CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

Abstract

We have studied the effects of carcinoembryonic antigenrelated 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 Â CEACAM1 endo þ 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 Â CEACAM1 endo þ mice exhibited enhanced tumoral vascularization owing to CEACAM1 þ 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 þ (MMP9 þ ) leukocytes and stromal cells. Vascular instability and alterations in ECM structure were accompanied by a significant increase in pulmonary metastases in CEACAM1-null/WAP-T mice, whereas only occasional metastases were observed in CEACAM1 þ hosts. In CEACAM1 þ hosts, intratumoral vessels did not express CEACAM1, but they were intact, extensively covered with pericytes and framed by a well-organized perivascular ECM. MMP9 þ 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 þ 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.

Soluble Carcinoembryonic Antigen Activates Endothelial Cells and Tumor Angiogenesis

“…Further interaction partners, however, such as the VEGF-interacting proteins neuropilins (39) or other members of the CEACAM-family (40), can currently not be excluded. Thus, the transmembrane signaling molecule CEACAM1 has been shown to affect angiogenesis (41,42) and in NK cells CEA was described to interact with CEACAM1 (22). In experimental settings, we also detected CEACAM1 expression in endothelial cells, but a partial downregulation of CEACAM1 was dispensable for CEA-induced signaling ( Supplementary Fig.…”

Carcinoembryonic Antigen–Related Cell Adhesion Molecule 1 Inhibits MMP-9–Mediated Blood–Brain–Barrier Breakdown in a Mouse Model for Ischemic Stroke

“…Contradicting these results, vascular hyperpermeability in Ceacam1 −/− mice has been reported in endothelium of the lung, in tumors, and after topical application of mustard oil or injection of vascular endothelial growth factor. 36,38 However, we reported earlier that endothelial CEACAM1 is of a lesser vasoprotective relevance during vascular remodeling, because transfer of CEACAM1 + myeloid cells into CEACAM1-deficient hosts could remedy defects in collateral formation and wound healing. On the contrary, depletion of CEACAM1 + CD11b + granulocyte antigen 1 + cells compromised this beneficial effect.…”

“…13,14,16,35,36 We and others described CEACAM1 as a regulator of vascular homeostasis and integrity decreasing basal and acute vascular permeability. [36][37][38] Under hypoxic conditions, CEACAM1 is up-regulated after hypoxic preconditioning in myocardial ischemia on myocardiocytes and endothelia and was suspected to elicit cardioprotective effects. 39 Furthermore, CEACAM1-expressing myeloid cells catalyze collateral formation and improve tissue perfusion after permanent femoral artery occlusion in mouse model for hindlimb ischemia.…”

Expression profiling of angiogenesis-related genes in brain metastases of lung cancer and melanoma

“…In line with the previous observation of mouse models showing a clear difference of angiogenesis morphology in BM of different primaries, our data could classify patients with identical diagnosis in similar clusters based on their angiogenic gene expression signature. Genes with known involvement in angiogenic processes including VEGFA [7], CEACAM1 [30], PECAM1 [31], CXCL12 (also known as SDF1-α) [32], KIT [33], TNF [34], and collagens [35,36] were at least 10 times upregulated in all groups indicating the necessity of those factors for the establishment of the basic characteristics of the angiogenesis process. These genes are mainly involved in proliferation of endothelial cells and activation of growth factors [30,31,33].…”