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

Oncogene volume 30, pages 4275–4288 (2011)Cite this article

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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 × CEACAM1endo+ 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 × CEACAM1endo+ 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.

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Abbreviations

CEACAM1:

carcinoembryonic antigen-related cell adhesion molecule-1

collI:

collagen I

collIV:

collagen IV

collVI:

collagen VI

DCIS:

ductal carcinoma in situ

ECM:

extracellular matrix

eNOS:

endothelial nitric oxide synthetase

fpVCT:

flat-panel volume computed tomography

MMP9, matrix metalloproteinase 9|WAP-T:

whey-acidic protein promoter-driven large T-antigen-driven expression

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Acknowledgements

This work was supported by the German Research Foundation, Priority Program SPP1190: the tumor–vessel interface to WD, CW, AKH and FA.

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Author notes

  1. D Gerstel and F Wegwitz: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Clinical Chemistry, Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    D Gerstel, P Ludewig, K Scheike, C Wagener & A K Horst

  2. Department of Tumor Virology, Heinrich-Pette-Institute, Hamburg, Germany

    F Wegwitz & W Deppert

  3. Department of Hematology and Oncology, Georg-August-University, University Medical Center Göttingen, Göttingen, Germany

    K Jannasch & F Alves

  4. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    N Beauchemin

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  1. D Gerstel
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Correspondence to A K Horst.

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Gerstel, D., Wegwitz, F., Jannasch, K. et al. CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation. Oncogene 30, 4275–4288 (2011). https://doi.org/10.1038/onc.2011.146

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