TITLE:
Tumorigenic Responses of Cancer-Associated Stromal Fibroblasts after Ablative Radiotherapy: A Transcriptome-Profiling Study
AUTHORS:
Inigo Martinez-Zubiaurre, Christopher G. Fenton, Hagar Taman, Ingvild Pettersen, Turid Hellevik, Ruth H. Paulssen
KEYWORDS:
Stereotactic Ablative Radiotherapy (SART); Gene Expression; Cancer-Associated Fibroblasts (CAFs)
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.4 No.1,
February
20,
2013
ABSTRACT: Cancer-associated fibroblasts (CAFs) are key elements in the progression of cancer and thereby represent important targets for cancer therapies. Increased attention has been given to ablative radiotherapy in the clinics. Therefore, in this study we have aimed at identifying the transcriptional responses occurring in primary CAFs exposed to high-dose irradiation. Established primary CAFs obtained from non-small-cell lung cancer (NSCLC) patient material were irradiated with a single dose of 18 Gy and total RNA was isolated 24 hrs after treatment. Radiation-induced transcriptional alterations were investigated by gene expression analysis using genome-wide microarrays. Obtained results were verified by qRT-PCR of relevant genes. Confirmation of gene expression outcomes was achieved by diverse functional and expression assays including DNA damage response, measurements of reactive oxygen species (ROS) by flow cytometry and senescence-associated β-galactosidase. Irradiation resulted in differential expression of 680 genes of which 557 were up- and 127 down-regulated. Of those, 153 genes were differentially expressed with a fold-change greater than 1.0 and an adjusted p-value less than 0.05 across different comparisons (non-irradiated vs. irradiated). Expression patterns revealed profound changes in biological functions and processes involved in DNA repair, apoptosis, p53 pathway, autophagy, senescence, ROS production and immune response. CAFs display pro- and anti-tumorigenic effects after having received a single high-dose radiation. The measured effects will have an impact on the tumor microenvironment in respect to tumor growth and metastasis.