Targeting Stress Erythropoiesis Pathways in Cancer

Abstract

Cancer-related anemia (CRA) is a common multifactorial disorder that adversely affects the quality of life and overall prognosis in patients with cancer. Safety concerns associated with the most common CRA treatment options, including intravenous iron therapy and erythropoietic-stimulating agents, have often resulted in no or suboptimal anemia management for many cancer patients. Chronic anemia creates a vital need to restore normal erythropoietic output and therefore activates the mechanisms of stress erythropoiesis (SE). A growing body of evidence demonstrates that bone morphogenetic protein 4 (BMP4) signaling, along with glucocorticoids, erythropoietin, stem cell factor, growth differentiation factor 15 (GDF15) and hypoxia-inducible factors, plays a pivotal role in SE. Nevertheless, a chronic state of SE may lead to ineffective erythropoiesis, characterized by the expansion of erythroid progenitor pool, that largely fails to differentiate and give rise to mature red blood cells, further aggravating CRA. In this review, we summarize the current state of knowledge on the emerging roles for stress erythroid progenitors and activated SE pathways in tumor progression, highlighting the urgent need to suppress ineffective erythropoiesis in cancer patients and develop an optimal treatment strategy as well as a personalized approach to CRA management.

Keywords: anemia; cancer; erythroid progenitors; erythropoietin; stress erythropoiesis.

FIGURE 1

Erythropoiesis in cancer. Tumor-induced inflammatory cytokines suppress erythropoiesis in the bone marrow either directly or via macrophage activation, resulting in decreased red blood cells production. Anemia activates stress erythropoiesis pathways at extramedullary sites to provide rapid expansion of nucleated erythroid cells. Both activated stress erythropoiesis pathways and nucleated erythroid cells may promote tumor progression. Abbreviations: EPO, erythropoietin, ROS, reactive oxygen species; BMP4, bone morphogenic protein 4; SCF, stem cell factor; GDF15, growth differentiation factor 15. Created with BioRender.com.

FIGURE 2

Schematic representation of the tumor-promoting activity of nucleated erythroid cells. Nucleated erythroid cells promote tumor angiogenesis (vascular growth) through the secretion of vascular endothelial growth factor (VEGF). By producing reactive oxygen species (ROS), transforming growth factor (TGF-β), interleukin 10 (IL-10), and expressing programmed death-ligand 1 (PD-L1), nucleated erythroid cells decrease anti-tumor immune response (T-cell suppression). Released ROS also contribute to antiangiogenic drug resistance via regulating lipid metabolism (through AMP-activated protein kinase (AMPK)-acetyl CoA carboxylase (ACC)-carnitine palmitoyl transferase 1 (CPT1A) pathway) and induce cancer-associated adipocytes to feed tumor with free fatty acids (FFA). By releasing a neurotrophic peptide—artemin, nucleated erythroid cells promote tumor proliferation (MAPK signaling pathway), invasion (stimulate expression of TRIOBP and integrin beta5 through PI-3K and p38 signaling pathway), migration (Akt/PKB signaling pathway), and survival (anti-apoptotic effect through ERK activation and phosphorylation of caspase-9). Abbreviations: MAPK, mitogen activated protein kinase; TRIOBP, TRIO and F-actin Binding Protein; PI-3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; ERK, extracellular signal-regulated kinase. Created with BioRender.com.