Development of novel therapy for hepatocellular carcinoma targeting of bone marrow-derived angiogenesis precursor

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Angiogenesis is a critical step in the development of vascular-rich hepatocellular carcinoma (HCC). TIE-2, a receptor of angiopoietins, conveys pro-angiogenic signals. We thus aimed to clarify the roles of TIE2-expressing monocytes (TEMs) in the clinical management of HCC and to identify molecules involving in the differentiation of TEMs. In HCC patients, the frequency of TEMs in the periphery and in the liver was significantly higher than those in non-HCC groups. In patients who underwent local ablation of HCC, the frequency of TEMs changed in parallel with the recurrence of HCC. A significant positive correlation was observed between micro-vessel density in HCC tissues and the frequencies of TEMs, suggesting that TEMs are involved in angiogenesis in the liver. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 levels as a diagnostic for HCC. TEMs were generated from TIE2-negative monocytes in the presence of M-CSF, TNF-α and IL-1β. In conclusion, the frequency of TEMs can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.