Angiotensin II is involved in tumor growth; however, the precise mechanism is not known. Platelets also contribute to tumor growth, and angiotensin II type 1 receptor (AT1) is expressed on the platelet surface. We hypothesized that interaction of platelets with tumor cells through AT1 receptor signaling promotes tumor metastasis. B16F1 melanoma cells were intravenously injected into Agtr1a knockout mice (AT1a(-/-)) and wild-type littermates (WT); the AT1a(-/-) mice exhibited a reduction in lung colonies. Angiotensin II induced expression of P-selectin on platelets in WT but not in AT1a(-/-) mice. A selective P-selectin neutralizing antibody decreased lung colony numbers in WT but not in AT1a(-/-) mice. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) receptor in platelets at metastatic locus were lower in AT1a(-/-) mice. Treatment of neutralizing antibodies against VEGF and CXCR4 decreased lung colony numbers in WT but not in AT1a(-/-) mice. In AT1a(-/-) mice, and both mobilization of progenitor cells expressing CXCR4(+)VEGFR1(+) cells from bone marrow and their recruitment to lung tissues were suppressed. These results suggest that AT1A signaling plays a critical role in tumor metastasis through P-selectin-mediated interactions of platelets with tumor and endothelial cells and through the AT1A signaling-dependent production of VEGF and SDF-1, which may be involved in mobilization of CXCR4(+)VEGFR1(+) cells.

译文

:血管紧张素II参与肿瘤生长;但是,确切的机制尚不清楚。血小板也有助于肿瘤的生长,并且血管紧张素II 1型受体(AT1)在血小板表面表达。我们假设血小板与肿瘤细胞通过AT1受体信号传导的相互作用促进了肿瘤转移。将B16F1黑色素瘤细胞静脉内注射到Agtr1a基因敲除小鼠(AT1a(-/-))和野生型同窝小鼠(WT)中; AT1a(-/-)小鼠肺集落减少。血管紧张素II诱导WT中血小板上P-选择蛋白的表达,而AT1a(-/-)小鼠中没有。选择性P-选择素中和抗体可降低WT小鼠的肺菌落数量,但不会降低AT1a(-/-)小鼠的肺菌落数量。在AT1a(-/-)小鼠中,转移部位的血小板中血管内皮生长因子(VEGF)和基质细胞衍生因子1(SDF-1)受体的水平较低。抗VEGF和CXCR4的中和抗体的治疗可降低WT小鼠的肺菌落数量,但不会降低AT1a(-/-)小鼠的肺菌落数量。在AT1a(-/-)小鼠中,表达CXCR4()VEGFR1()的祖细胞从骨髓动员到肺组织的动员都受到抑制。这些结果表明,AT1A信号传导通过P-选择蛋白介导的血小板与肿瘤和内皮细胞的相互作用以及通过AT1A信号依赖的VEGF和SDF-1的产生在肿瘤转移中起关键作用,这可能与CXCR4的动员有关。 ()VEGFR1()细胞。

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