Gross appearance of hepatocellular carcinoma reflects E‐cadherin expression and risk of early recurrence after surgical treatment

Inayoshi, Jun; Ichida, Takafumi; Sugitani, Soichi; Tsuboi, Yasunori; Genda, Takuya; Honma, Naoki; Asakura, Hitoshi

doi:10.1046/j.1440-1746.2003.03021.x

Cited by 54 publications

(56 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…24 In a variety of cancers, such as lobular breast carcinoma, diffuse gastric carcinoma, endometrial and ovarian carcinoma, and hepatocellular carcinoma, reduced expression of E-cadherin due to genetic mutations, in combination with loss of heterozygosity at the E-cadherin gene (CDH1), has been correlated with the disruption of cell-cell contacts, epithelialmesenchymal transition, invasiveness, and metastatic potential. 20,[25][26][27][28][29][30] In this study, hepatocytes in normal liver and in hepatocellular adenoma showed a uniformly high expression of E-cadherin. Hepatocellular carcinoma with cirrhosis had a significantly MMPs are a group of zinc-dependent endopeptidases that share many structural and functional properties, but have different substrate specificities.…”

Section: Discussionmentioning

confidence: 94%

Distinction of hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase immunohistochemistry

et al. 2009

View full text Add to dashboard Cite

We studied the tumor cell expression patterns of E-cadherin and matrix metalloproteinase-1, -2, -7, and -9 in a tissue microarray composed of 20 normal livers, 10 hepatocellular adenomas, 43 hepatocellular carcinomas with cirrhosis and 33 hepatocellular carcinomas without cirrhosis. Hepatocellular adenoma was characterized by the complete absence of matrix metalloproteinase-7 expression; hepatocellular carcinoma with cirrhosis was characterized by a significantly low expression of E-cadherin; and hepatocellular carcinoma without cirrhosis was characterized by low matrix metalloproteinase-9 expression. The staining intensity score of E-cadherin ¼ 3, matrix a metalloproteinase-7o1, and matrix metalloproteinase-9Z2 can be used as the diagnostic criteria for hepatocellular adenoma and for distinguishing hepatocellular adenoma from normal, hepatocellular carcinoma with cirrhosis, and hepatocellular carcinoma without cirrhosis. E-cadherino2 and matrix metalloproteinase-9o2 can be used for distinguishing both hepatocellular carcinoma with cirrhosis and hepatocellular carcinoma without cirrhosis from normal. Although statistically not significant, hepatocellular carcinoma without cirrhosis showed a higher E-cadherin expression and a lower matrix metalloproteinase-9 expression than hepatocellular carcinoma with cirrhosis, which could be partially responsible for the less aggressive behavior found in hepatocellular carcinoma without cirrhosis when compared with hepatocellular carcinoma with cirrhosis. These results, if confirmed in a further study of small biopsy specimens and of histologically ambiguous cases, could lead to the application of these markers in the diagnosis and differential diagnosis of hepatocellular neoplasms in our surgical pathology practice.

show abstract

Section: Discussionmentioning

confidence: 94%

Distinction of hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase immunohistochemistry

et al. 2009

View full text Add to dashboard Cite

show abstract

“…25,26 This is the first study suggesting that inhibition of the TGF-␤1 pathway with LY2109761 may be a promising therapy in HCC patients, but more studies are needed to better define patients whose biological characteristics make them candidates for such a therapy.…”

