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: Lynn Feys, Benedicte Descamps, Christian Vanhove, Anne Vral, Liv Veldeman, Stefan Vermeulen, Carlos De Wagter, Marc Bracke, Olivier De Wever
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 29 Pg. 26615-32 (Sep 29 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26396176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzylamines
• CXCL12 protein, human
• CXCR4 protein, human
• CXCR4 protein, mouse
• Chemokine CXCL12
• Culture Media, Conditioned
• Cxcl12 protein, mouse
• Cyclams
• Heterocyclic Compounds
• Macrophage Migration-Inhibitory Factors
• Receptors, CXCR4
• Recombinant Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Intramolecular Oxidoreductases
• MIF protein, human
• Mif protein, mouse
• plerixafor

Topics

• Animals
• Benzylamines
• Breast Neoplasms (complications, pathology, radiotherapy)
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Cell Survival
• Cellular Senescence
• Chemokine CXCL12 (metabolism)
• Culture Media, Conditioned
• Cyclams
• DNA Breaks, Double-Stranded
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Heterocyclic Compounds (chemistry)
• Humans
• Intramolecular Oxidoreductases (metabolism)
• Lung (radiation effects)
• Lung Diseases (etiology)
• Lung Neoplasms (metabolism, secondary)
• Macrophage Migration-Inhibitory Factors (metabolism)
• Mice
• Neoplasm Metastasis
• Neoplasm Transplantation
• Proto-Oncogene Proteins c-akt (metabolism)
• Radiotherapy (adverse effects)
• Receptors, CXCR4 (metabolism)
• Recombinant Proteins (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction