title: CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation.
abstract: 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.
authors.affiliation: Institute of Clinical Chemistry, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Gerstel
authors.forename: F
authors.initials: F
authors.lastname: Wegwitz
authors.forename: K
authors.initials: K
authors.lastname: Jannasch
authors.forename: P
authors.initials: P
authors.lastname: Ludewig
authors.forename: K
authors.initials: K
authors.lastname: Scheike
authors.forename: F
authors.initials: F
authors.lastname: Alves
authors.forename: N
authors.initials: N
authors.lastname: Beauchemin
authors.forename: W
authors.initials: W
authors.lastname: Deppert
authors.forename: C
authors.initials: C
authors.lastname: Wagener
authors.forename: A K
authors.initials: AK
authors.lastname: Horst
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000952:Antigens, Polyomavirus Transforming; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D008894:Milk Proteins; C024471:whey acidic proteins; D020780:Matrix Metalloproteinase 9