Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer.
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.
Vasiljeva
Olga
O
Institut für Molekulare Medizin und Zellforschung and Institut für Biometrie und Medizinische Informatik, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Papazoglou
Anna
A
Krüger
Achim
A
Brodoefel
Harald
H
Korovin
Matvey
M
Deussing
Jan
J
Augustin
Nicole
N
Nielsen
Boye S
BS
Almholt
Kasper
K
Bogyo
Matthew
M
Peters
Christoph
C
Reinheckel
Thomas
T
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002401:Cathepsin B / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D018450:Disease Progression; D005260:Female; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic
D000952:Antigens, Polyomavirus Transforming; D002403:Cathepsins; D002401:Cathepsin B; D056657:Cathepsin K; C534132:Ctsk protein, mouse