Rhu-Epo down-regulates pro-tumorigenic activity of cancer-associated fibroblasts in multiple myeloma
- 136 Downloads
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.
KeywordsAngiogenesis Erythropoietin Cancer-associated fibroblasts Monoclonal gammopathy of undetermined significance Multiple myeloma
This work was supported by the Grant L’eritropoietina media l’attività pro-angiogenica dei fibroblasti isolati dal midollo osseo di pazienti affetti da mieloma multiplo from «Ricerca corrente 2017- IRCCS Istituto Tumori «Giovanni Paolo II», Bari, Italy» to Domenico Ribatti.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest and that they do not have a financial relationship with the organization that sponsored the research.
- 12.Lamanuzzi A, Saltarella I, Ferrucci A, Ria R, Ruggieri S, Racanelli V, Rao L, Annese T, Nico B, Vacca A, Ribatti D (2016) Role of erythropoietin in the angiogenic activity of bone marrow endothelial cells of MGUS and multiple myeloma patients. Oncotarget 7:14510–14521CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Su J, Li Z, Cui S, Ji L, Geng H, Chai K, Ma X, Bai Z, Yang Y, Wuren T, Ge RL, Rondina MT (2015) The local HIF-2α/EPO pathway in the bone marrow is associated with excessive erythrocytosis and the increase in bone marrow microvessel density in chronic mountain sickness. High Altitude Med Biol 16:318–330CrossRefGoogle Scholar
- 16.Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (2000) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59:5002–5011Google Scholar
- 17.Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348CrossRefPubMedGoogle Scholar