Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Morimoto, Yuki; Nouso, Kazuhiro; Wada, Nozomu; Takeuchi, Yasuto; Kinugasa, Hideaki; Miyahara, Koji; Yasunaka, Tetsuya; Kuwaki, Kenji; Onishi, Hideki; Ikeda, Fusao; Miyake, Yasuhiro; Nakamura, Shinichiro; Shiraha, Hidenori; Takaki, Akinobu; Yamamoto, Kazuhide

doi:10.1111/hepr.12315

Cited by 35 publications

(47 citation statements)

References 25 publications

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“…(6,26) Whereas extensive experimental research has outlined the platelet-cancer loop, clinical studies also support the importance of platelets by demonstrating an association between PLT and poor prognosis in cancers of various organs including the liver. (7,9,27) Of interest, sorafenib, which is the first systemic drug to be approved for the management of advanced HCC, suppresses HCC progress by inhibiting cellular signaling mediated by platelet-derived growth factors such as vascular endothelial growth factor and platelet-derived growth factor. (28) The current and previous studies have consistently demonstrated that early posttransplant PLT is mainly determined by preoperative PLT.…”

Section: Discussionmentioning

confidence: 99%

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Han¹,

Lee

Yang

et al. 2017

Liver Transpl

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Platelets interact with tumor cells and promote metastasis. The importance of platelets in posttransplant hepatocellular carcinoma (HCC) recurrence is unclear. Thus, we aimed to evaluate the association between preoperative platelet count (PLT) and HCC recurrence after living donor liver transplantation. Of 359 recipients of livers from living donors for HCC, 209 of 240 patients who had preoperative PLT £ 75 3 10 9 /L were matched with 97 of 119 patients who had preoperative PLT >75 3 10 9 /L using propensity score matching, with an unfixed matching ratio based on factors such as tumor biology. The cutoff value of 75 3 10 9 /L was set based on optimum stratification analysis. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. The median follow-up time was 59 months. Before matching, recurrence probability at 1, 2, and 5 years after transplantation was 4.7%, 9.2%, and 11.3% for the low platelet group and 14.5%, 23.0%, and 30.5% for the high platelet group. Recurrence risk was significantly greater in the high platelet group in both univariate (hazard ratio [HR] 5 3.09; 95% confidence interval [CI], 1.86-5.14; P < 0.001) and multivariate analyses (HR 5 2.10; 95% CI, 1.23-3.60; P 5 0.007). In the matched analysis, recurrence risk was also greater in the high platelet group in both univariate (HR 5 2.33; 95% CI, 1.36-4.01; P 5 0.002) and multivariate analyses (HR 5 1.90; 95% CI, 1.02-3.54; P 5 0.04). Preoperative PLT had no interaction with the Milan criteria, alpha-fetoprotein level, Edmonson grade, microvascular invasion, or intrahepatic metastasis. Incorporation of preoperative PLT into the Milan criteria significantly improved predictive power. Inflammation-based scores including neutrophil-tolymphocyte ratio, platelet-to-lymphocyte ratio, and the inflammation-based index did not show superiority to preoperative PLT in predicting HCC recurrence. In conclusion, preoperative PLT appears to be an important host factor affecting HCC recurrence after living donor liver transplantation.Liver Transplantation 24 44-55 2018 AASLD. Liver transplantation is a well-established therapeutic option for treatment of hepatocellular carcinoma (HCC), addressing both underlying liver disease, which is considered a premalignant lesion, and tumor burden. However, many recipients experience tumor recurrence and recurrent HCC is a major cause of death. Thus, better understanding of the contributing factors for HCC metastasis will help improve liver transplant outcome. (1,2) The platelet is the primary cell for hemostasis and tissue repair, (3) but extensive experimental evidence has also illuminated the involvement of platelets in tumor growth and metastasis. (4)(5)(6) Clinical evidence has demonstrated an association between higher platelet counts (PLTs) and shorter survival time and increased recurrence after treatment in various solid tumors. (7) In terms of HCC, a retrospective analysis using a large database of biopsy-proven HCC patients reported a positive Abbrevi...

