C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis.
C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis.
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发表时间：
2003-08
期刊：
影响因子：
11.2
通讯作者：
A. Myoui;R. Nishimura;Paul J. Williams;T. Hiraga;D. Tamura;T. Michigami;G. Mundy;T. Yoneda
中科院分区：
文献类型：
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作者：
A. Myoui;R. Nishimura;Paul J. Williams;T. Hiraga;D. Tamura;T. Michigami;G. Mundy;T. Yoneda
原癌基因c-src与乳腺癌的发生有关。然而，c-src与远处转移的关系尚不清楚。此外，c-src在乳腺癌器官优先转移中的作用尚不清楚。由于乳腺癌有很强的倾向于转移到骨，我们研究了c-src在骨转移中的作用，使用动物模型，其中MDA-231人乳腺癌细胞接种到左心室优先发展溶骨性骨转移在雌性裸鼠。与亲本细胞相比，具有增加的骨转移能力的MDA-231的克隆表现出升高的c-src酪氨酸激酶（TK）活性。与MDA-231 EV或MDAsrcWT相比，MDAsrc 527细胞导致溶骨性骨转移灶的大小显著增加，破骨细胞和有丝分裂癌细胞的数量增加。相比之下，MDAsrc 295细胞导致骨转移受损。值得注意的是，与接种MDA-231 EV细胞的小鼠相比，经尾静脉接种MDAsrc 295细胞的小鼠肺转移减少，生存期延长，表明c-src TK不太可能在骨转移中发挥特异性作用。MDAsrc 527促进了体外和体内的生长以及甲状旁腺相关蛋白（乳腺癌溶骨性骨转移发病机制中的关键细胞因子）的产生，而MDAsrc 295则减少。这些结果表明，c-src TK与乳腺癌转移到骨的能力，通过调节细胞生长和甲状旁腺相关蛋白的生产。我们的研究结果以及c-src是破骨细胞（溶骨性骨转移的核心参与者）骨吸收的重要分子这一事实，支持c-src TK是设计新型治疗干预措施的潜在靶分子的观点，特别是对于乳腺癌骨转移。
The proto-oncogene, c-src, has been implicated in the tumorigenesis in breast cancer. However, the relationship of c-src with distant metastasis is unclear. Moreover, the role of c-src in organ-preferential metastasis of breast cancer is unknown. Because breast cancer has a strong predilection for metastasizing to bone, we examined the role of c-src in bone metastases using an animal model in which inoculation of the MDA-231 human breast cancer cells into the left cardiac ventricle preferentially developed osteolytic bone metastases in female nude mice. A clone of the MDA-231 with the increased capacity of bone metastasis exhibited elevated c-src tyrosine kinase (TK) activity compared with parental cells. MDAsrc527 cells caused significantly increased size of the osteolytic bone metastases with increased number of osteoclasts and mitotic cancer cells compared with MDA-231EV or MDAsrcWT. In contrast, MDAsrc295 cells caused impaired metastases to bone. Of note, mice inoculated with MDAsrc295 cells via tail vein developed reduced lung metastases and prolonged survival compared with mice with MDA-231EV cells, suggesting that c-src TK is unlikely to play a specific role in bone metastases. The growth in vitro and in vivo and production of parathyroid hormone-related protein, a key cytokine in the pathogenesis of osteolytic bone metastases in breast cancer, were promoted in MDAsrc527 and diminished in MDAsrc295. These results suggest that c-src TK is associated with the capacity of breast cancer to metastasize to bone through regulating cell growth and parathyroid hormone-related protein production. Our results together with the fact that c-src is an essential molecule for bone resorption by osteoclasts, which are central players in osteolytic bone metastases, support the notion that c-src TK is a potential target molecule for designing novel therapeutic interventions, especially for bone metastases in breast cancer.