Deletion of the Endothelial Bmx Tyrosine Kinase Decreases Tumor Angiogenesis and Growth

作者：Holopainen, Tanja; Lopez-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D'Amico, Gabriela; Wiener, Zoltan; Andersson, Leif C.; Pihlajaniemi, Taina; Min, Wang; Alitalo, Kari^*

来源：Cancer Research, 2012, 72(14): 3512-3521.

DOI：10.1158/0008-5472.CAN-11-1070

• ISCHEMIA-MEDIATED ARTERIOGENESIS
• ETK/BMX
• CHROMOSOME
• ACTIVATION
• EXPRESSION
• BMX/ETK
• GENE
• VEGF

Bmx (Bone marrow kinase in chromosome X), 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. Cancer Res; 72(14); 3512-21.

• 出版日期2012-7-15