Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma

Abstract

Aim: Type VI collagen, is emerging as a signaling collagen originating from different types of fibroblasts. A specific fragment of Type VI collagen, the pro-peptide, is also known as the hormone endotrophin. We hypothesized that this fibroblast hormone would be of particular relevance in cancer types with a high amount of fibrosis activity, namely for outcome in hepatocellular carcinoma (HCC) cirrhotic patients. Patients & methods: Plasma C6M, PRO-C6 and alphafeto-protein (AFP) were assessed in 309 patients with mixed etiologies (hepatitis C, hepatitis B, alcohol and nonalcoholic fatty liver) diagnosed as cirrhotics, cirrhotics with HCC, noncirrhotics and healthy controls. Progression-free survival and overall survival (OS) data were collected up to 6120 days after diagnosis. The ability of each marker to predict survival was investigated. Results & conclusion: The level of endotrophin assessed by PRO-C6 was able to separate healthy controls, noncirrhotics and cirrhotics from HCC (p < 0.05–0.0001). Both endotrophin and C6M provided value in the prediction of OS in cirrhotic patients with HCC. In the multivariate analysis for identifying HCC, in patients with high endotrophin (highest quartile) and that were positive for AFP (≥20 IU/ml), the hazard ratio for predicting OS was increased from 3.7 (p = 0.0006) to 14.4 (p = 0.0001) when comparing with AFP positive as a stand-alone marker. In conclusion, plasma levels for markers of Type VI collagen remodeling were associated with survival in cirrhotic patients with HCC. A combination of AFP with endotrophin improved the prognostic value compared with AFP alone for predicting OS in cirrhotic patients with HCC.

Keywords::

• biomarkers
• collagen
• endotrophin
• extracellular matrix
• hepatocellular carcinoma

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/hep-2020-0030

Author contributions

DJ Leeming and MA Karsdal prepared the manuscript. DJ Leeming and S Holm-Nielsen did the statistical analysis. R Vongsuvanh, P Uchila, Dvd Poorten, M Eslam and J George collected the clinical study; AL Reese-Petersen provided valuable endotrophin supervision. J George, MA Karsdal and DJ Leeming designed the study. All authors read the manuscript.

Acknowledgments

The authors thanked technician EA Madsen for her help during sample measurements.

Financial & competing interests disclosure

This work was funded by the Danish Innovation Foundation and Danish Research Foundation. J George is supported by grants from the NSW Cancer Council (APP1145008; APP1070076 to CL and LQ), the RW Storr Bequest to the Sydney Medical Foundation, University of Sydney and National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422). D Schuppan receives project related support by the EU Horizon 2020 under grant agreement no. 634413 (EPoS, European Project on Steatohepatitis) and 777377 (LITMUS, Liver Investigation on Marker Utility in Steatohepatitis), and by the German Research Foundation collaborative research project grants DFG CRC 1066/B3 and CRC 1292/08. MA Karsdal, SH Nielsen, MJ Nielsen, AL Reese-Petersen and DJ Leeming are full-time employees of Nordic Bioscience. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study protocol was approved by the Human Ethics Committee of the Sydney West Area Health Service (HREC No.2002/12/4.9 (1564)) in compliance with the Helsinki Declaration. The protocol may be accessed through Westmead Hospital. Written informed consent was obtained from all participants.