Abstract
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.
Highlights
Oesophageal cancer is the 8th most common cancer worldwide with approximately 456,000 new cases diagnosed annually [1]
Elevated circulating leukaemia inhibitory factor (LIF) is a marker of poor response to neo-adjuvant treatment in Oesophageal Adenocarinoma (OAC) and secretion of this chemokine from the tumour is tightly linked with pro-tumourigenic mediators including basic fibroblast growth factor (bFGF), Vascular Endothelial Growth Factor (VEGF)-A and Interleukin 8 (IL-8)
Our findings suggest that LIF and LIF receptor (LIFR) may be expressed at higher levels in radiation-resistant OAC cells when compared to radiation sensitive cells this is not significant, and that radiation treatment significantly increases the secretion of LIF by OE33R cells
Summary
Oesophageal cancer is the 8th most common cancer worldwide with approximately 456,000 new cases diagnosed annually [1]. Oesophageal cancer is an aggressive disease and the 6th most common cause of cancer related death, accounting for approximately 400,000 deaths annually [1]. The current standard of care for OAC focuses on neoadjuvant treatment with chemotherapy (neoCT) alone or in combination with radiation; neoadjuvant chemoradiation (neoCRT) for locally advanced tumours, prior to surgery [3]. A Cancer Trials Irelandsponsored randomised, phase III clinical trial, Neo-AEGIS, is comparing neoadjuvant and adjuvant chemotherapy (MAGIC protocol) to neoadjuvant CRT (CROSS protocol) in OAC [6]. Surgery offers the best chance of locoregional control and neoadjuvant treatment aims to reduce tumour burden prior to surgery to improve post-operative outcome, neoCRT in combination with surgery has been associated with higher rates of overall survival [3, 7, 8]. There are currently no clinicopathological markers available to stratify patients who will achieve a beneficial response to radiation therapy
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