title: Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.
abstract: Bmx, [corrected] also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth.
authors.affiliation: Molecular/Cancer Biology Program, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Research Programs Unit, Biomedicum Helsinki, Finland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.forename: Vanessa
authors.initials: V
authors.lastname: López-Alpuche
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
authors.forename: Dennis
authors.initials: D
authors.lastname: Jones
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Denis
authors.initials: D
authors.lastname: Tvorogov
authors.forename: Gabriela
authors.initials: G
authors.lastname: D'Amico
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Wiener
authors.forename: Leif C
authors.initials: LC
authors.lastname: Andersson
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D005260:Female; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases