title: Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis.
abstract: Adrenomedullin (AM) is a potent lymphangiogenic factor that promotes lymphatic endothelial cell (LEC) proliferation through a pharmacologically tractable G-protein-coupled receptor. Numerous types of human cancers have increased levels of AM; however, the functional consequences of this fact have not been characterized. Therefore, we evaluated whether modulating adrenomedullin (Adm) gene dosage within tumor cells affects lymphangiogenesis. Murine Lewis lung carcinoma (LLC) cells that overexpress or underexpress Adm were injected subcutaneously into C57BL/6 mice, and tumors were evaluated for growth and vascularization. A dosage range from ∼10 to 200% of wild-type Adm expression did not affect LLC proliferation in vitro or in vivo, nor did it affect angiogenesis. Notably, the dosage of Adm markedly and significantly influenced tumor lymphangiogenesis. Reduced Adm expression in tumors decreased the proliferation of LECs and the number of lymphatic vessels, while elevated tumor Adm expression led to enlarged lymphatic vessels. Moreover, overexpression of Adm in tumors induced sentinel lymph node lymphangiogenesis and led to an increased incidence of Ki67-positive foci within the lung. These data show that tumor-secreted AM is a critical factor for driving both tumor and lymph node lymphangiogenesis. Thus, pharmacological targeting of AM signaling may provide a new avenue for inhibition of tumor lymphangiogenesis.
authors.affiliation: Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
authors.forename: Natalie O
authors.initials: NO
authors.lastname: Karpinich
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Kechele
authors.forename: Scott T
authors.initials: ST
authors.lastname: Espenschied
authors.forename: Helen H
authors.initials: HH
authors.lastname: Willcockson
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fedoriw
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Caron
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D042583:Lymphangiogenesis / Q000235:genetics*; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D053607:Adrenomedullin