title: Tumoural Expression of Connective Tissue Growth Factor (CTGF) Impacts on Survival in Patients Diagnosed with Hepatocellular Carcinoma (HCC).
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) tends to develop in the liver when there is a high level of background inflammation (cirrhosis). Treatment options are limited and mainly based on systemic therapies such as anti-angiogenic drugs (e.g. sorafenib). Connective tissue growth factor (CTGF) is a matricellular protein involved in inflammation, tumour growth and angiogenesis. The aim of this study is to determine the expression of CTGF and hypoxia inducible factors (HIF) in HCC and to clarify its impact on relapse and survival.
  
  
  METHODS
  Eligibility criteria for the study consisted of patients with a diagnosis of HCC, formalin-fixed and paraffin-embedded (FFPE) biopsy tissue, as well as relapse and available survival data. A tissue microarray was constructed from ≥ 70% tumoural sections. The expressions of CTGF, HIF1α and HIF2α were analysed by immunohistochemistry. The relationship between expression of CTGF/HIF1α and CTGF/HIF2α were analysed. Univariate and multivariate analyses were performed.
  
  
  RESULTS
  Fifty-three patients were screened; 39 patients were eligible for this study. Patients were treated with radical intent. At the end of follow up, 59% patients relapsed (28.2% locally, 10.3% multicentric liver relapse and 7.7% distant metastases). Estimated median disease-free survival (DFS) and overall survival (OS) were 23.4 (95%CI 7.18-39.66) and 38.6 months (95%CI 30.7-46.6), respectively. Expression of CTGF was: negative 23.1%, focal 48.7% and diffuse 23.1%. A non-statistically significant relationship between expression of CTGF and HIF was shown supporting an alternative pathway for CTGF expression in HCC. In multivariate analysis CTGF expression was an independent factor related to OS, with shorter survival in those patients with focal/diffuse CTGF expression (HR 2.46; 95%CI 1.18-5.15).
  
  
  CONCLUSIONS
  Our results support that expression of CTGF is an independent factor associated with shorter OS in HCC. Further analysis of CTGF expression in a larger series of HCC patients is required to confirm CTGF as a prognostic biomarker in HCC.
authors.forename: Angela
authors.initials: A
authors.lastname: Lamarca
authors.forename: Marta
authors.initials: M
authors.lastname: Mendiola
authors.forename: Elsa
authors.initials: E
authors.lastname: Bernal
authors.forename: Victoria
authors.initials: V
authors.lastname: Heredia
authors.forename: Esther
authors.initials: E
authors.lastname: Díaz
authors.forename: María
authors.initials: M
authors.lastname: Miguel
authors.forename: Laura G
authors.initials: LG
authors.lastname: Pastrian
authors.forename: Emilio
authors.initials: E
authors.lastname: Burgos
authors.forename: Jaime
authors.initials: J
authors.lastname: Feliu
authors.affiliation: Translational Oncology Group, IdIPAZ, La Paz University Hospital, Faculty of Life Sciences, University of Manchester, Manchester, UK, Dover Street, M13 9PL, Manchester, UK. Jorge.Barriuso@manchester.ac.uk.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barriuso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends
chemical_list: D014408:Biomarkers, Tumor; C526317:CCN2 protein, human; D055513:Connective Tissue Growth Factor