Abstract
Cancer-induced anemia (CIA) is a common consequence of neoplasia and has a multifactorial pathophysiology. The immune response and tumor treatment, both intended to primarily target malignant cells, also affect erythropoiesis in the bone marrow. In parallel, immune activation inevitably induces the iron-regulatory hormone hepcidin to direct iron fluxes away from erythroid progenitors and into compartments of the mononuclear phagocyte system. Moreover, many inflammatory mediators inhibit the synthesis of erythropoietin, which is essential for stimulation and differentiation of erythroid progenitor cells to mature cells ready for release into the blood stream. These pathophysiological hallmarks of CIA imply that the bone marrow is not only deprived of iron as nutrient but also of erythropoietin as central growth factor for erythropoiesis. Tumor-associated macrophages (TAM) are present in the tumor microenvironment and display altered immune and iron phenotypes. On the one hand, their functions are altered by adjacent tumor cells so that they promote rather than inhibit the growth of malignant cells. As consequences, TAM may deliver iron to tumor cells and produce reduced amounts of cytotoxic mediators. Furthermore, their ability to stimulate adaptive anti-tumor immune responses is severely compromised. On the other hand, TAM are potential off-targets of therapeutic interventions against CIA. Red blood cell transfusions, intravenous iron preparations, erythropoiesis-stimulating agents and novel treatment options for CIA may interfere with TAM function and thus exhibit secondary effects on the underlying malignancy. In this Hypothesis and Theory, we summarize the pathophysiological hallmarks, clinical implications and treatment strategies for CIA. Focusing on TAM, we speculate on the potential intended and unintended effects that therapeutic options for CIA may have on the innate immune response and, consequently, on the course of the underlying malignancy.
Highlights
Many inflammatory mediators inhibit the synthesis of erythropoietin, which is essential for stimulation and differentiation of erythroid progenitor cells to mature cells ready for release into the blood stream
In this Hypothesis and Theory, we summarize the pathophysiological hallmarks, clinical implications and treatment strategies for Cancer-induced anemia (CIA)
CIA forms a spectrum which can broadly be categorized into three principal etiologies: First, CIA present before the initiation of anti-tumor therapy is typical of advanced disease stages with infiltration and replacement of the bone marrow or when the primary neoplasia results in substantial bleeding such as in colorectal or genitourinary malignancies
Summary
All inner organs depend on a sufficient supply with oxygen from its iron-containing carrier Hb. The direct replacement of RBC and rise in Hb levels promptly ameliorates oxygen supply to vital organs including the central nervous system and myocardium and promotes quality of life and exercise capacity This strategy can worsen the underlying malignancy because oxygen delivery to neoplastic cells will increase, too. EPO may induce apoptosis in myeloma cells [187] This may be relevant for erythroid island macrophages, on which EPOR is highly expressed and may be important for their nursing function and for the delivery of iron to adjacent EP [188]. In breast cancer patients with CIA treatment with ESA may not affect overall survival yet increase the risk of venous thromboembolic events [190, 191]. We need further preclinical and clinical research to characterize the cellular mechanisms and molecular pathways by which ESA affect thrombogenesis and tumor growth in patients with CIA [195]
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