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Section: Discussionmentioning

confidence: 99%

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Han¹,

Lee

Yang

et al. 2017

Liver Transpl

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“…High levels of DCP have been found to be associated with invasion and metastasis of hepatocellular carcinoma, portal vein tumor invasion, hepatic vein tumor thrombosis [67]. In our study, DCP was found to possess the activity of stimulation HCC release matrix metalloproteinase (MMPs) [64].…”

Section: The Stimulator Of Hcc Growth and Invasionmentioning

confidence: 95%

Des-γ-Carboxy Prothrombin (DCP) as a Potential Autologous Growth Factor for the Development of Hepatocellular Carcinoma

Zhang

Chu

Cui

et al. 2014

Cell Physiol Biochem

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Des-γ-carboxy prothrombin (DCP) is a prothrombin precursor produced in hepatocellular carcinoma (HCC). Because of deficiency of vitamin K or γ-glutamyl carboxylase in HCC cells, the 10 glutamic acid (Glu) residues in prothrombin precursor did not completely carboxylate to γ-carboxylated glutamic acid (Gla) residues, leaving some Glu residues remained in N-terminal domain. These prothrombin precursors with Glu residues are called DCPs. DCP displays insufficient coagulation activity. Since Liebman reported an elevated plasma DCP in patients with HCC, DCP has been used in the diagnosis of HCC. Recently, its biological malignant potential has been specified to describe DCP as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells. DCP was found to stimulate HCC growth through activation of the DCP-Met-JAK1-STAT3 signaling pathway. DCP might increase HCC invasion and metastasis through activation of matrix metalloproteinase (MMPs) and the ERK1/2 MAPK signaling pathway. DCP has also been found to play a crucial role in the formation of angiogenesis. DCP could increase the angiogenic factors released from HCC and vascular endothelial cells. These effects of DCP in angiogenesis might be related to activation of the DCP-KDR-PLC-γ-MAPK signaling pathway. In this article, we summarized recent studies on DCP in biological roles related to cancer progression and angiogenesis in HCC.

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“…Abnormal PLT counts were observed in patients with malignant tumors and were identified as prognostic factors in various solid cancers . Similarly, PLT counts were associated with distinct large HCC phenotypes, especially in HCC with vascular invasion . Moreover, anti‐PLT treatment reduced the risk for cancer metastasis …”

Section: Introductionmentioning

confidence: 99%

Thrombocytopenia: A prognostic factor for hepatocellular carcinoma patients with portal vein tumor thrombus after hepatectomy

Cheng

Wang

Zhang

et al. 2018

J of Gastro and Hepatol

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Background and Aim Portal vein tumor thrombus (PVTT) predicts a poor prognosis in hepatocellular carcinoma (HCC) patients. Platelets (PLTs) play an important role in HCC progression and metastasis. However, the relationship between PLTs and PVTT remains unclear. This study aimed to evaluate the value of PLT counts in the prognosis of HCC patients with PVTT after hepatectomy. Methods From January 2002 to December 2012, 694 HCC patients with PVTT after hepatectomy were evaluated. The patients were divided into the thrombocytopenia group (PLT < 100 × 109/L), the normal group, and the thrombocytosis group (PLT > 300 × 109/L) based on the preoperative PLT level. A propensity score matching (PSM) analysis was used. Results Before the PSM, PVTT patients with thrombocytopenia exhibited longer recurrence‐free survival (RFS) and overall survival (OS) compared with those with normal PLT counts (both P < 0.001) or thrombocytosis (P = 0.008 and P = 0.046). For the thrombocytopenia group and the normal group, the 1‐, 2‐, and 3‐year RFS values were 30.0%, 17.6%, and 15.7% and were 10.8%, 6.6%, and 5.8% (P < 0.001), respectively; the 1‐, 2‐, and 3‐year OS values were 61.9%, 37.9%, and 31.2% and were 38.3%, 23.3%, and 16.0% (P < 0.001), respectively. After the PSM, the median survival time was 16.6 versus 8.6 months (P < 0.002) in the two groups. A subgroup analysis revealed that thrombocytopenia is associated with improved OS in those with type I PVTT (P = 0.021) or type II PVTT (P = 0.029). Conclusion According to the PSM, preoperative thrombocytopenia predicts an increased RFS and OS in HCC patients with PVTT after hepatectomy.

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Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Abstract: HCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

Cited by 35 publications

References 25 publications

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Des-γ-Carboxy Prothrombin (DCP) as a Potential Autologous Growth Factor for the Development of Hepatocellular Carcinoma

Thrombocytopenia: A prognostic factor for hepatocellular carcinoma patients with portal vein tumor thrombus after hepatectomy

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Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Abstract: HCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

Cited by 35 publications

References 25 publications

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Des-&#947;-Carboxy Prothrombin (DCP) as a Potential Autologous Growth Factor for the Development of Hepatocellular Carcinoma

Thrombocytopenia: A prognostic factor for hepatocellular carcinoma patients with portal vein tumor thrombus after hepatectomy

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Des-γ-Carboxy Prothrombin (DCP) as a Potential Autologous Growth Factor for the Development of Hepatocellular Carcinoma