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 doseand 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 þ macrophages in tumor-draining lymph nodes. Finally, EPO increased VEGF-C expression in lymph node-derived CD11b þ 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. Cancer Res; 71(13); 4506-17. Ó2011 AACR.

Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy

“…Nearly all intrinsic renal cells have a basal level of autophagy (14,30,31). However, the manner in which the autophagy process changes in these cells in DN remains unclear.…”

SIRT2 Regulates LPS-Induced Renal Tubular CXCL2 and CCL2 Expression

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Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal

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