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Tumor Cell–Derived and Macrophage-Derived Cathepsin B Promotes Progression and Lung Metastasis of Mammary Cancer

¹ Institut für Molekulare Medizin und Zellforschung and ² Institut für Biometrie und Medizinische Informatik, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; ³ Klinikum rechts der Isar der Technischen Universität München, Institut für Experimentelle Onkologie und Therapieforschung, Munich, Germany; ⁴ Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark; and ⁵ Departments of Pathology, Microbiology, and Immunology, Stanford University School of Medicine, Stanford, California

Requests for reprints: Thomas Reinheckel, Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, Stefan Meier Strasse 17, D-79104 Freiburg, Germany. Phone: 49-761-203-9606; Fax: 49-761-203-9634; E-mail: Thomas.Reinheckel{at}uniklinik-freiburg.de.

Proteolysis in close vicinity of tumor cells is a hallmark of cancer invasion and metastasis. We show here that mouse mammary tumor virus–polyoma middle T antigen (PyMT) transgenic mice deficient for the cysteine protease cathepsin B (CTSB) exhibited a significantly delayed onset and reduced growth rate of mammary cancers compared with wild-type PyMT mice. Lung metastasis volumes were significantly reduced in PyMT;ctsb^+/–, an effect that was not further enhanced in PyMT;ctsb^–/– mice. Furthermore, lung colonization studies of PyMT cells with different CTSB genotypes injected into congenic wild-type mice and in vitro Matrigel invasion assays confirmed a specific role for tumor-derived CTSB in invasion and metastasis. Interestingly, cell surface labeling of cysteine cathepsins by the active site probe DCG-04 detected up-regulation of cathepsin X on PyMT;ctsb^–/– cells. Treatment of cells with a neutralizing anti-cathepsin X antibody significantly reduced Matrigel invasion of PyMT;ctsb^–/– cells but did not affect invasion of PyMT;ctsb^+/+ or PyMT;ctsb^+/– cells, indicating a compensatory function of cathepsin X in CTSB-deficient tumor cells. Finally, an adoptive transfer model, in which ctsb^+/+, ctsb^+/–, and ctsb^–/– recipient mice were challenged with PyMT;ctsb^+/+ cells, was used to address the role of stroma-derived CTSB in lung metastasis formation. Notably, ctsb^–/– mice showed reduced number and volume of lung colonies, and infiltrating macrophages showed a strongly up-regulated expression of CTSB within metastatic cell populations. These results indicate that both cancer cell–derived and stroma cell–derived (i.e., macrophages) CTSB plays an important role in tumor progression and metastasis. (Cancer Res 2006; 66(10): 5242-50)

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