Priority Research Papers:
Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling
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Lynn Feys1, Benedicte Descamps2, Christian Vanhove2, Anne Vral3, Liv Veldeman4, Stefan Vermeulen5, Carlos De Wagter4, Marc Bracke1 and Olivier De Wever1
1 Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium
2 Department of Electronics and Information System, iMinds-IBiTech-MEDISIP, Ghent University, Ghent, Belgium
3 Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium
4 Department of Radiation Oncology and Experimental Cancer Research, Gent University Hospital, Ghent, Belgium
5 Department of Biomedical Science, HoGent, Ghent, Belgium
Olivier De Wever, email:
Keywords: radiotherapy, triple-negative breast cancer, CXCL12, MIF, AMD3100
Received: July 22, 2015 Accepted: August 29, 2015 Published: September 15, 2015
Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.
Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.
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