Institute of Clinical Chemistry, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Oncogene. 2011 Oct 13;30(41):4275-88. doi: 10.1038/onc.2011.146. Epub 2011 May 2.
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 CEACAM1null mice, and with Tie2-Ceacam1 transgenics, in which the Tie2 promoter drives endothelial overexpression of CEACAM1 (WAP-T × 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 × 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.
我们研究了癌胚抗原相关细胞黏附分子 1（CEACAM1）对小鼠乳腺导管腺癌肿瘤血管生成的影响。我们将乳清酸性蛋白启动子驱动大 T 抗原表达的转基因小鼠（WAP-T 小鼠）与致癌基因诱导的乳腺肿瘤发生与 CEACAM1null 小鼠，以及与 Tie2-Ceacam1 转基因小鼠（其中 Tie2 启动子驱动内皮细胞 CEACAM1 过表达，WAP-T×CEACAM1（endo+）小鼠）进行杂交，并分析这些小鼠的肿瘤血管生成、血管生成和血管成熟。使用平板容积 CT（fpVCT）和组织学，我们发现 WAP-T×CEACAM1（endo+）小鼠由于肿瘤周边的 CEACAM1（+）血管而表现出增强的肿瘤血管生成，并且与对照组相比，肿瘤内血管生成增加。相比之下，CEACAM1null/WAP-T 衍生肿瘤的血管生成较差，肿瘤血管扩张、渗漏且周细胞覆盖不良。因此，fpVCT 无法在 CEACAM1null/WAP-T 小鼠中可视化肿瘤血管，并且我们观察到血管周围细胞外基质（ECM）的组织不良，伴随着胶原 IV 降解的基质金属蛋白酶 9（MMP9（+））白细胞和基质细胞的积累。血管不稳定和 ECM 结构改变伴随着 CEACAM1null/WAP-T 小鼠肺部转移的显著增加，而在 CEACAM1（+）宿主中仅观察到偶尔的转移。在 CEACAM1（+）宿主中，肿瘤内血管不表达 CEACAM1，但它们完整，被大量周细胞覆盖，并被组织良好的血管周围 ECM 包围。MMP9（+）辅助细胞大部分不存在。将原发性 WAP-T 和 CEACAM1null/WAP-T 肿瘤原位移植到所有三种小鼠系中证实，CEACAM1（+）宿主环境是肿瘤血管生成重塑的必要条件。因此，肿瘤周边的 CEACAM1 表达决定了肿瘤的血管表型，而系统性缺乏 CEACAM1 会干扰有组织的肿瘤基质形成和肿瘤内血管成熟。
