Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced

Radiation Oncology

Iñigo Martinez-Zubiaurre³  Anthony Chalmers⁵  Roy Bremnes³  Lill-Tove Busund⁶  Ruth H Paulssen³  Kristian Bartnes²  Bjørn T Moe⁶  Jan Olof Winberg¹  Vivian Berg³  Ingvild Pettersen³  Turid Hellevik⁴ 

[1]Department of Medical Biology, University of Tromsø, 9037 Tromsø, Norway

[2]Department of Cardiothoracic and Vascular Surgery, University Hospital of Northern Norway, 9038 Tromsø, Norway

[3]Department of Clinical Medicine, University of Tromsø, 9037, Tromsø, Norway

[4]Department of Oncology, University Hospital of Northern Norway, 9038 Tromsø, Norway

[5]Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

[6]Department of Clinical Pathology, University Hospital of Northern Norway, 9038 Tromsø, Norway

关键词: Focal adhesion;    Integrins;    Invasion;    Ablative radiation;    Cancer-associated fibroblasts;   

Others  :  1160857
DOI  :  10.1186/1748-717X-7-59

 received in 2011-12-13, accepted in 2012-04-13,  发布年份 2012

【 摘 要 】

Background

Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non-small-cell lung cancers.

Methods

CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining.

Results

Exposing CAFs to 1 × 18 Gy resulted in a potent induction of multiple nuclear DDR foci (> 9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins α2, β1 and α5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed.

Conclusions

Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins.

【 授权许可】

   
2012 Hellevik et al; licensee BioMed Central Ltd.

【 图 表 】

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