Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma
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Amy M. Buckley1, Niamh Lynam-Lennon1, Susan A. Kennedy1, Margaret R. Dunne1, John J. Aird2, Emma K. Foley1, Niamh Clarke1, Narayanasamy Ravi1, Dermot O’Toole3, John V. Reynolds1, Breandán N. Kennedy4 and Jacintha O’Sullivan1
1Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
2Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College Dublin, Dublin, Ireland
3Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
4UCD Conway Institute & UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
Jacintha O’Sullivan, email: OSULLIJ4@tcd.ie
Keywords: LIF; oesophageal cancer; LIFR; treatment resistance; radiation
Received: May 05, 2018 Accepted: July 13, 2018 Published: September 14, 2018
Oesophageal cancer is an aggressive disease with a poor 5 year survival rate of <20% of diagnosed patients. Unfortunately, only 20-30% Oesophageal Adenocarinoma (OAC) patients show a beneficial response to neoadjuvant therapy (neoCT). Inflammation influences OAC given the increased risk of cancer development and poor outcome for obese patients where altered secretion of adipokines and cytokines from adipose tissue contributes a pro-tumourigenic environment. We carried out a large proteomics screen of 184 proteins to compare the inflammatory and oncogenic profiles of an isogenic radioresistant in-vitro model of OAC. We found that leukaemia inhibitory factor (LIF), an IL-6 type cytokine, was significantly elevated in radioresistant OAC cells (p=0.007). Furthermore, significantly higher circulating levels of LIF were present in the serum from treatment-naive OAC patients who had a subsequent poor pathological response to neo-adjuvant therapy, (p=0.037). Quantitative PCR analysis revealed expression of LIF receptor (LIFR) may function as a predictive indicator of response to neo-adjuvant chemoradiation therapy in OAC. LIF was demonstrated to be actively secreted from human OAC treatment-naïve biopsies and significantly correlated with the secretion of bFGF, VEGF-A and IL-8 (p<0.05, R=1), (p<0.05, R=0.9429), and (p<0.05, R=1) respectively. Importantly, LIF secretion negatively correlated with tumour infiltrating lymphocytes in pre-treatment OAC patient biopsies, (r=-0.8783, p=0.033). Elevated circulating LIF is a marker of poor response to neo-adjuvant treatment in OAC and secretion of this chemokine from the tumour is tightly linked with pro-tumourigenic mediators including bFGF, VEGF-A and IL-8. Targeting this pathway may be a novel mechanism enhance neoadjuvant treatment responses in OAC.
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