Rhu-Epo down-regulates pro-tumorigenic activity of cancer-associated fibroblasts in multiple myeloma

Abstract

We have previously demonstrated that recombinant human erythropoietin (rHuEpo) is involved in the regulation of the angiogenic response in multiple myeloma (MM) through a direct effect on macrophages and endothelial cells isolated from the bone marrow of patients with MM. The aim of the present study was designed to determine the effects of rHuEpo on cancer-associated fibroblasts (CAFs) from monoclonal gammopathy of undetermined significance (MGUS) and MM patients by means of in vitro and in vivo assays. rHuEpo treatment reduces the expression of mRNA levels of fibroblast activation markers, namely alpha smooth actin (αSMA) and fibroblast activation protein (FAP) in MGUS and MM CAFs, and of pro-inflammatory and pro-angiogenic cytokines, including interleukin (IL)-6 and IL-8, vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF) in MM CAFs. Moreover, rHuEpo inhibits the proliferative activity of MM CAFs and increased the apoptosis of MGUS and MM CAFs. Overall, these data suggest that rHu-Epo down-regulates CAFs pro-tumorigenic activity. Moreover, these results are not suggestive for a pro-angiogenic activity of rHuEpo on CAFs. In fact, rHuEpo pre-treatment induces a low angiogenic response in vivo in the chorioallantoic membrane (CAM) assay of MGUS and MM CAFs conditioned medium, not comparable to that of a well-known angiogenic cytokine, VEGF-A, tested in the same assay.

Signaling Through the Erythropoietin Receptor Affects Angiogenesis in Retinovascular Disease

“…28 In certain cancers, such as multiple myeloma, recombinant EPO was shown to downregulate angiogenic factors. 35 Part of the effect in this study may be due to the uniqueness of the animal model affecting EPOR signaling throughout the entire mouse that may have compensatory signaling effects in other cell types that then affect signaling within the vasculature of the retina. Future studies to consider the effects of EPOR signaling specifically in retinal endothelial cells will also be considered as will the identification of potential angiogenic inhibitors.…”

Erythrotropin for Treating Anemia in Multiple Myeloma: Response to Treatment and Survival

“…Recombinant human erythropoietin suppresses tumor growth and induces tumor regression through a variety of mechanisms, accelerates treatment response, and lengthens survival. [7][8][9][10][11][12][13][14][15][16][17][18][19][20]31,32] It mainly affects the immune system and even in uences the proliferation of myeloma. [7][8][9][10][11][12][13] The erythropoietin receptor is expressed on the surface of myeloma cell lines, and activating receptor signaling reduced the viability of myeloma cell in vitro.…”

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

“…The state-of-the-art knowledge of the crucial mechanisms promoting angiogenesis and mediating immunosuppression during DLBCL development, progression [ 77 , 78 ], and sensitivity to drugs [ 26 , 79 ] needs further in-depth analysis. Solid and hematological neoplasms propagate and progress through several vicious cycles, feeding into the surrounding tumoral milieu [ 80 , 81 , 82 , 83 ], and emergent knowledge pinpoints angiogenesis and immunosuppression as simultaneous processes in response to this reciprocal loop [ 84 , 85 ] and to a plethora of paracrine and exogenous stimuli [ 86 , 87 , 88 ]. Lymphoproliferative disorders [ 89 , 90 ] and DLBCL [ 91 ] are no exception.…”