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L233P mutation in the bovine leukemia virus Tax protein depresses endothelial cell recruitment and tumorigenesis in athymic nude mice

Mori, Hiroshi, Tomiyasu, Takafumi, Nishiyama, Kanako, Matsumoto, Maiko, Osawa, Yoshiaki, Okazaki, Katsunori
Archives of virology 2019 v.164 no.5 pp. 1343-1351
Bovine leukemia virus, amino acids, angiogenesis, blood vessels, carcinogenesis, cattle, cell lines, chemoattractants, chemotaxis, fibroblasts, human umbilical vein endothelial cells, mice, mutation, neoplasm cells, neoplasms, rats, stem cells, viruses
Bovine leukemia virus (BLV) can be divided into two categories based on the amino acid at position 233 in the Tax protein, which probably plays a crucial role in leukemogenesis. We show here that a rat fibroblast cell line stably expressing L233-Tax formed significantly larger tumors than P233-Tax-expressing cells in a murine xenograft study. Although the microvessel density was comparable in both tumors, visible blood vessel invasion was observed only on tumors from L233-Tax-expressing cells. Endothelial cell tube formation assays using human umbilical vein endothelial cells showed no significant difference in angiogenic activity between conditioned medium from L233- and P233-Tax-expressing cells, whereas in vitro chemotaxis assays revealed that only L233-Tax-expressing cells produced a chemoattractant for endothelial cells. Since pathological neovascularization can occur from the recruitment of endothelial progenitor cells, these results suggest that L233-Tax-expressing cells recruit murine endothelial progenitor cells and promote neovascularization to support tumor growth. BLV-infected lymphoma cells may also recruit bovine endothelial progenitor cells to promote neovascularization. The findings of this study are consistent with our previous observation that BLV carrying P233-Tax has a significantly longer incubation period for developing tumors than the virus carrying L233-Tax and provide insight into the function of Tax in leukemogenesis by BLV.