IGFBP1 in Epithelial Circulating Tumor Cells as a Potential Response Marker to Selective Internal Radiation Therapy in Hepatocellular Carcinoma

Abstract

Background: Local ablative techniques such as selective internal radiation therapy (SIRT) have become the mainstay of treating hepatocellular carcinoma (HCC) in the bridging-to-transplant and palliative setting. We recently demonstrated that epithelial circulating tumor cells (CTCs) correlate to an unfavorable outcome. We wanted to scrutinize whether molecular markers detected in this specific CTC subgroup may also have clinical implications. Materials & methods: Mononuclear cells and CTCs were isolated from peripheral blood samples using density gradient centrifugation followed by depletion of hematopoietic and enrichment of epithelial (EpCAM⁺) cells employing immunomagnetic beads. The mRNA expression of candidate markers was correlated with response to SIRT in 25 patients using quantitative real-time reverse-transcription PCR. Results:IGFBP1 mRNA expression levels were significantly correlated with time to progression in a Kaplan–Meier log rank test (p = 0.04; 0 vs 4 months) and receiver operating characteristic analysis demonstrated a potential use to predict patients with shortened time to progression (area under the curve: 0.8; 95% CI: 0.44–0.98; p = 0.03). Conclusion: The EpCAM fraction of CTCs may be useful to detect novel molecular markers to individualize treatment decision in patients with HCC.

Keywords::

• AFP
• circulating tumor cells
• EpCAM
• epithelial cells
• hepatocellular carcinoma
• IGFBP1
• peripheral blood
• SIRT

Authors' contributions

Conception and design: A-C Hoffmann and JF Schlaak; technical support and study supervision: B Sitek, HE Meyer and C Stephan; provision of study materials or patients: J Ertle, F Weber, JF Schlaak and HA Baba; proofreading of manuscript: A-C Hoffmann and JF Schlaak; collection and assembly of data: I Nel; data analysis and interpretation: I Nel, HA Baba and A-C Hoffmann; manuscript writing: I Nel and A-C Hoffmann; final approval of manuscript: A-C Hoffmann.

Financial & competing interests disclosure

This project is financed by funds of the 'Ziel 2 – Programm NRW 2007-2013, Bio. NRW', the European fund for regional development (Europäischer Fondsfürregionale Entwicklung [EFRE], 'Investition in unsereZukunft') and from the Ministry of Innovation, Science and Research of North Rhine-Westphalia, Germany. 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 authors state that they have obtained appropriate insti­tutional review board approval or have followed the princi­ples outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investi­gations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This project is financed by funds of the 'Ziel 2 – Programm NRW 2007-2013, Bio. NRW', the European fund for regional development (Europäischer Fondsfürregionale Entwicklung [EFRE], 'Investition in unsereZukunft') and from the Ministry of Innovation, Science and Research of North Rhine-Westphalia, Germany. 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.