Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma

Amicone, Laura; Marchetti, Alessandra

doi:10.21037/tgh.2018.04.05

Cited by 40 publications

(35 citation statements)

References 130 publications

(136 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the role of the tumor microenvironment in tumor progression is well established (Amicone and Marchetti, ; Kamil and Rowe, ), the cross‐talk between HSC and HCC cells in liver cancer metastasis has hardly been explored. Our previous study showed that activated HSCs create an immunosuppressive microenvironment in an orthotopic liver tumor mouse model by inducing expansion of the Tregs and MDSCs (Zhao et al , ) (Zhao et al , ).…”

Section: Discussionmentioning

confidence: 99%

Elevated N‐methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform

Shang

Zhang

et al. 2019

Molecular Oncology

View full text Add to dashboard Cite

The cross‐talk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, but the underlying mechanism is largely unknown. We report here that activated HSCs induce upregulation of nicotinamide N‐methyltransferase (NNMT), which is known to regulate multiple metabolic pathways in hepatoma cells of the liver. High levels of NNMT in HCC tissues were positively correlated with vascular invasion, increased serum HBV‐DNA levels, and distant metastasis. In addition, functional assays showed that NNMT promoted HCC cell invasion and metastasis by altering the histone H3 methylation on 27 methylation pattern and transcriptionally activating cluster of differentiation 44 (CD44). NNMT‐mediated N6‐methyladenosine modification of CD44 mRNA resulted in the formation of a CD44v3 splice variant, while its product 1‐methyl‐nicotinamide stabilized CD44 protein by preventing ubiquitin‐mediated degradation. Finally, NNMT was also shown to be a target of statins that inhibited metastasis of hepatoma cells. Taken together, our study shows for the first time that the NNMT/CD44v3 axis regulates HCC metastasis and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Elevated N‐methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform

Shang

Zhang

et al. 2019

Molecular Oncology

View full text Add to dashboard Cite

show abstract

“…Several types of cells in the tumor microenvironment (immune cells, endothelial cells, and fibroblasts, etc.) support this process [74,75]. Fibrosis is particularly important for HCC development as 80-90% of the cases develops in a background of advanced liver fibrosis and cirrhosis [5].…”

Section: Activated Hscs/cafs Hcc Drug Resistance and Hcc Immunotherapymentioning

confidence: 96%

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

et al. 2020

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)-and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

show abstract

“…Thus, the increase of both Raf and PCNA in the lung parenchyma surrounding NDMA-induced lung tumors suggesting an important lung tumor–macrophage interaction ( Ramakrishna et al, 2002 ). IL-1β is also able to contribute to fibrosis while TNF-α increases anti-apoptotic signals to avoid cell death ( Amicone & Marchetti, 2018 ). Importantly, while carcinogens can induce inflammation, chronic inflammation can also increase carcinogen exposure and uptake within the body by weakening barrier functions ( Greten & Grivennikov, 2019 ).…”

Section: Mechanisms Of Pro-tumorigenic Activity By Carcinogensmentioning

confidence: 99%

Carcinogenesis: Failure of resolution of inflammation?

Fishbein

Hammock

Serhan

et al. 2021

Pharmacology & Therapeutics

138

View full text Add to dashboard Cite

Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.

show abstract

Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma

Cited by 40 publications

References 130 publications

Elevated N‐methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform

Elevated N‐methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform

Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

Carcinogenesis: Failure of resolution of inflammation?

Contact Info

Product

Resources

About