Section: Discussionmentioning

confidence: 99%

Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells

et al. 2008

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) treatment is challenging because the mechanisms underlying tumor progression are still largely unknown. Transforming growth factor (TGF)-␤1 is considered a crucial molecule in HCC tumorigenesis because increased levels of patients' serum and urine are associated with disease progression. The aim of the present study was to investigate the inhibition of TGF-␤ signaling and its impact on HCC progression. Human HCC cell lines were treated with a TGF-␤ receptor kinase inhibitor (LY2109761) whose selectivity was determined in a kinase assay. Exogenous TGF-␤1 phosphorylates the TGF-␤ receptor, consequently activating Smad-2, whereas the drug selectively blocks this effect and dephosphorylates autocrine p-Smad-2 at concentrations ranging from 0.001 to 0.1 M. A cytotoxic effect documented by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), trypan blue, and propidium iodide staining assays was observed at 10 M, whereas the drug inhibits (P < 0.001) the migration of HCC cells on fibronectin, laminin-5, and vitronectin and invasion through Matrigel (P < 0.001) at concentrations up to 0.1 M. LY2109761 up-regulates (P < 0.001) E-cadherin mRNA and protein levels. This increase was localized at the cellular membrane where E-cadherin mediates anchorage that is cell-cell dependent. Consistently, a functional monoclonal antibody that inhibits E-cadherin-dependent cell-cell contact restores the migratory and invasive activity. Finally, nonmetastatic HCC tissues from 7 patients were cultured with TGF-␤1 in the presence or absence of LY2109761. E-cadherin expression was reduced by TGF-␤1 and was significantly (P < 0.0001) increased by LY2109761 treatment, measured by quantitative real-time PCR on microdissected tissues and by immunohistochemistry on serial sections. In 72 patients, E-cadherin tissue expression was more weakly expressed in metastatic than in nonmetastatic HCC (P < 0.0001). Conclusion: LY2109761 blocks migration and invasion of HCC cells by upregulating E-cadherin, suggesting that there could be a mechanistic use for this molecule in clinical trials. (HEPATOLOGY 2008;47:1557-1566 H epatocellular carcinoma (HCC) is a highly malignant cancer that is the third most frequent cause of tumor-related death in the United States and Europe. 1 Current therapeutic options are invasive and aim to physically remove or destroy the tumor mass. However, later recurrence and/or metastatic spread are common and negatively affect survival. The overall prognosis is still unsatisfactory, and little progress has been made in finding new treatment options. However, a recent study with sorafenib suggests that targeting the vasculature may provide additional insights into how to develop future treatment options for patients with HCC. 2 Based on the recent clinical observations with sorafenib, the focus for developing new treatments in HCC has shifted from targeting the cancer to targeting the tissue microenvironment and its role in modulating the biological behavior of HCC. 3 Transforming grow...

show abstract

“…Because of this adhesive function, E-cadherin has been suggested as an invasion suppressor molecule [10]. Since E-cadherin expression is inversely correlated with the degree of invasiveness in hepatocellular carcinoma [11], E-cadherin levels are considered as a potential biomarker of these tumors [12]. The epithelial-mesenchymal transition (EMT), a process in which epithelial cells acquire mesenchyme-like properties, is characterized by loss of E-cadherin and is associated with development and tumor progression.…”

Section: +mentioning

confidence: 99%

Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction

Lin

Chen

et al. 2006

FEBS Letters

View full text Add to dashboard Cite

Tumor-associated macrophages play an important role in tumor progression, but whether they exert a tumor-progressive effect remains controversial. Here, we demonstrated that activated macrophage-conditioned medium (AMCM) obtained from RAW macrophages (RAW/AMCM) induced epithelial-mesenchymal transition (EMT) and stimulated the migratory and invasive activities of HepG2 cells, whereas control conditioned media had no effect. Epithelial-cadherin (E-cadherin) and b-catenin staining patterns were altered at the adherens junctions by RAW/AMCM treatment, with an approximately 50% decrease in E-cadherin and b-catenin in the cell membrane. Importantly, levels of b-cateninassociated E-cadherin were also decreased. Following RAW/ AMCM treatment, enhanced activation of c-Src was seen prior to increased tyrosine phosphorylation of b-catenin, and this led to the destabilization of adherens junctions. Pretreatment of HepG2 cells with the Src kinase inhibitor, PP2, completely abolished the effects of RAW/AMCM on the EMT, migration, invasion, and expression and association of E-cadherin and bcatenin. AMCMs obtained from human THP-1 monocytes and mouse peritoneal macrophages also caused disassembly of the adherens junctions and migration of HepG2 cells. Furthermore, inhibition of the epidermal growth factor receptor (EGFR) with gefitinib partially prevented the downregulation of E-cadherin and b-catenin at the adherens junctions and migration behavior induced by RAW/AMCM. Our results suggest that activated macrophages have a tumor-progressive effect on HepG2 cells which involves the c-Src-and EGFR-dependent signaling cascades.

show abstract

Gross appearance of hepatocellular carcinoma reflects E‐cadherin expression and risk of early recurrence after surgical treatment

Abstract: Types 2 and 3 HCC have marked metastatic and invasive potential and reduced expression of E-cadherin, predicting a high risk of recurrence after surgical treatment.

Cited by 54 publications

References 13 publications

Distinction of hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase immunohistochemistry

Distinction of hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase immunohistochemistry

Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells

Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction

Contact Info

Product

Resources

About