CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation
CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation
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DOI：
10.1038/onc.2011.146
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发表时间：
2011-10-01
期刊：
影响因子：
8
通讯作者：
Horst, A. K.
中科院分区：
文献类型：
--
作者：
Gerstel, D.;Wegwitz, F.;Horst, A. K.
我们研究了癌胚抗原相关细胞黏附分子1(CEACAM1)对小鼠乳腺导管癌细胞血管生成的影响。我们将带有乳清酸性蛋白启动子驱动的大T抗原表达的转基因小鼠(WAP-T小鼠)与癌基因诱导的乳腺癌与CEA-CAM1缺失的小鼠和Tie2-Ceacam1转基因小鼠(其中Tie2启动子驱动CEACAM1(Endo+)小鼠)杂交，并分析了这些小鼠的肿瘤血管形成、血管生成和血管成熟。利用平板体积计算机断层扫描(FpVCT)和组织学方法，我们发现与对照组相比，WAP-T x CEACAM1(Endo+)小鼠的肿瘤周边CEACAM1(+)血管生成增强，肿瘤血管生成增加。相反，CEACAM1/WAP-T来源的肿瘤血管生成较差，肿瘤血管扩张、渗漏，周细胞覆盖率较低。因此，FpVCT不能显示CEACAM1ull/WAP-T小鼠的肿瘤血管，我们观察到血管周围细胞外基质(ECM)组织不良，并伴有IV型胶原降解的基质金属蛋白酶9(+)(MMP9(+))白细胞和基质细胞的积聚。CEACAM1/WAP-T小鼠的血管不稳定和ECM结构的改变伴随着肺转移的显著增加，而在CEACAM1(+)宿主中仅观察到偶尔的转移。在CEACAM1(+)宿主中，瘤内血管不表达CEACAM1，但它们完整，被广泛的周细胞覆盖，并被组织良好的血管周围ECM所包围。MMP9(+)辅助细胞基本缺失。将原代WAP-T-和CEACAM1/WAP-T肿瘤原位移植到所有三个小鼠系中证实，CEACAM1(+)宿主环境是肿瘤微环境有效的血管生成重塑的先决条件。因此，CEACAM1在肿瘤外围的表达决定了肿瘤的血管表型，而全身CEACAM1的缺失干扰了肿瘤基质的形成和肿瘤内血管的成熟。Oncogene(2011年)30,4275-4288；doi：10.1038/onc.2011.146；2011年5月2日在线发布
We have studied the effects of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on tumor angiogenesis in murine ductal mammary adenocarcinomas. We crossed transgenic mice with whey acidic protein promoter-driven large T-antigen expression (WAP-T mice) with oncogene-induced mammary carcinogenesis with CEA-CAM1null mice, and with Tie2-Ceacam1 transgenics, in which the Tie2 promoter drives endothelial overexpression of CEACAM1 (WAP-T x CEACAM1(endo+) mice), and analyzed tumor vascularization, angiogenesis and vessel maturation in these mice. Using flat-panel volume computed tomography (fpVCT) and histology, we found that WAP-T x CEACAM1(endo+) mice exhibited enhanced tumoral vascularization owing to CEACAM1(+) vessels in the tumor periphery, and increased intratumoral angiogenesis compared with controls. In contrast, vascularization of CEACAM1null/WAP-T-derived tumors was poor, and tumor vessels were dilated, leaky and showed poor pericyte coverage. Consequently, the tumoral vasculature could not be visualized in CEACAM1null/WAP-T mice by fpVCT, and we observed poor organization of the perivascular extracellular matrix (ECM), accompanied by the accumulation of collagen IV-degrading matrix metalloproteinase 9(+) (MMP9(+)) leukocytes and stromal cells. Vascular instability and alterations in ECM structure were accompanied by a significant increase in pulmonary metastases in CEACAM1null/WAP-T mice, whereas only occasional metastases were observed in CEACAM1(+) hosts. In CEACAM1(+) hosts, intratumoral vessels did not express CEACAM1, but they were intact, extensively covered with pericytes and framed by a well-organized perivascular ECM. MMP9(+) accessory cells were largely absent. Orthotopic transplantation of primary WAP-T- and CEACAM1null/WAP-T tumors into all three mouse lines confirmed that a CEACAM1(+) host environment is a prerequisite for productive angiogenic remodeling of the tumor microenvironment. Hence, CEACAM1 expression in the tumor periphery determines the vascular phenotype in a tumor, whereas systemic absence of CEACAM1 interferes with the formation of an organized tumor matrix and intratumoral vessel maturation. Oncogene (2011) 30, 4275-4288; doi: 10.1038/onc.2011.146; published online 2 May 2011