Changes in plasma chemokine C-C motif ligand 2 levels during treatment with eicosapentaenoic acid predict outcome in patients undergoing surgery for colorectal cancer liver metastasis

// Milene Volpato 1 , Sarah L Perry 1 , Gemma Marston 1 , Nicola Ingram 1 , Andrew J. Cockbain 1 , Heather Burghel 1 , Jake Mann 1 , David Lowes 1 , Erica Wilson 2 , Alastair Droop 2, 3 , Juliette Randerson-Moor 2 , P Louise Coletta 1 , Mark A Hull 1 1 Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, United Kingdom 2 Leeds Institute of Cancer Studies and Pathology, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF, United Kingdom 3 MRC Medical Bioinformatics Centre, University of Leeds, Leeds, LS2 9NL, UK Correspondence to: Milene Volpato, email: M.Volpato@leeds.ac.uk Keywords: colorectal cancer, molecular pharmacology, prognosis, eicosapentaenoic acid and biomarker Received: February 02, 2016 Accepted: March 18, 2016 Published: April 4, 2016 ABSTRACT The mechanism of the anti-colorectal cancer (CRC) activity of the omega-3 fatty acid eicosapentaenoic acid (EPA) is not understood. We tested the hypothesis that EPA reduces expression of chemokine C-C motif ligand 2 (CCL2), a pro-inflammatory chemokine with known roles in metastasis. We measured CCL2 in clinical samples from a randomized trial of EPA in patients undergoing liver surgery for CRC liver metastasis (LM) and preclinical models. Genome-wide transcriptional profiling of tumors from EPA-treated patients was performed. EPA decreased CCL2 synthesis by CRC cells in a dose-dependent manner. CCL2 was localized to malignant epithelial cells in human CRCLM. EPA did not reduce CCL2 content in human or mouse tumors compare to control. However, EPA treatment was associated with decreased plasma CCL2 levels compared with controls (P=0.04). Reduction in plasma CCL2 following EPA treatment predicted improved disease-free survival (HR 0.32; P=0.003). Lack of ‘CCL2 response’ was associated with a specific CRCLM gene expression signature. In conclusion, reduction in plasma CCL2 in patients with CRCLM treated with EPA predicts better clinical outcome and a specific tumor gene expression profile. Further work is needed to validate CCL2 as a therapeutic response biomarker for omega-3 fatty acid treatment of CRC patients.