TY - JOUR
T1 - Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities
AU - Teresa Pinto, Ana
AU - Laranjeiro Pinto, Marta
AU - Patrícia Cardoso, Ana
AU - Monteiro, Cátia
AU - Teixeira Pinto, Marta
AU - Filipe Maia, André
AU - Castro, Patrícia
AU - Figueira, Rita
AU - Monteiro, Armanda
AU - Marques, Margarida
AU - Mareel, Marc
AU - Dos Santos, Susana Gomes
AU - Seruca, Raquel
AU - Adolfo Barbosa, Mário
AU - Rocha, Sónia
AU - JoséOliveira, Maria
N1 - his work was financially supported by the Portuguese Science and Technology Foundation FCT/MEC (PTDC-SAU-ONC/112511/2009 and UID/BIM/04293/2013), through National Funds and, when applicable, co-financed by the FEDER via the PT2020 Partnership Agreement under the 4293 Unit I&D. We also acknowledge the Program COMPETE FCOMP-01-0124-FEDER-010915 and the Prize L’Óreal for Women in Science (Foundation L’Óreal/FCT/UNESCO). Authors also thank the International Iberian Nanotechnology Laboratory (INL), FCT (PhD fellowships: SFRH/BD/74144/2010 and SFRH/BD/81103/2011; FCT-Program Ciência2008 and FCT2012-Investigator Program), EMBO and ESTRO travel Fellowships, North Region Operational Program (ON.2) (NORTE-07-0124-FEDER-000005-QREN), Cancer Research UK (C99667/A12918) and Wellcome Trust (097945/B/11/Z) for their grant support. Finally, we would like to perform a special acknowledgement to all members of Radiotherapy Service (CHSJ), especially to radiotherapy technicians, for the welcome, commitment, availability and support provided to this project.
PY - 2016/1/6
Y1 - 2016/1/6
N2 - In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2 Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro-survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10 Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more pro-inflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy.
AB - In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2 Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro-survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10 Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more pro-inflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy.
UR - http://www.scopus.com/inward/record.url?scp=84954288518&partnerID=8YFLogxK
U2 - 10.1038/srep18765
DO - 10.1038/srep18765
M3 - Article
C2 - 26735768
AN - SCOPUS:84954288518
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 18765
ER -