3 Of note, a recent study documented significantly enhanced TIE2 expression in the circulating

monocytes of colorectal cancer patients, compared to healthy subjects.17 Matsubara et al.3 also identified TEMs in HCC specimens and observed that these cells preferentially localize phosphatase inhibitor library in perivascular tumor areas, in agreement with findings in mouse models of cancer.13 Furthermore, it was found that a higher TEM infiltration correlated with increased microvessel density in the tumors, possibly suggesting that HCC-infiltrating TEMs are proangiogenic. Although the biological significance of the findings of Matsubara et al.3 need to be investigated in ad-hoc Sirolimus mouse models

of hepatocellular carcinogenesis, the current study is the first to present evidence suggesting that circulating TEMs may be a diagnostic biomarker for both early- and late-stage HCC. Future studies should address several important issues raised by these observations.3 According to Matsubara et al.,3 high circulating and intratumoral TEM levels correlate with a more-advanced Child-Pugh stage, a finding that may suggest that

TEM frequency correlates positively with the degree of liver inflammation/stage Nintedanib (BIBF 1120) of cirrhosis and negatively with liver function. In this regard—and contrary to the findings of Matsubara et al.3— a recent study showed that circulating and intrahepatic TEMs are significantly increased in HCV-infected patients without HCC, compared to healthy subjects.18 In that study, HCV patients who responded to antiviral therapy had significantly lower TEM levels than naïve (untreated) or nonresponder patients.18 These interesting findings suggest that chronic liver inflammation may be a stimulus for TEM mobilization from the BM, their differentiation/expansion in the periphery, and/or the up-regulation of TIE2 in nonclassical monocytes. Although Rodriguez-Munoz et al.18 analyzed a relatively small cohort of HCV-infected patients, their data raise the concern that mobilization/expansion of TEMs may not be strictly HCC driven, but more generally associated with chronic liver infection. Virtually nothing is known about the biology underlying TEM’s involvement in human tumor angiogenesis and progression.