title: Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.
abstract: 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.
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium.
authors.forename: Lynn
authors.initials: L
authors.lastname: Feys
authors.affiliation: Department of Electronics and Information System, iMinds-IBiTech-MEDISIP, Ghent University, Ghent, Belgium.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.affiliation: Department of Electronics and Information System, iMinds-IBiTech-MEDISIP, Ghent University, Ghent, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.affiliation: Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Vral
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Gent University Hospital, Ghent, Belgium.
authors.forename: Liv
authors.initials: L
authors.lastname: Veldeman
authors.affiliation: Department of Biomedical Science, HoGent, Ghent, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vermeulen
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Gent University Hospital, Ghent, Belgium.
authors.forename: Carlos
authors.initials: C
authors.lastname: De Wagter
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
mesh_terms: D000818:Animals; D001596:Benzylamines; D001943:Breast Neoplasms / Q000150:complications / Q000473:pathology* / Q000532:radiotherapy*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D016922:Cellular Senescence; D054377:Chemokine CXCL12 / Q000378:metabolism; D017077:Culture Media, Conditioned; D000080027:Cyclams; D053903:DNA Breaks, Double-Stranded; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008168:Lung / Q000528:radiation effects*; D008171:Lung Diseases / Q000209:etiology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011878:Radiotherapy / Q000009:adverse effects; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008263:Macrophage Migration-Inhibitory Factors; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse; C088327:plerixafor
keywords: AMD3100; CXCL12; MIF; radiotherapy; triple-negative breast cancer