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Increased Expression of CCN2, Epithelial Membrane Antigen, and Fibroblast Activation Protein in Hepatocellular Carcinoma with Fibrous Stroma Showing Aggressive Behavior

 Gi Jeong Kim  ;  Hyungjin Rhee  ;  Jeong Eun Yoo  ;  Jung Eun Ko  ;  Jee San Lee  ;  Hyunki Kim  ;  Jin Sub Choi  ;  Young Nyun Park 
 PLOS ONE, Vol.9(8) : e105094, 2014 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/metabolism* ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/mortality ; Carcinoma, Hepatocellular/pathology ; Connective Tissue Growth Factor/metabolism* ; Disease-Free Survival ; Female ; Gelatinases/metabolism* ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/metabolism* ; Liver Neoplasms/mortality ; Liver Neoplasms/pathology ; Male ; Membrane Proteins/metabolism* ; Middle Aged ; Mucin-1/metabolism* ; Proportional Hazards Models ; Serine Endopeptidases/metabolism* ; Tumor Microenvironment
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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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Ko, Jung Eun(고정은)
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
Lee, Jee San(이지산)
Rhee, Hyungjin(이형진) ORCID logo https://orcid.org/0000-0001-7759-4458
Choi, Jin Sub(최진섭)
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