Angiogenic miRNAs, the angiopoietin axis and related TIE2-expressing monocytes affect outcomes in cholangiocarcinoma
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Georgi Atanasov1,2, Corinna Dietel3, Linda Feldbrügge1,2, Christian Benzing1, Felix Krenzien1,2, Andreas Brandl1, Shadi Katou1, Katrin Schierle4, Simon C. Robson5, Katrin Splith1, Georg Wiltberger6, Anja Reutzel-Selke1, Sven Jonas7, Andreas Pascher1, Marcus Bahra1, Johann Pratschke1 and Moritz Schmelzle1
1Department of Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany
2Berlin Institute of Health, Berlin, Germany
3Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
4Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
5The Transplant Institute and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
6Department of General, Visceral and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany
7Department of General and Visceral Surgery, 310Klinik Nürnberg, Nürnberg, Germany
Georgi Atanasov, email: firstname.lastname@example.org
Keywords: cholangiocarcinoma; TIE2-expressing monocytes; microRNAs; angiopoietins; miR-126
Received: January 22, 2018 Accepted: June 12, 2018 Published: July 06, 2018
Background: Tumour angiogenesis is modulated on both an epigenetic and protein level and has potential implications for immune cell responses. However, the importance of related angiogenic biomarkers in cholangiocarcinoma (CCA) is unknown. This study assessed human CCA samples for the expression of angiogenesis-associated microRNAs, angiopoietins (Angs) and monocytes expressing the Ang-receptor, TIE2, with regards to prognostic significance after liver resection.
Methods: Angiogenic miRNAs were analysed in frozen samples of intrahepatic CCA (iCC; n = 43) and hilar CCA (HC; n = 45). Ang-1 and Ang-2, as well as TIE2-expressing monocytes (TEMs), were detected in paraffin-embedded iCC sections (n = 88). MiRNA expression and the abundance of TEMs and Angs were correlated with clinicopathological characteristics and survival.
Results: MiR-126 was downregulated in 76.7% of all CCA samples, with high relative expression associated with smaller tumours and reduced lymph node metastasis. High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all p < 0.05). The absence of TEMs in iCC correlated with elevated CA19-9 levels. High relative miR-126 and low miR-128 levels were associated with improved survival in iCC and HC, respectively (all p < 0.05). High miR-126, low miR-128 and TEMs were independent prognostic factors for recurrence-free and overall survival (all p < 0.05).
Conclusions: These results suggest that angiogenic miRNAs, Angs and TEMs are of prognostic value in CCA. In addition to the possible functional links between angiogenic miRNA expression profiles, Angs and immune-cell responses by TEMs, these data have clinical implications as novel diagnostic tools.
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