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Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis.
MedLine Citation:
PMID:  21586615     Owner:  NLM     Status:  Publisher    
Cancer therapy often produces anemia in patients that is treated with erthropoietin (EPO) to stimulate red blood cell 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 co-treatment with specific inhibitors of PI3K or MAP kinase, under conditions where EPO increased Akt and ERK1/2 phosphorylation. Intraperitoneal administration of EPO stimulated peritoneal lymphangiogenesis and systemic treatment of EPO increased infiltration of CD11b+ macrophages in tumor draining lymph nodes. Lastly, 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.
Ae Sin Lee; Duk Hoon Kim; Jung Eun Lee; Yu Jin Jung; Kyung Pyo Kang; Sik Lee; Sung Kwang Park; Jae Yong Kwak; Sang Yong Lee; Suk Tae Lim; Mi Jung Sung; Suk Ran Yun; Won Kim
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-17
Journal Detail:
Title:  Cancer research     Volume:  -     ISSN:  1538-7445     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Internal Medicine, Chonbuk National University Medical School.
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