Abstract 569: Comprehensive analyses of serum biomarkers associating with the increase of pro-angiogenic Tie2-expressing monocytes in patients with hepatocellular carcinoma
Authors: Shoji Hirotaka , Kanto Tatsuya , Mano Yohei , Aoki Yoshihiko , Yoshio Sachiyo , Sugiyama Masaya , Taketomi Akinobu , Mizokami Masashi 
Published: August 2015

Background/Aim: Tie2, a receptor for angiopoietins (ANGs), is expressed on a specialized types of monocytes. We reported that Tie2-expressing monocytes (TEMs) are increased in patients with hepatocellular carcinoma (HCC), the frequency of which is well correlated with the degree of angiogenesis in the HCC liver (Hepatology, 2013). A possibility has been raised that the dampening a genesis of TEMs could be of therapeutic value for HCC. However, the precise mechanisms of in vivo generation of TEMs are largely unknown. We aimed to identify the factors involving in the increase of TEMs in patients with HCC in order to gain insights in the establishment of anti-angiogenesis therapy for HCC.

Method: We enrolled 71 chronically HCV-infected patients and 7 healthy volunteers (HVs), including 54 patients with HCC, 9 with liver cirrhosis (LC) and, 8 with chronic hepatitis (CH). We measured the frequency of TEMs (CD14+CD16+Tie2+) in CD14+ monocytes by FACS as reported previously. We assayed 39 humoral factors by means of a multiplexed system and ELISA, such as cytokines, chemokines and growth factors simultaneously in serum samples of the subjects (Bio-Plex 3D system, Cancer biomarker and Cytokine assay panels) (Bio-Rad). The correlation of the results, clinical parameters and the frequency of TEMs was analyzed.

Results: The frequency of TEMs were higher in patients with HCC than those in the LC or CH patients or the HV group. In HCC patients, the levels of HGF, IL-8, or IP-10 were significantly higher than those in the HVs (HGF; P = 0.02, IL-8; P = 0.004, IP-10; P = 0.01). By the ROC analysis, we had set a cut-off value of TEM frequency defining the HCC from LC group as 2.75%. In HCC patients with high TEM frequency (&gt;2.75%), the levels of HGF, Osteopontin (OPN), Follistatin (FSN) were significantly higher than those in patients with low TEM frequency (&lt;2.75%) (HGF; P = 0.02, OPN; P = 0.02, FSN; P = 0.04). In addition, higher trend in VEGF level was observed in the TEM high group than those in the TEM low group (P = 0.05). In clinical parameters, we found that HCC patients in the TEM high group displayed a more advanced Child-Pugh grade, a higher model for end-stage liver disease (MELD) score, lower plasma prothrombin time and albumin level, suggesting that the TEM high group had more advanced liver disease. No correlation was found among HGF, OPN, FSN and VEGF with any of clinical parameters.

Conclusion: In patients with HCC, HGF, Osteopontin and Follistatin are associated with the increase of TEMs, suggesting the plausibility of these as molecular targets for anti-angiogenesis therapy for HCC.

Citation Format: Hirotaka Shoji, Tatsuya Kanto, Yohei Mano, Yoshihiko Aoki, Sachiyo Yoshio, Masaya Sugiyama, Akinobu Taketomi, Masashi Mizokami. Comprehensive analyses of serum biomarkers associating with the increase of pro-angiogenic Tie2-expressing monocytes in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 569. doi:10.1158/1538-7445.AM2015-569