New mechanistic insights of integrin β1 in breast cancer bone colonization
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Laure Thibaudeau1,*, Anna V. Taubenberger1,2,*, Christina Theodoropoulos1, Boris M. Holzapfel1,3, Olivier Ramuz4, Melanie Straub5 and Dietmar W. Hutmacher1,6,7
1 Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Brisbane, Australia
2 TU Dresden, Biotechnology Center, Tatzberg, Dresden, Germany
3 Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Brettreichstraße, Wuerzburg, Germany
4 Department of Anatomical Pathology and Cytopathology, Pathology Queensland Central Laboratory, Royal Brisbane and Women’s Hospital, Herston QLD, Australia
5 Institute of Pathology, University Clinic Rechts der Isar, Technical University Munich, Trogerstr, Munich, Germany
6 George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, United States of America
7 Institute for Advanced Study, Technical University Munich, Lichtenbergstraße, Garching, Germany
* These authors contributed equally to this work
Dietmar W. Hutmacher, email:
Keywords: bone colonization, breast cancer, β1 integrin, humanized bone models, tissue engineering
Received: November 04, 2014 Accepted: November 14, 2014 Published: November 15, 2014
Bone metastasis is a frequent and life-threatening complication of breast cancer. The molecular mechanisms supporting the establishment of breast cancer cells in the skeleton are still not fully understood, which may be attributed to the lack of suitable models that interrogate interactions between human breast cancer cells and the bone microenvironment. Although it is well-known that integrins mediate adhesion of malignant cells to bone extracellular matrix, their role during bone colonization remains unclear. Here, the role of β1 integrins in bone colonization was investigated using tissue-engineered humanized in vitro and in vivo bone models. In vitro, bone-metastatic breast cancer cells with suppressed integrin β1 expression showed reduced attachment, spreading, and migration within human bone matrix compared to control cells. Cell proliferation in vitro was not affected by β1 integrin knockdown, yet tumor growth in vivo within humanized bone microenvironments was significantly inhibited upon β1 integrin suppression, as revealed by quantitative in/ex vivo fluorescence imaging and histological analysis. Tumor cells invaded bone marrow spaces in the humanized bone and formed osteolytic lesions; osteoclastic bone resorption was, however, not reduced by β1 integrin knockdown. Taken together, we demonstrate that β1 integrins have a pivotal role in bone colonization using unique tissue-engineered humanized bone models.
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