RESUMEN
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.