Angiotensin II Type 1A Receptor Signaling Facilitates Tumor Metastasis Formation through P-Selectin-Mediated Interaction of Tumor Cells with Platelets and Endothelial Cells
Angiotensin II Type 1A Receptor Signaling Facilitates Tumor Metastasis Formation through P-Selectin-Mediated Interaction of Tumor Cells with Platelets and Endothelial Cells
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DOI：
10.1016/j.ajpath.2012.10.026
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发表时间：
2013-02-01
影响因子：
6
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Amano, Hideki;Ito, Yoshiya;Majima, Masataka
血管紧张素II参与肿瘤生长;然而，确切的机制尚不清楚。血小板也有助于肿瘤生长，并且血管紧张素II 1型受体（AT 1）在血小板表面上表达。我们假设血小板通过All受体信号与肿瘤细胞相互作用促进肿瘤转移。将B16 F1黑色素瘤细胞静脉注射到Agtr 1a基因敲除小鼠（AT 1a（-/-））和野生型同窝小鼠（WT）中; AT 1a（-/-）小鼠的肺集落减少。血管紧张素II诱导WT小鼠血小板P-选择素表达，但不诱导AT 1a（-/-）小鼠血小板P-选择素表达。选择性P-选择素中和抗体减少WT小鼠的肺集落数，但不减少AT 1a（-/-）小鼠的肺集落数。AT 1a（-/-）小鼠转移部位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）受体水平较低。抗VEGF和CXCR 4中和抗体治疗可减少WT小鼠的肺集落数，但在AT 1a（-/-）小鼠中则无此作用。在AT 1a（-/-）小鼠中，表达CXCR 4（+）VEGFR 1（+）细胞的祖细胞从骨髓中的动员及其向肺组织的募集均受到抑制。这些结果表明，AT 1A信号通过P-选择素介导的血小板与肿瘤和内皮细胞的相互作用以及通过AT 1A信号依赖性VEGF和SDF-1的产生在肿瘤转移中起关键作用，其可能参与CXCR 4（+）VEGFR 1（+）细胞的动员。(Am J Pathol 2013，182：553-564; http：//dx·doi·org/10·1016/j·ajpath·2012·10·026）
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 All 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. (Am J Pathol 2013, 182:553-564; http://dx.doi.org/10.1016/j.ajpath.2012.10.026)