Abstract
Lack of differentiation in hepatocellular carcinoma (HCC) is associated with increased circulating platelet size. We measured platelet activation and plasma adenosine diphosphate (ADP) levels in HCC patients based on differentiation status. Local platelet accumulation and platelet-hepatoma cell binding were measured using immunohistochemistry (IHC) or flow cytometry. Using a xenograft assay in NON/SCID mice, we tested the effects of the anti-platelet drug clopidogrel on platelet activation, platelet infiltration, platelet-tumor cell binding and tumor cell differentiation. HCC patients with poor differentiation status displayed elevated platelet activation and higher ADP levels. Platelets accumulated within poorly differentiated tissues and localized at hepatoma cell membranes. Platelet-tumor cell binding was existed in carcinoma tissues, largely mediated by P-selectin on platelets. NOD/SCID mice with xenograft tumors also exhibited increased platelet activation and platelet-tumor cell binding. Clopidogrel therapy triggered hepatoma cell differentiation by attenuating platelet activation and platelet-tumor cell binding. TCF4 knockdown promoted HepG-2 cell differentiation and inhibited tumor formation, and TCF4 could be the potential downstream target for clopidogrel therapy.
Highlights
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide [1]
Platelet count had no differences among the three groups, while MPV, platelet distribution width (PDW) and the proportion of large platelets were considerably greater in the moderately and poorly differentiated groups (Figure 1A–1D, Table 1)
In vivo, transfected HepG-2 cells exhibited reduced tumorigenicity compared with control cells (Figure 7G). These results suggested that TCF4 knockdown induced HepG-2 cell differentiation and reduced tumorigenicity. We used both clinical data and xenograft assay in NOD/SCID mice to investigate the potential role of platelets in inhibiting hepatoma cell differentiation
Summary
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide [1]. Degree of differentiation is widely accepted as an important prognostic indicator of metastasis, recurrence and chemotherapy resistance in solid tumors, including HCC [3,4,5,6]. Up to 40% of HCC patients have PVT at the time of diagnosis [9], and are more likely to experience metastasis and shortened survival compared to patients without PVT [10,11,12]. This indicates that platelets are hyperactivated in HCC. Activated platelets are reportedly involved in critical steps in cancer progression, including facilitating tumor cell growth and migration within vasculature [17]
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