest that IL-1β and lactate increase the phagocytic activity of splenocytes to engulf healthy RBCs. Thus, exercise might ameliorate RBC life span by preventing the tumor-induced elevation in IL-1β and lactate level.
Collectively, their data reveal that exercise ameliorates the development of tumor-associated anemia by preserving a favorable environment for RBCs and thereby promoting RBC survival. This results in a substantial improvement in physical performance that can have meaningful implications for patients with cancer suffering from anemia and fatigue.
Sherry
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