A decade's studies on metastasis of hepatocellular carcinoma.
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.
Tang
Zhao-You
ZY
Liver Cancer Institute, Zhongshan Hospital, 136 Yi Xue Yuan Road, 200032, Shanghai, PR China. ztang@srcap.stc.sh.cn
Ye
Sheng-Long
SL
Liu
Yin-Kun
YK
Qin
Lun-Xiu
LX
Sun
Hui-Chuan
HC
Ye
Qin-Hai
QH
Wang
Lu
L
Zhou
Jian
J
Qiu
Shuang-Jian
SJ
Li
Yan
Y
Ji
Xue-Ning
XN
Liu
Hu
H
Xia
Jing-Ling
JL
Wu
Zhi-Quan
ZQ
Fan
Jia
J
Ma
Zeng-Chen
ZC
Zhou
Xin-Da
XD
Lin
Zhi-Ying
ZY
Liu
Kang-Da
KD
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics* / Q000556:secondary*; D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8; D018076:DNA, Complementary / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D015180:Electrophoresis, Gel, Two-Dimensional; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007633:Keratins / Q000032:analysis; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D014408:Biomarkers, Tumor; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D007633:Keratins