Response to stereotactic ablative radiotherapy in a novel orthotopic model of non-small cell lung cancer
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Ayman Oweida1, Siham Sabri2,3, Areej Al-Rabea2, Mojgan Ebrahimi4, Russel Ruo5, Richard Fraser5, Jan Seuntjens5 and Bassam Abdulkarim2,3
1Department of Radiation Oncology, University of Colorado Denver, Aurora, Colorado 80045, USA
2Division of Radiation Oncology, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada
3Department of Oncology, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada
4Department of Pathology, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada
5Medical Physics Unit, McGill University Health Center, Montreal, Quebec H4A 3J1, Canada
Bassam Abdulkarim, email: [email protected]
Keywords: radiation therapy; lung cancer; radioresistance; metastasis
Received: May 14, 2017 Accepted: October 28, 2017 Published: November 28, 2017
Stereotactic ablative radiotherapy (SABR) is the main treatment for inoperable early-stage non-small cell lung cancer (NSCLC). Despite the widespread use of SABR, the biological determinants of response to SABR remain poorly investigated. We developed an orthotopic NSCLC animal model to study the response to clinically-relevant doses of SABR. Image-guided intra-thoracic injection of NSCLC cells was performed in the right lung of nude rats. A highly conformal dose of 34 Gy was delivered in a single fraction using clinical photon energies. Animals were sacrificed 10–60 days post treatment. Lung tumors were assessed for tumor differentiation, proliferation and invasiveness. An analysis of 770 cancer-related genes was performed on tumor-derived cell lines from treated animals at early and late time points after SABR. The majority of animals receiving SABR demonstrated complete response (67%), while 33% demonstrated local failure. 50% of animals with complete response failed distantly. Analysis of cancer-related genes revealed significant differences between tumors treated with SABR and untreated tumors. SABR significantly modulated expression of genes involved in adhesion, migration and angiogenesis. In particular, interleukin-8 (IL8) which plays a critical role in promoting tumor invasion was found to be secreted at high levels after SABR. In vitro invasion assays confirmed SABR-induced invasion and demonstrated induction of IL-8 secretion in multiple NSCLC cell lines. Our findings underscore the importance of developing targeted therapies that can circumvent the pro-invasive effects of SABR in NSCLC.
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