10 This subtype, which has intermediate features between HCC and CC, showed distinct pathobiological characteristics enriched with stem-cell–like gene traits BYL719 and therefore poorer clinical outcomes. However, the histopathological characteristics of these intermediate tumors have not yet been fully evaluated. Therefore, we hypothesized that the HCC phenotype with a fibrous stromal component (S-HCC) may share common genomic features with CC-like HCC, such as CC-like and/or stem-cell–like expression traits. To evaluate our hypothesis, we performed a gene-expression
profiling analysis of S-HCC and compared the profiles of S-HCC with those of HCC (i.e., classical HCC without fibrous tissue) and CC. In addition, it has been reported that scirrhous-type cancers, including gastric cancer, become invasive and metastatic by stimulating epithelial-mesenchymal transition (EMT).11 EMT is the differentiation
switch from polarized epithelial cells to contractile and motile mesenchymal cells.12 EMT is thought to be a fundamental process that governs morphogenesis during embryogenesis and is reactivated in fibrogenic disease, provoking tumor progression.13 Snail and Twist, the key molecules of EMT, are associated with invasion 5-Fluoracil cost and tumor metastasis and are also independent markers for worse prognosis in HCC.14, 15 A recent study also demonstrated that EMT induction by ectopic expression of either Snail or Twist transcription factors is able to generate cancer stem-cell properties in human breast cancer cells.16 These results suggest that EMT may play a critical role in the aggressive behavior and acquisition of stem-cell–like traits in S-HCC. With respect to these notions, we further evaluated whether EMT is involved in the HCC phenotype with fibrous stroma (S-HCC). AFP, alpha-fetoprotein; CC, cholangiocarcinoma; CD, cluster of differentiation; CHC, combined hepatocellular-cholangiocarcinoma; cRNA, complementary find more RNA; DFS, disease-free survival; EMT, epithelial-mesenchymal
transition; EpCAM, epithelial cell adhesion molecule; GSEA, gene set enrichment analysis; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; K, keratin; mRNA, messenger RNA; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; RT, reverse transcription; S-HCC, scirrhous hepatocellular carcinoma; SPC, stem/progenitor cell; TGF-β, transforming growth factor beta; TGFβRI, transforming growth factor beta receptor I; TGFβRII, transforming growth factor beta receptor II. A total of 57 cases of primary liver carcinomas showing the following features were studied: (1) 14 patients with S-HCC, which had fibrous stroma in ≥50% of the tumor area by histological morphometry in the greatest dimension of cut surface9, 10, 17; (2) 24 patients with HCC, which had very little or no fibrous stroma; and (3) 19 patients with typical CCs.