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Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype

Oncogene volume 27, pages 3567–3575 (2008)Cite this article

Abstract

Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-β (TGF-β). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-β signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-β. In 3D spheroid confrontation assays between breast tumor cells and TGF-β-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-β antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.

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Abbreviations

FCS:

fetal calf serum

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

MMP:

matrix metalloproteinase

RT–PCR:

reverse transcription PCR

PAI-1:

plasminogen activator inhibitor-1

TGF:

transforming growth factor

References

  • Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A et al. (2006). Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol 17: 945–951.

    Article  CAS  PubMed  Google Scholar 

  • Beck IM, Muller M, Mentlein R, Sadowski T, Mueller MS, Paus R et al. (2007). Matrix metalloproteinase-19 expression in keratinocytes is repressed by transcription factors Tst-1 and Skn-1a: implications for keratinocyte differentiation. J Invest Dermatol 127: 1107–1114.

    Article  CAS  PubMed  Google Scholar 

  • Bowden ET, Barth M, Thomas D, Glazer RI, Mueller SC . (1999). An invasion-related complex of cortactin, paxillin and PKCμ associates with invadopodia at sites of extracellular matrix degradation. Oncogene 18: 4440–4449.

    Article  CAS  PubMed  Google Scholar 

  • Djonov V, Högger K, Sedlacek R, Laissue J, Draeger A . (2001). MMP-19: cellular localization of a novel metalloproteinase within normal breast tissue and mammary gland tumours. J Pathol 195: 147–155.

    Article  CAS  PubMed  Google Scholar 

  • Fidler IJ . (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3: 1–6.

    Article  Google Scholar 

  • Fonsatti E, Altomonte M, Nicotra MR, Natali PG, Maio M . (2003). Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene 22: 6557–6563.

    Article  CAS  PubMed  Google Scholar 

  • Fonsatti E, Del Vecchio L, Altomonte M, Sigalotti L, Nicotra MR, Coral S et al. (2001). Endoglin: an accessory component of the TGF-beta-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies. J Cell Physiol 188: 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Forstreuter F, Lucius R, Mentlein R . (2002). Vascular endothelial growth factor (VEGF) induces chemotaxis and proliferation of microglial cells. J Neuroimmunol 132: 93–98.

    Article  CAS  PubMed  Google Scholar 

  • Friedl P, Wolf K . (2003). Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3: 362–374.

    Article  CAS  PubMed  Google Scholar 

  • Gougos A, Letarte M . (1990). Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 265: 8361–8364.

    CAS  PubMed  Google Scholar 

  • Held-Feindt J, Lütjohann B, Ungefroren H, Mehdorn HM, Mentlein R . (2003). Interaction of transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) in human glioma cells. J Neurooncol 63: 117–127.

    Article  PubMed  Google Scholar 

  • Kousidou OC, Roussidis AE, Theocharis AD, Karamanos NK . (2004). Expression of MMPs and TIMPs genes in human breast cancer epithelial cells depends on cell culture conditions and is associated with their invasive potential. Anticancer Res 24: 4025–4030.

    CAS  PubMed  Google Scholar 

  • Lastres P, Martin-Perez J, Langa C, Bernabeu C . (1994). Phosphorylation of the human-transforming-growth-factor-beta-binding protein endoglin. Biochem J 301: 765–768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ludwig A, Schulte A, Schnack C, Hundhausen C, Reiss K, Brodway N et al. (2005). Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells. J Neurochem 93: 1293–1303.

    Article  CAS  PubMed  Google Scholar 

  • Mazar AP, Henkin J, Goldfarb RH . (1999). The urokinase plasminogen activator system in cancer: implications for tumor angiogenesis and metastasis. Angiogenesis 3: 15–32.

    Article  CAS  PubMed  Google Scholar 

  • Mentlein R, Forstreuter F, Mehdorn H M, Held-Feindt J . (2004). Functional significance of vascular endothelial growth factor receptor expression on human glioma cells. J Neurooncol 67: 9–18.

    Article  PubMed  Google Scholar 

  • Muñoz-Nájar UM, Neurath KM, Vumbaca F, Claffey KP . (2006). Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene 25: 2379–2392.

    Article  PubMed  Google Scholar 

  • Palmieri D, Bronder JL, Herring JM, Yoneda T, Weil RJ, Stark AM et al. (2007). Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67: 4190–4198.

    Article  CAS  PubMed  Google Scholar 

  • Postiglione L, Di Domenico G, Caraglia M, Marra M, Giuberti G, Del Vecchio L et al. (2005). Differential expression and cytoplasm/membrane distribution of endoglin (CD105) in human tumour cell lines: implications in the modulation of cell proliferation. Int J Oncol 26: 1193–1201.

    CAS  PubMed  Google Scholar 

  • Stark AM, Tscheslog H, Buhl R, Held-Feindt J, Mehdorn HM . (2005). Surgical treatment for brain metastases: prognostic factors and survival in 177 patients. Neurosurg Rev 28: 115–119.

    Article  PubMed  Google Scholar 

  • Stark AM, Anuszkiewicz B, Mentlein R, Yoneda T, Mehdorn HM, Held-Feindt J . (2007). Differential expression of matrix metalloproteinases in brain- and bone-seeking clones of metastatic MDA-MB-231 breast cancer cells. J Neurooncol 81: 39–48.

    Article  CAS  PubMed  Google Scholar 

  • Steeg PS . (2006). Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12: 895–904.

    Article  CAS  PubMed  Google Scholar 

  • Stoppini L, Buchs PA, Muller D . (1991). A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 37: 173–182.

    Article  CAS  PubMed  Google Scholar 

  • Weaver AM . (2006). Invadopodia: specialized cell structures for cancer invasion. Clin Exp Metastasis 3: 97–105.

    Article  Google Scholar 

  • Weil R, Palmieri D, Bronder JL, Stark AM, Steeg PS . (2005). Breast cancer metastasis to the central nervous system. Am J Pathol 167: 913–920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R . (2001). A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res 16: 1486–1495.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants of ‘Universitätsklinikum Schleswig-Holstein Campus Kiel’ (JH-F and RM) and the State of Schleswig-Holstein ‘Molecular Imaging in the North MOIN’ (RM). We thank Martina Burmester, Dagmar Freier, Miriam Lemmer and Ursula Prange for their expert technical assistance.

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Authors and Affiliations

  1. Department of Anatomy, University of Kiel, Kiel, Germany

    D Oxmann, K Hattermann & R Mentlein

  2. Department of Neurosurgery, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany

    J Held-Feindt & A M Stark

  3. Division of Endocrinology and Metabolism, University of Texas Health Science Center, San Antonio, TX, USA

    T Yoneda

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  1. D Oxmann
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  2. J Held-Feindt
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Correspondence to R Mentlein.

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Oxmann, D., Held-Feindt, J., Stark, A. et al. Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype. Oncogene 27, 3567–3575 (2008). https://doi.org/10.1038/sj.onc.1211025

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