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YKL-40, a secreted glycoprotein, promotes tumor angiogenesis

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Abstract

Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, which is a secreted heparin-binding glycoprotein, have been associated with a worse prognosis from various advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. In this study, we showed that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and in HCT-116 colon cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affinity-purified recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the effects of which are similar to the activities observed using MDA-MB-231 and HCT-116 cell-conditioned medium after transfection with YKL-40. Furthermore, YKL-40 was found to induce coordination of membrane-bound receptor syndecan-1 and integrin αvβ3 and to activate an intracellular signaling cascade, including focal adhesion kinase and mitogen-activated protein kinase extracellular signal-related kinase1/2 in endothelial cells. Moreover, blockade of YKL-40 using small-interfering RNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer showed a correlation between YKL-40 expression and blood vessel density. These findings provide novel insights into angiogenic activities and molecular mechanisms of YKL-40 in cancer development.

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Acknowledgements

We thank Drs A Schneyer, S Schneider and S Scully for their critical comments. This work was supported by NCI R01 CA120659 and DOD W81XWH-06-1-0563 (RS), Collaborative Biomedical Research Program, Baystate Medical Center/University of Massachusetts at Amherst (RS, QJC and RBA) and Rays of Hope, Baystate Medical Center (QJC and RS).

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Authors and Affiliations

  1. Pioneer Valley Life Sciences Institute, Springfield, MA, USA

    R Shao, B Bentley & W Yan

  2. Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA, USA

    R Shao, K Hamel & L Petersen

  3. Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA

    R Shao

  4. Department of Pathology, Baystate Medical Center, Springfield, MA, USA

    Q J Cao

  5. Department of Surgery, Baystate Medical Center, Springfield, MA, USA

    R B Arenas

  6. Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA, USA

    C Bigelow

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  1. R Shao
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  2. K Hamel
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Correspondence to R Shao.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Shao, R., Hamel, K., Petersen, L. et al. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene 28, 4456–4468 (2009). https://doi.org/10.1038/onc.2009.292

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