Effects of irradiation on lung cancer associated fibroblasts (CAFs)
Inigo Martinez-Zubiaurre,
Norway
SP-0350
Abstract
Effects of irradiation on lung cancer associated fibroblasts (CAFs)
Authors: Inigo Martinez-Zubiaurre1, Rodrigo Berzaghi1, Kristin Lode1, Turid Hellevik2
1University of Tromsø, Clinical Medicine, Tromsø, Norway; 2University Hospital of Northern Norway, Radiation Oncology Dpt., Tromsø, Norway
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Abstract Text
Background
Cancer-associated fibroblasts (CAFs) represent a heterogeneous population of connective tissue cells that are both numerically and functionally prominent constituents of solid tumors. The role that CAFs play on tumor responses to radiotherapy remains poorly understood. This study was undertaken to explore changes provoked by radiotherapy on CAF abundance and functions.
Methodology
Phenotypic and functional changes induced by radiation was studied on freshly primary human NSCLC CAFs. The impact that RT has on CAFs in vivo was also studied in three different preclinical models comprising LLC (lung cancer), CT26 (colon cancer) and 4662PDA (pancreatic cancer). Subcutaneous tumors were irradiated at different radiation regimens and the levels of tumor-associated CAF markers were analyzed 1-week post-RT by flow cytometry, histology, IHC and non-invasively by the use of a CAF-specific PET imaging radiotracer.
In parallel, the effects of RT on CAFs were studied in a cohort of cervical cancer patients treated with neoadjuvant chemoradiotherapy, and levels of aSMA-positive cells in tumor tissues was compared before and after treatment. The impact of aSMA and collagen expression on treatment response has been investigated.
Results
Our in vitro data show a dose-dependent induction of cell senescence in CAFs by radiation, with a concomitant reduction of the proliferative and migratory capacity. The expression of CAF activation markers FAP-1, FSP-1, PDGFR/ and α-SMA remained unchanged following IR, whereas the expression of podoplanin was reduced. In vivo observations indicated that radiation did not alter the amount or the phenotype of CAFs in LLC or CT26 tumors, whereas the levels of CAFs in 4662PDA tumors became reduced. Analyses of CAF-markers in human specimens are being conducted and final outcomes, including prognostic and predictive impact, will be presented at the meeting.
Conclusions
Radiation induces important phenotypic changes in CAFs, however irradiation do not seem to alter substantially the CAF-mediated pro-tumorigenic or radioprotective functions on tumor cells. CAFs abundance and phenotype remain largely unchanged upon external beam radiotherapy of subcutaneously grown tumors. The ultimate role of CAFs on tumor responses to radiotherapy warrant further investigations.