Highlights d We build the genomic and transcriptomic landscape of 133 cHCC-ICCs d Integrative genomic analysis reveals distinct cHCC-ICC subtypes d Both mono-and multiclonal origins of cHCC-ICC are identified d Nestin expression can serve as a biomarker for the diagnosis and prognosis of cHCC-ICC

The extent of intratumor heterogeneity varies considerably among patients with HCC. Therefore, sequence analysis of a single lesion cannot completely characterize the genomic features of HCC in some patients. Genomic comparisons of multiple lesions associated with HCCs will provide important information on the genetic changes associated with tumor progression.

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Liver cancer is the second most common cause of cancer-related death worldwide. Approximately 70–90% of primary liver cancers are hepatocellular carcinoma (HCC). Currently, HCC patient prognosis is unsatisfactory due to high metastasis and/or post-surgical recurrence rates. Therefore, new therapeutic methods for inhibiting metastasis and recurrence are urgently needed. Exosomes are small lipid-bilayer vesicles that are implicated in tumour development and metastasis. Rab27a, a small GTPase, regulates exosome secretion by mediating multivesicular endosome docking at the plasma membrane. However, whether Rab27a participates in HCC cell-derived exosome exocytosis is unclear. Epithelial-mesenchymal transition (EMT) frequently initiates metastasis. The role of HCC cell-derived exosomes in EMT remains unknown. We found that exosomes from highly metastatic MHCC97H cells could communicate with low metastatic HCC cells, increasing their migration, chemotaxis and invasion. Rab27a knockdown inhibited MHCC97H-derived exosome secretion, which consequently promoted migration, chemotaxis and invasion in parental MHCC97H cells. Mechanistic studies showed that the biological alterations in HCC cells treated with MHCC97H-derived exosomes or MHCC97H cells with reduced self-derived exosome secretion were caused by inducing EMT via MAPK/ERK signalling. Animal experiments indicated that exosome secretion blockade was associated with enhanced lung and intrahepatic metastasis of parental MHCC97H cells, while ectopic overexpression of Rab27a in MHCC97H cells could rescue this enhancement of metastasis in vivo. Injection of MHCC97H cell-derived exosomes through the tail vein promoted intrahepatic recurrence of HLE tumours in vivo. Clinically, Rab27a was positively associated with serum alpha-fetoprotein (AFP) level, vascular invasion and liver cirrhosis. Our study elucidated the role of exosomes in HCC metastasis and recurrence, suggesting that they are promising therapeutic and prognostic targets for HCC patients.

Abstract. Vasculogenic mimicry (VM) has increasingly been recognized as a form of angiogenesis. In VM, epithelial cells are integrated into the malignant tumor vasculature. An association has been observed between VM and poor clinical prognosis in some malignant tumors. However, whether VM is present and clinically significant in hepatocellular carcinoma (HCC) is unknown. In this study, we determined whether VM was present in HCC and whether it was associated with tumor grade, invasion and metastasis, and survival duration. We collected paraffin-embedded HCC tumor samples, along with complete clinical and pathologic data for all the cases, and performed immunohistochemical staining for CD31, CD105 (endoglin), hepatocyte, vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9. The VM status was compared with the clinical and pathological data using statistical tests. Kaplan-Meier survival analysis and log-rank test were used to compare survival durations between patients with and without VM. The VM vessel cells were CD31 and CD105-negative and hepatocyte and vascular endothelial growth factor-positive, showing that they were not derived from endothelial cells but were HCC tumor cells. Patients with VM had a higher metastasis rate than did those without VM (P=0.003). Consistent with this finding, MMP-2 and MMP-9 were present in all the VM cases but were found less frequently in non-VM cases (P<0.05). The Kaplan-Meier survival analysis showed that patients in the VM group had a significantly shorter survival duration than did those in the non-VM group. In conclusion, VM is a marker of poor clinical prognosis in HCC: Its presence may be associated with a high tumor grade, invasion and metastasis, and short survival.