A decade?s studies on metastasis of hepatocellular carcinoma

Abstract

Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. This paper summarized a decade's studies on HCC metastasis at the Liver Cancer Institute of Fudan University. We have established a stepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with high metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cell clones (MHCC97H, HCCLM3, and HCCLM6) from their parent MHCC97 cell. Endeavors have been made for searching human HCC metastasis-related chromosomes/proteins/genes. Monogene-based studies revealed that HCC invasion/metastasis was similar to that of other solid tumors, and the biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophoresis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin as a lead gene in the signature, and found that genes favoring metastasis progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, was associated with HCC metastasis. Cytokeratin 19 was identified as one of the proteins, which was found in MHCC97H, but not in MHCC97L cells. Experimental interventions using the high metastatic nude mice model have provided clues for the prevention of HCC metastasis. Translation from workbench to bedside demonstrated that serum VEGF, microvessel density, and p53 scoring may be of value for the prediction of postoperative metastatic recurrence. Interferon alpha proved effective for the prevention of recurrence both experimentally and clinically. In conclusion, HCC metastasis that probably initiated in the primary tumor is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of the metastatic recurrence of HCC.

Clusterin plays an important role in hepatocellular carcinoma metastasis

“…To date, metastasis has remained one of the major challenges in the treatment of HCC (Tang et al, 2004).…”

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

“…27,28 The cells were cultured in Dulbecco's modified Eagle medium (DMEM) (Invitrogen, Gibco, Carlsbad, CA) containing 10% fetal bovine serum (Invitrogen) plus streptomycin and penicillin (Sigma, St. Louis, MO) at 37 C and 5% CO 2 . The Hep3B and PLC cell lines were defined as nonmetastatic cells because these cells could not metastasize from the liver to the lung in an orthotopic liver implantation mouse model (data not shown), whereas 97L and 97H cells were metastatic cells because 40% (97L) to 100% (97H) liver to lung metastatic behavior was observed in a mouse model.…”

“…The Hep3B and PLC cell lines were defined as nonmetastatic cells because these cells could not metastasize from the liver to the lung in an orthotopic liver implantation mouse model (data not shown), whereas 97L and 97H cells were metastatic cells because 40% (97L) to 100% (97H) liver to lung metastatic behavior was observed in a mouse model. 28 Vector-based siRNA (shRNA) has stronger in vivo inhibitory effects than synthetic siRNA; thus, shRNA-Notch1 and shRNA-control plasmids (GeneScript Corp., Piscataway, NJ) were used in the experiments. Purified plasmid DNA was transfected into 97L cells, which were then exposed to 200 lg of G418 selection for 4 weeks.…”

HTPAP gene on chromosome 8p is a candidate metastasis suppressor for human hepatocellular carcinoma

“…HCC metastasis is a multistep process that involves multiple genes (Liotta et al, 1991;Tang et al, 2004). During the past few years, many efforts have been paid to explore the mechanisms involved in the metastasis of HCC, and some metastasis-and invasion-related factors have been identified.…”