title: 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.
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.
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Milene
authors.initials: M
authors.lastname: Volpato
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Perry
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Gemma
authors.initials: G
authors.lastname: Marston
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ingram
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cockbain
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Heather
authors.initials: H
authors.lastname: Burghel
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Jake
authors.initials: J
authors.lastname: Mann
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Lowes
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Erica
authors.initials: E
authors.lastname: Wilson
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.|MRC Medical Bioinformatics Centre, University of Leeds, Leeds, LS2 9NL, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Droop
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Juliette
authors.initials: J
authors.lastname: Randerson-Moor
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: P Louise
authors.initials: PL
authors.lastname: Coletta
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hull
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018932:Chemokine CCL2 / Q000097:blood*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D015118:Eicosapentaenoic Acid / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015118:Eicosapentaenoic Acid
keywords: colorectal cancer; eicosapentaenoic acid and biomarker; molecular pharmacology; prognosis