title: Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis.
abstract: Cancer therapy often produces anemia, which is treated with erthropoietin (EPO) to stimulate erythrocyte production. However, concerns have recently arisen that EPO treatment may promote later tumor metastasis and mortality. The mechanisms underlying such effects are unknown, but it is clear that EPO has pleiotropic effects in cell types other than hematopoietic cells. In this study, we investigated how EPO affects lymphangiogenesis and lymph node tumor metastasis in mouse models of breast cancer and melanoma. In these models, EPO increased lymph node lymphangiogenesis and lymph node tumor metastasis in a manner associated with increased migration, capillary-like tube formation, and dose- and time-dependent proliferation of human lymphatic endothelial cells. EPO increased sprouting of these cells in a thoracic duct lymphatic ring assay. These effects were abrogated by cotreatment with specific inhibitors of phosphoinositide 3-kinase or mitogen-activated protein kinase, under conditions in which EPO increased Akt and extracellular signal-regulated kinase 1/2 phosphorylation. Intraperitoneal administration of EPO stimulated peritoneal lymphangiogenesis, and systemic treatment of EPO increased infiltration of CD11b(+) macrophages in tumor-draining lymph nodes. Finally, EPO increased VEGF-C expression in lymph node-derived CD11b(+) macrophages as well as in bone marrow-derived macrophages in a dose- and time-dependent manner. Our results establish that EPO exerts a powerful lymphangiogenic function and can drive both lymph node lymphangiogenesis and nodal metastasis in tumor-bearing animals.
authors.affiliation: Departments of Internal Medicine, Diagnostic Radiology, and Nuclear Medicine, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, South Korea.
authors.forename: Ae Sin
authors.initials: AS
authors.lastname: Lee
authors.forename: Duk Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Kwak
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Suk Tae
authors.initials: ST
authors.lastname: Lim
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Sung
authors.forename: Suk Ran
authors.initials: SR
authors.lastname: Yoon
authors.forename: Won
authors.initials: W
authors.lastname: Kim
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D008198:Lymph Nodes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis
chemical_list: D039481:CD11b Antigen; D042582:Vascular Endothelial Growth Factor C; D004921:Erythropoietin; D051058:Oncogene Protein v-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3