Tumor microenviroment and hepatocellular carcinoma metastasis

Wang, Hongyang; Chen, Lei

doi:10.1111/jgh.12091

Cited by 84 publications

(62 citation statements)

References 83 publications

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“…However, the sensitivity to sorafenib after development of resistance can partially be restored using PI3K/Akt-or BCRP/Hedgehog-inhibitors in vitro. In addition to hepatocytes, noncellular tumor components may also play a role [49] . They manipulate hepatocellular carcinoma invasion and metastasis by facilitating epithelial-mesenchymal transition, increasing the proteolytic activity of matrix metalloproteinases, and regulating antitumor immunity.…”

Section: Epithelial-mesenchymal Transition and Sorafenib Resistancementioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.

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Section: Epithelial-mesenchymal Transition and Sorafenib Resistancementioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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“…118 High NK cell infiltration in tumor sites correlates with a better prognosis and improved survival. 11 NK cells express chemokine receptors, such as CCR2, CCR5, CXCR3 and CX3CR1, and can migrate to inflamed sites or to tumors in response to their respective chemokines. CXCR3 and CX3CR1 are key chemokine receptors responsible for NK cell migration to tumors.…”

Section: Nk Function and Chemokinesmentioning

confidence: 99%

“…It has been demonstrated that tumor-infiltrating immune cells play an important role in host immune defense against tumor progression in various cancers. [8][9][10][11] These observations seem to provide a reasonable treatment direction and impel an increasing number of researchers to focus on immune responses in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono-and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC. Keywords: activating receptor; hepatocellular carcinoma; inhibitory receptor; natural killer cell; natural killer receptor INTRODUCTION Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. 1 Common clinical risk factors for HCC include hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, heavy alcohol intake, steatohepatitis and diabetes. 2 Approximately 50% of HCC cases worldwide can be attributed to chronic HBV infection (CHB) and almost 75% of HCC cases occur in developing countries where HBV is endemic. 3,4 According to statistics, older male patients who are infected with HBV genotype C or co-infected with HCV, have high levels of viral load and have been exposed to the aflatoxin, or older male patients who have a family history of HCC tend to have a high risk of developing HCC. [5][6][7] Accumulating clinical and epidemiological evidence shows a significant correlation between chronic HBV infection and hepatocarcinogenesis. However, the underlying mechanisms

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“…Hepatocellular carcinoma (HCC) is the most common liver cancer and has a very poor treatment outcome [1][2][3]. Nevertheless, although our understanding of the pathogenesis of HCC has significantly improved in the past years, the precise molecular basis underlying HCC cell growth and survival from chemotherapy remains not clarified [4].…”

Section: Introductionmentioning

confidence: 99%

Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling

Sun

Luo

et al. 2014

Tumor Biol.

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Autophagy is a cellular degradation process for the clearance of damaged or superfluous proteins and organelles, the recycling of which serves as an alternative energy source during periods of metabolic stress to maintain cell homeostasis and viability. The anti-necrotic function of autophagy is critical for tumorigenesis of many tumor cells, including hepatocellular carcinoma (HCC). However, the underlying mechanism is not clarified yet. Ammonium chloride (NH4Cl) is a well-known autophagy inhibitor, whereas its interaction with SMAD2 signaling pathway has not been reported previously. Here, we show that NH4Cl significantly inhibited rapamycin-induced autophagy in HCC cells through decreasing the levels of Beclin-1, autophagy-related protein 7 (ATG7), p62, and autophagosome marker LC3 and significantly decreased the level of phosphorylated SMAD2 in rapamycin-treated HCC cells. In order to find out whether NH4Cl may inhibit the autophagy in rapamycin-treated HCC cells through inhibition of SMAD2 signaling, we used transforming growth factor β1 (TGFβ1) to induce phosphorylation of SMAD2 in HCC cells. We found that induction of SMAD2 in HCC cells completely abolished the inhibitory effect of NH4Cl on rapamycin-induced autophagy in HCC cells, suggesting that NH4Cl inhibits autophagy of HCC cells through inhibiting SMAD2 signaling.

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Tumor microenviroment and hepatocellular carcinoma metastasis

Cited by 84 publications

References 83 publications

New knowledge of the mechanisms of sorafenib resistance in liver cancer

New knowledge of the mechanisms of sorafenib resistance in liver cancer

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling

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