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Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma.

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.

SUBMITTER: Buckley AM

PROVIDER: S-EPMC6154751 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma.

Buckley Amy M AM Lynam-Lennon Niamh N Kennedy Susan A SA Dunne Margaret R MR Aird John J JJ Foley Emma K EK Clarke Niamh N Ravi Narayanasamy N O'Toole Dermot D Reynolds John V JV Kennedy Breandán N BN O'Sullivan Jacintha J

Oncotarget 20180914 72

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 scre ...[more]

PMID: 30263091

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Project description:Cisplatin (cis-diamminedichloroplatinum) is widely used for the treatment of solid malignancies; however, the development of chemoresistance hinders the success of this chemotherapeutic in the clinic. This study provides novel insights into the molecular and phenotypic changes in an isogenic oesophageal adenocarcinoma (OAC) model of acquired cisplatin resistance. Key differences that could be targeted to overcome cisplatin resistance are highlighted. We characterise the differences in treatment sensitivity, gene expression, inflammatory protein secretions, and metabolic rate in an isogenic cell culture model of acquired cisplatin resistance in OAC. Cisplatin-resistant cells (OE33 Cis R) were significantly more sensitive to other cytotoxic modalities, such as 2 Gy radiation (p = 0.0055) and 5-fluorouracil (5-FU) (p = 0.0032) treatment than parental cisplatin-sensitive cells (OE33 Cis P). Gene expression profiling identified differences at the gene level between cisplatin-sensitive and cisplatin-resistant cells, uncovering 692 genes that were significantly altered between OE33 Cis R cells and OE33 Cis P cells. OAC is an inflammatory-driven cancer, and inflammatory secretome profiling identified 18 proteins secreted at significantly altered levels in OE33 Cis R cells compared to OE33 Cis P cells. IL-7 was the only cytokine to be secreted at a significantly higher levels from OE33 Cis R cells compared to OE33 Cis P cells. Additionally, we profiled the metabolic phenotype of OE33 Cis P and OE33 Cis R cells under normoxic and hypoxic conditions. The oxygen consumption rate, as a measure of oxidative phosphorylation, is significantly higher in OE33 Cis R cells under normoxic conditions. In contrast, under hypoxic conditions of 0.5% O₂, the oxygen consumption rate is significantly lower in OE33 Cis R cells than OE33 Cis P cells. This study provides novel insights into the molecular and phenotypic changes in an isogenic OAC model of acquired cisplatin resistance, and highlights therapeutic targets to overcome cisplatin resistance in OAC.

Dataset Information

Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma.

Publications

Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma.

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