CD105 is a prognostic marker and valid endothelial target for microbubble platforms in cholangiocarcinoma
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ORIGINAL PAPER
CD105 is a prognostic marker and valid endothelial target for microbubble platforms in cholangiocarcinoma Amit Nair 1 & Nicola Ingram 1 & Eldo T. Verghese 1 & Imeshi Wijetunga 1 & Alexander F. Markham 1 & Judy Wyatt 2 & K. Rajendra Prasad 3 & P. Louise Coletta 1 Accepted: 30 April 2020 # The Author(s) 2020
Abstract Purpose The current treatment outcomes in cholangiocarcinoma are poor with cure afforded only by surgical extirpation. The efficacy of targeting the tumoural endothelial marker CD105 in cholangiocarcinoma, as a basis for potential microbubble-based treatment, is unknown and was explored here. Methods Tissue expression of CD105 was quantified using immunohistochemistry in 54 perihilar cholangiocarcinoma samples from patients who underwent resection in a single centre over a ten-year period, and analysed against clinicopathological data. In vitro flow assays using microbubbles functionalised with CD105 antibody were conducted to ascertain specificity of binding to murine SVR endothelial cells. Finally, CD105-microbubbles were intravenously administered to 10 Balb/c nude mice bearing heterotopic subcutaneous human extrahepatic cholangiocarcinoma (TFK-1 and EGI-1) xenografts after which in vivo binding was assessed following contrast-enhanced destruction replenishment ultrasound application. Results Though not significantly associated with any examined clinicopathological variable, we found that higher CD105 expression was independently associated with poorer patient survival (median 12 vs 31 months; p = 0.002). In vitro studies revealed significant binding of CD105-microbubbles to SVR endothelial cells in comparison to isotype control (p = 0.01), as well as in vivo to TFK-1 (p = 0.02) and EGI-1 (p = 0.04) mouse xenograft vasculature. Conclusion Our results indicate that CD105 is a biomarker eminently suitable for cholangiocarcinoma targeting using functionalised microbubbles. Keywords Perihilar cholangiocarcinoma . Bile duct cancer . Biliary tract cancer . Endoglin . CD105 . Microbubble
1 Introduction Cholangiocarcinoma (CCA) is an aggressive malignancy of biliary tract epithelium accounting for 10–15% of primary liver cancers [1]. Peri-hilar cholangiocarcinoma (pCCA) is the most common variant (60–70%) of CCA and is typically associated with locally advanced disease at presentation with
* Amit Nair [email protected] 1
Leeds Institute of Medical Research, St James’s University Hospital, Leeds LS9 7TF, UK
2
Department of Histopathology, St James’s University Hospital, Leeds LS9 7TF, UK
3
Department of Hepatobiliary and Transplant Surgery, St James’s University Hospital, Leeds LS9 7TF, UK
widely varying surgical extirpation rates ranging from 28 to 95% [2]. Complete resection with clear (R0) margins nonetheless remains the only means for cure. In addition, the efficacy of chemotherapy in adjuvant or palliative settings is modest [3, 4]. Therefore, new strategies are needed to facilitate earlier pCCA diagnosis and improve its prognosis. Molecular targeting of tumour vasculature
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