ArticlePloS one2014
Increased expression of CCN2, epithelial membrane antigen, and fibroblast activation protein in hepatocellular carcinoma with fibrous stroma showing aggressive behavior.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it, 52 citations in OpenAlex.
- Association of future cancer metastases with fibroblast activation protein-α: a systematic review and meta-analysis.Frontiers in oncology · 2024Pooled it
- Connective Tissue Growth Factor in Digestive System Cancers: A Review and Meta-Analysis.BioMed research international · 2020Pooled it
- Hotspots and frontiers of the relationship between hepatocellular carcinoma and cancer-associated fibroblasts: a bibliometric analysis and review.Discover oncology · 2025Article
- Systematic review and meta-analysis of the prognostic role of fibroblast-activation protein in gastrointestinal cancers.Journal of gastrointestinal oncology · 2024Article
- Article
- Diagnostic Performances of PET/CT Using Fibroblast Activation Protein Inhibitors in Patients with Primary and Metastatic Liver Tumors: A Comprehensive Literature Review.International journal of molecular sciences · 2024Review
- From basic research to clinical application: targeting fibroblast activation protein for cancer diagnosis and treatment.Cellular oncology (Dordrecht, Netherlands) · 2024Review
- Advances in Histological and Molecular Classification of Hepatocellular Carcinoma.Biomedicines · 2023Review
- Efficiency of Promoters of Human GenesInternational journal of molecular sciences · 2023Article
- The role of epithelial membrane antigen (EMA) overexpression in the prognosis of prostatic adenocarcinoma.Journal of medicine and life · 2022Article
- Prognostic value of the immunohistochemistry markers CD56, TTF-1, synaptophysin, CEA, EMA and NSE in surgically resected lung carcinoid tumors.Molecular and clinical oncology · 2022Article
- Review
- Imaging fibroblast activation protein in liver cancer: a single-center post hoc retrospective analysis to compare [European journal of nuclear medicine and molecular imaging · 2021Article
- Scirrhous Hepatocellular Carcinoma: Systematic Review and Pooled Data Analysis of Clinical, Radiological, and Histopathological Features.Journal of hepatocellular carcinoma · 2021Article
- The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment.Frontiers in oncology · 2021Review
- Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges.Frontiers in cell and developmental biology · 2021Review
- Fibroblast imaging of hepatic carcinoma withEuropean journal of nuclear medicine and molecular imaging · 2021Article
- Clinicopathological Features of Two Extremely Rare Hepatocellular Carcinoma Variants: a Brief Review of Fibrolamellar and Scirrhous Hepatocellular Carcinoma.Journal of gastrointestinal cancer · 2020Review
- Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma.Journal of hematology & oncology · 2019Review
- Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics.Oncogene · 2018Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor behavior is affected by the tumor microenvironment, composed of cancer-associated fibroblasts (CAFs). Meanwhile, hepatocellular carcinomas (HCC) with fibrous stroma reportedly exhibit aggressive behavior suggestive of tumor-stroma interaction. However, evidence of the crosstalk remains unclear. In this study, CCN2, epithelial membrane antigen (EMA), fibroblast activation protein (FAP), and keratin 19 (K19) expression was studied in 314 HCCs (cohort 1), 42 scirrhous HCCs (cohort 2), and 36 chronic hepatitis/cirrhosis specimens by immunohistochemistry. Clinicopathological parameters were analyzed according to the expressions of these markers. In tumor epithelial cells from cohort 1, CCN2 and EMA were expressed in 15.3% and 17.2%, respectively, and their expressions were more frequent in HCCs with fibrous stroma (≥5% of tumor area) than those without (P<0.05 for all); CCN2 expression was well correlated with K19 and EMA expression. In tumor stromal cells, FAP expression was found in 6.7%. In cohort 2, CCN2, EMA, and FAP expression was noted in 40.5%, 40.5%, and 66.7%, respectively, which was more frequent than that in cohort 1 (P<0.05 for all). Additionally, EMA expression was associated with the expression of K19, CCN2, and FAP (P<0.05 for all); EMA expressing tumor epithelial cells showed a topographic closeness to FAP-expressing CAFs. Analysis of disease-free survival revealed CCN2 expression to be a worse prognostic factor in both cohort 1 (P = 0.005) and cohort 2 (P = 0.023), as well as EMA as a worse prognostic factor in cohort 2 (P = 0.048). In conclusion, expression of CCN2, EMA, and FAP may be involved in the activation of CAFs in HCC, giving rise to aggressive behavior. Significant correlation between EMA-expressing tumor cells and FAP-expressing CAFs and their topographic closeness suggests possible cross-talk between tumor epithelial cells and stromal cells in the tumor microenvironment of HCC.
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