Effects of thrombopoietin on growth of hepatocellular carcinoma: Is thrombopoietin therapy for liver disease safe or not?

Nozaki, Reiji; Murata, Soichiro; Nowatari, Takeshi; Maruyama, Takehito; Ikeda, Naoya; Kawasaki, Takuya; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

doi:10.1111/hepr.12006

Cited by 20 publications

(23 citation statements)

References 48 publications

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“…TPO receptor expression has been identified on the cells of non-haematological tumours. In the case of hepatocellular carcinoma, exposure to supplemental TPO in vitro and in vivo had no effect on tumour proliferation, growth or spread [95].…”

Section: Romiplostimmentioning

confidence: 89%

Immune thrombocytopenia – what are the new treatment options?

Hallam

Newland

2013

Expert Opinion on Biological Therapy

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There is an increasing understanding of the natural history of ITP and an increasing evidence-based approach to the disease and its management. Treatment should be aimed at the patient with a bleeding risk and should minimise the risk of adverse effects while maximising the chances of response. Few, if any, treatments are curative and treatment strategies need to be designed in ITP that manage patients with what can be a life-long condition with periodic relapses.

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Section: Romiplostimmentioning

confidence: 89%

Immune thrombocytopenia – what are the new treatment options?

Hallam

Newland

2013

Expert Opinion on Biological Therapy

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“…However, it has been reported that TPO itself had no proliferative effect on HCC in in vitro and in vivo experiments. 76 Currently, two TPO-R agonists, eltrombopag and romiplostim, have been approved for treatment of chronic immune thrombocytopenic purpura. Eltrombopag is a small-molecule, non-peptide TPO-R agonist, whereas romiplostim is a peptide TPO-R agonist that is composed of an IgG Fc fragment.…”

Section: Limitations Of Platelet Increment Therapy For Cld and Cirrhosismentioning

confidence: 99%

Novel functions of platelets in the liver

Kurokawa

Zheng

Ohkohchi

2016

J of Gastro and Hepatol

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Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease.

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“…Furthermore, TPO-R is expressed in hepatoma cell lines, such as Huh7, Hep3B and HepG2 (13,14); these observations indicate that eltrombopag may accelerate the progression of HCC. Although eltrombopag has been administered to treat tumor-bearing patients (4,15), the effect of eltrombopag on tumor progression has not previously been reported.…”

Section: Discussionmentioning

confidence: 99%

“…TPO-R expression has previously been found to be lower in hepatoma cell lines compared with expression in primary hepatocytes (14) and HCC tissues do not express TPO-R (13). In addition, TPO does not activate the extracellular signal-regulated kinases 1/2 or the signal transducers and activators of transcription 3 and 5 pathways, or affect the proliferation, migration or invasion of Huh7 cells (14).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, TPO does not activate the extracellular signal-regulated kinases 1/2 or the signal transducers and activators of transcription 3 and 5 pathways, or affect the proliferation, migration or invasion of Huh7 cells (14). Furthermore, TPO does not upregulate Bax, Bcl-2 or cleaved caspase 3 and does not induce anti-apoptotic effects in Huh7 cells (14).…”

Section: Discussionmentioning

confidence: 99%

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Usefulness of short-term eltrombopag treatment as a supportive treatment in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia: A report of two cases

Kawaguchi¹,

Nakano²,

Satani³

et al. 2014

Oncology Letters

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Eltrombopag is an oral thrombopoietin (TPO) receptor agonist that increases platelet counts in patients with idiopathic thrombocytopenic purpura and in patients with liver cirrhosis. When cirrhotic patients with thrombocytopenia undergo elective invasive procedures, eltrombopag treatment reduces the requirement for platelet transfusions. However, TPO is known to have proliferative effects on hepatic progenitor cells and hepatic sinusoidal endothelial cells, which indicates that eltrombopag may accelerate tumor progression. Thus, the effect of eltrombopag on hepatocellular carcinoma (HCC) progression is an important issue. The current study describes two cases of HCC with cirrhosis-related thrombocytopenia. A two-week administration of eltrombopag increased platelet counts from 4.8 to 11.3×104 /μl in case 1 and 4.5 to 23.2×104 /μl in case 2. However, no changes were identified in the serum levels of tumor markers or HCC size following eltrombopag administration in the two cases. These HCCs were curatively treated by radiofrequency ablation without platelet transfusions or serious bleeding. Thus, short-term eltrombopag administration may not accelerate HCC proliferation and may be beneficial for invasive HCC treatment in cirrhotic patients with thrombocytopenia.

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Effects of thrombopoietin on growth of hepatocellular carcinoma: Is thrombopoietin therapy for liver disease safe or not?

Abstract: TPO had no proliferative effect on HCC in vitro or in vivo, and could therefore be useful in the treatment of liver cirrhosis.

Cited by 20 publications

References 48 publications

Immune thrombocytopenia – what are the new treatment options?

Immune thrombocytopenia – what are the new treatment options?

Novel functions of platelets in the liver

Usefulness of short-term eltrombopag treatment as a supportive treatment in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia: A report of two cases

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