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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Antigens, Polyomavirus Transforming / genetics
  • Blood Vessels / metabolism
  • Blood Vessels / pathology
  • Blotting, Western
  • Carcinoembryonic Antigen / genetics
  • Carcinoembryonic Antigen / metabolism
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Leukocytes / metabolism
  • Leukocytes / pathology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Male
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Milk Proteins / genetics
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Promoter Regions, Genetic / genetics
  • Tumor Microenvironment / genetics*


  • Antigens, CD
  • Antigens, Polyomavirus Transforming
  • CD66 antigens
  • Carcinoembryonic Antigen
  • Cell Adhesion Molecules
  • Milk Proteins
  • whey acidic proteins
  • Matrix Metalloproteinase 9