Hedgehog Signaling Activation in Hepatic Stellate Cells Promotes Angiogenesis and Vascular Mimicry in Hepatocellular Carcinoma

Li, Wei; Miao, Shuanlin; Miao, Manyuan; Li, Renshuan; Cao, Xiaopeng; Zhang, Kun; Huang, Genzuan; Fu, Bin

doi:10.1080/07357907.2016.1227442

Cited by 20 publications

(14 citation statements)

References 27 publications

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“…Hh also induces an epithelial to mesenchymal transition in malignant cells, favoring migration and invasiveness (Chen et al, 2014; Byrne et al, 2015). Finally, cancer-associated stromal cells release Hh ligands that promote malignant cell proliferation, angiogenesis and metastasis (Chan et al, 2014; Liu et al, 2016; Li et al, 2016). In human hepatocellular carcinoma, excessive Hh signaling occurs relatively frequently (Sicklick et al, 2006; Cheng et al, 2009; Al-Bahrani et al, 2015; Dugum et al, 2016), and the level of Hh pathway activity positively correlates with tumor size, invasion, chemoresistance, metastasis and mortality (Sicklick et al, 2006; Cheng et al, 2009; Chen et al, 2011; Lu et al, 2012; Che et al, 2012).…”

Section: Hedgehog Pathway In Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

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Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting Hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hedgehog pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

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Section: Hedgehog Pathway In Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

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“…Hedgehog signaling pathway activation can promote tumor cell growth, migration, metastasis and in vivo tumorigenesis . In hepatic stellate cells, the Hedgehog signaling pathway is activated, which promotes hepatoma cell angiogenesis and vasculogenic mimicry . Previous studies have indicated that activated Hedgehog signaling has important functions in HCC occurrence and development.…”

Section: Introductionmentioning

confidence: 99%

Krüppel‐like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway

Lin

Nie

et al. 2019

Cancer Science

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The most important reason for the occurrence of HCC is hepatitis C or B infection. Moreover, genetic factors play an important role in the tumorigenesis of HCC. Here, we demonstrated that Krüppel‐like factor 2 (KLF2) expression was downregulated in HCC samples compared with adjacent tissues. Additionally, KLF2 was shown to inhibit the growth, migration and colony‐formation ability of liver cancer cells. Further mechanistic studies revealed that KLF2 can compete with Gli1 for interaction with HDAC1 and restrains Hedgehog signal activation. Together, our results suggest that KLF2 has potential as a diagnostic biomarker and therapeutic target for the treatment of HCC.

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“…The Hh signaling pathway has been implicated in the regulation of angiogenesis in normal tissues (77, 78) and cancer (79, 80) through induction of angiogenic factors including VEGFs and ANG1, 2. Examination of CD31 expression, a marker of endothelial cells, showed decreased blood vessel density in LAD tumors treated with anti-SHH/IHH 5E1 antibody compared to IgG 1 treated tumors (Fig.…”

Section: Resultsmentioning

confidence: 99%

Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Kasiri

Chen

Wilson

et al. 2019

Preprint

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Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. We demonstrate that the Hh signaling pathway is activated in lung stroma in a paracrine manner. Genetic deletion of Shh in autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, not SHH, activates the pathway in stroma to drive its tumor suppressive effects - a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased reactive oxygen species (ROS). Treatment of KP mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor ROS levels, inhibited tumor growth and prolonged mouse survival suggesting that increased ROS levels from stromal Hh pathway inhibition spurred lung tumor growth. Thus, IHH induces stromal Hh pathway activation to suppress tumor growth and metastases, in part, by limiting ROS production.

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Hedgehog Signaling Activation in Hepatic Stellate Cells Promotes Angiogenesis and Vascular Mimicry in Hepatocellular Carcinoma

Cited by 20 publications

References 27 publications

The hedgehog pathway in nonalcoholic fatty liver disease

The hedgehog pathway in nonalcoholic fatty liver disease

Krüppel‐like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway

Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

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