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Transgenic expression of human cathepsin B promotes progression and metastasis of polyoma-middle-T-induced breast cancer in mice

Oncogene volume 30, pages 54–64 (2011)Cite this article

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Abstract

Elevated expression of the cysteine protease cathepsin B (CTSB) has been correlated with a poor prognosis for cancer patients. In order to model high CTSB expression in mammary cancer, transgenic mice expressing human CTSB were crossed with transgenic polyoma virus middle T oncogene breast cancer mice (mouse mammary tumor virus-PymT), resulting in a 20-fold increase in cathepsin B activity in the tumors of double-transgenic animals. CTSB expression did not affect tumor onset, but CTSB transgenic mice showed accelerated tumor growth with significant increase in weight for end-stage tumors, as well as an overall worsening in their histopathological grades. Notably, the lung metastases in the CTSB transgenic animals were found to be both significantly larger and to occur at a significantly higher frequency. Ex vivo analysis of primary PymT tumor cells revealed no significant effects from elevated CTSB levels on tumor cell characteristics, that is, the formation of tumor cell colonies and the sprouting of invasive strands from PymT cell spheroids. However, tumors from CTSB-overexpressing mice showed increased numbers of tumor-associated B cells and mast cells. In addition, more CD31+ endothelial cells were detected in these tumors, correlating with higher levels of vascular endothelial growth factor (VEGF) being present in the tumor and serum. We conclude that elevated proteolytic CTSB activity facilitates progression and metastasis of PymT-induced mammary carcinomas, and is associated with increased immune cell infiltration, enhanced VEGF levels and the promotion of tumor angiogenesis.

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Acknowledgements

The Tg(CTSB)+/0 mice were kindly provided by Dr L Pennacchio, Genomics Division, Lawrence Berkeley Laboratory. We thank Anne Schwinde, Ulrike Reif, Lisa Christiansson and Anna Heisswolf for excellent technical assistance. This work was supported by European Commission FP7 Grant 201279 (Microenvimet), Deutsche Forschungsgemeinschaft SFB 850 Project B7, and by the Excellence Initiative of the German Federal and State Governments (EXC 294 and GSC-4, Spemann Graduate School).

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Authors and Affiliations

  1. Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany

    L Sevenich, F Werner, U Schurigt, C Sieber, S Müller, C Peters & T Reinheckel

  2. Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany

    L Sevenich & F Werner

  3. Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University, Freiburg, Germany

    F Werner

  4. Institute of Pathology, Friedrich-Schiller-University Jena, Jena, Germany

    M Gajda

  5. Department of Hematology and Oncology, Core Facility, University Medical Center, Freiburg, Germany

    M Follo

  6. Ludwig-Heilmeyer Comprehensive Cancer Center and Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University, Freiburg, Germany

    C Peters & T Reinheckel

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  1. L Sevenich
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Sevenich, L., Werner, F., Gajda, M. et al. Transgenic expression of human cathepsin B promotes progression and metastasis of polyoma-middle-T-induced breast cancer in mice. Oncogene 30, 54–64 (2011). https://doi.org/10.1038/onc.2010.387

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