Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth
Bone marrow-derived EP3-expressing stromal cells enhance tumor-associated angiogenesis and tumor growth
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DOI：
10.1016/j.bbrc.2009.03.094
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发表时间：
2009-05-15
影响因子：
3.1
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
--
作者：
Ogawa, Yasuhumi;Suzuki, Tatsunori;Majima, Masataka
最近的结果表明，骨髓（BM）来源的造血细胞是肿瘤基质的主要成分，在肿瘤生长和血管生成中发挥着至关重要的作用。已知E型前列腺素可调节血管生成。我们研究了表达 E 型前列腺素受体亚型 (EP3) 的 BM 衍生细胞在肿瘤诱导的血管生成和肿瘤生长中的作用。用绿色荧光蛋白 (GFP) 转基因小鼠的 BM 细胞 (BMC) 替换野生型 (WT) BM 表明，基质是通过 BMC 的募集而发育的。通过移植来自 EP3 敲除 (EP3(-/-)) 小鼠的 BMC，通过招募缺乏 EP3 受体的转基因 BMC 来选择性敲除 EP3。在移植了来自 EP3(-/-) 小鼠的 BMC 的 WT 小鼠中，肿瘤生长和肿瘤相关血管生成受到抑制，但在移植有来自 EP1(-/-)、EP2(-/-) 或 EP4(-/-) 小鼠的 BMC 的小鼠中则没有。免疫组织化学分析显示，移植 EP3(-/-) 小鼠 BMC 的小鼠基质中血管内皮生长因子 (VEGF) 表达受到抑制。 EP3 信号传导在 VEGFR-1 和 VEGFR-2 阳性细胞从 BM 募集到基质的过程中发挥了重要作用。这些结果表明，骨髓来源细胞中表达的 EP3 信号传导在肿瘤相关血管生成和肿瘤生长中具有至关重要的作用，其中宿主基质 VEGF 的表达上调以及 VEGFR-1/VEGFR-2 阳性的招募。目前的研究表明，阻断 EP3 信号传导和招募表达 EP3 的基质细胞可能成为治疗实体瘤的新策略。 (C) 2009 年，爱思唯尔公司出版。
Recent results suggest that bone marrow (BM)-derived hematopoietic cells are major components of tumor stroma and play crucial roles in tumor growth and angiogenesis. An E-type prostaglandin is known to regulate angiogenesis. We examined the role of BM-derived cells expressing an E-type prostaglandin receptor subtype (EP3) in tumor-induced angiogenesis and tumor growth. The replacement of wild-type (WT) BM with BM cells (BMCs) from green fluorescent protein (GFP) transgenic mice revealed that the stroma developed via the recruitment of BMCs. Selective knockdown of EP3 by recruitment of genetically modified BMCs lacking EP3 receptors was performed by transplantation of BMCs from EP3 knockout (EP3(-/-)) mice. Tumor growth and tumor-associated angiogenesis were Suppressed in WT mice transplanted with BMCs from EP3(-/-) mice, but not in mice transplanted with BMCs from either EP1(-/-), EP2(-/-), or EP4(-/-) mice. Immunohistochemical analysis revealed that vascular endothelial growth factor (VEGF) expression was suppressed in the stroma of mice transplanted with BMCs from EP3(-/-) mice. EP3 signaling played a significant role in the recruitment of VEGFR-1- and VEGFR-2-positive cells from the BM to the stroma. These results indicate that the EP3 signaling expressed in bone marrow-derived cells has a crucial role in tumor-associated angiogenesis and tumor growth with upregulation of the expression of the host stromal VEGF together with the recruitment of VEGFR-1/VEGFR-2-positive. The present study suggests that the blockade of EP3 signaling and the recruitment of EP3-expressing stromal cells may become a novel Strategy to treat solid tumors. (C) 2009 Published by Elsevier Inc.