Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy
- Kuonen, François Division of Experimental Oncology, University of Lausanne, Switzertland
- Laurent, Julien Division of Experimental Oncology, University of Lausanne, Switzertland
- Secondini, Chiara Pathology, Department of Medicine, University of Fribourg, Switzertland
- Lorusso, Girieca Department of Medicine, Faculty of Science, University of Fribourg, Switzertland
- Stehle, Jean-Christophe Pathology, University of Lausanne, Switzertland
- Rausch, Thierry Pathology, University of Lausanne, Switzertland
- Hull, Eveline Faes-van't Division of Experimental Oncology, University of Lausanne, Switzertland
- Bieler, Gregory Pathology, Department of Medicine, University of Fribourg, Switzertland
- Alghisi, Gian Carlo Experiemental Oncology, Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzertland
- Schwendener, Reto A. Institute of Molecular Cancer Research, University of Zurich, Switzertland
- Andrejevic-Blant, Snezana Institute of Pathology Faculty of Biology and Medicine, University of Lausanne, Switzertland
- Mirimanoff, René-Olivier Centre Hospitalier Universitaire Vaudois, Department of Radio-Oncology, Switzertland
- Rüegg, Curzio Pathology, Department of Medicine, University of Fribourg, Switzertland
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08.06.2012
Published in:
- Clinical Cancer Research. - 2012, vol. 18, no. 16, p. 4365-4374
English
Purpose: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of post-radiation metastasis. Experimental Design: 4T1 cells were injected in 20 Gy pre-irradiated mammary tissue, to mimic post-radiation relapses, or in non-irradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histological analyses, adoptive cell transfer, genetic and pharmacological interventions were performed. Results: Tumors growing in pre-irradiated mammary tissue had reduced angiogenesis, were more hypoxic, invasive and metastatic to lung and lymph nodes compared to control tumors. Increased metastasis involved the mobilization of CD11b+c-Kit+Ly6GhighLy6Clow(Gr1+) myeloid cells through the HIF1-dependent expression of KitL by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and pre-metastatic lungs, to give rise to CD11b+c-Kit- cells. Pharmacological inhibition of HIF1, silencing of KitL expression in tumor cells and inhibition of c-Kit with an anti-c-Kit blocking antibody or with a tyrosine kinase inhibitor, prevented the mobilization of CD11b+c-Kit+ cells and attenuated metastasis. C-Kit inhibition was also effective in reducing mobilization of CD11b+c-Kit+ cells and inhibiting lung metastasis after irradiation of established tumors. Conclusions: Our work defines KitL/c-Kit as a previously unidentified axis critically involved in promoting metastasis of 4T1 tumors growing in pre-irradiated mammary tissue. Pharmacological inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 29580
- DOI 10.1158/1078-0432.ccr-11-3028
- Persistent URL
- https://folia.unifr.ch/unifr/documents/302449
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