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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2001; December 7(6):777-77 8

Moving toward an understanding of the metastatic process in hepatocellular carcinoma

W. Michael Korn


W. Michael Korn  Division of Gastroenterology and Comprehensive Cancer Center, University of California San Francisco, San Francisco,
CA 94143-0128, USA
Correspondence to UCSF Comprehensive Cancer Center, 2340 Sutter St. San Francisco, CA 94115, USA. mkorn@cc.ucsf.edu
Telephone: +1-415-502-2844, Fax: +1-415-502-3179
Received 2001-10-12 Accepted 2001-11-03

See article on Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q , Chen J, Gao DM,Bao WH. Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97.P World J Gastroenterol, 2001;7(5):630-636

Subject headings:
carcinoma, hepatocellular/pathology; clone cells; tumor cells, cultured; neoplasms metastasis

Korn WM. Moving Toward an Understanding of the Metastatic Proc ess in Hepatocellular Carcinoma.
World J Gastroenterol, 2001;7(6):777-77 8

INTRODUCTION
Clinical factors contributing to the therapeutic challenge of hepatocellul ar carcinoma (HCC) are manifold: tumors arise often in patients with compromised liver function, therefore limiting therapeutic options; symptoms develop only at later stages of tumor progression, and tumors tend to invade normal structures or occur in multiple locations simultaneously. Ninety percent of patients with tumors larger than 5 cm will have synchronous intrahepatic metastases at the tim e of presentation. In the majority of patients undergoing partial hepatectomy fo r HCC, intra-hepatic or distant metastases will occur[1]. Likewise, in about fifty percent of the patients who die within five years after liver transplantatio n for HCC, intra- and extrahepatic recurrences are the cause of death[2]. Tumor characteristics predicting recurrence of HCC following resection include portal vein invasion, intrahepatic metastasis, extratumoral spread, high mitotic index [3-5], and a sarcomatous phenotype[6]. Such observations demonstrate t hat tumor c ells that are easily invading normal tissues and achieve access to the circulati on harbor the greatest risk of tumor recurrence. The molecular events promoting invasiveness of HCC cells are still widely unknown. Further understanding of the se processes is urgently needed for the development of rational strategies for p revention and treatment of metastatic disease in HCC.

Investigations
 in different tumor types and murine models of cancer depict a characteristic ca scade of events necessary for a tumor to achieve successful dissemination of met astases from a primary tumor. After malignant transformation and initial tumor g rowth, the first step towards metastasis formation is the initiation of vascular ization of the tumor, a process known as the angiogenic switch. While the tumor progresses, new genetic changes occur leading to
a reduced cell-cell adhesi o n, and, alterations in the interaction of the tumor cell with the extracellu lar matrix, allowing invasion into surrounding tissues including blood vessels ( which are mediated by changes in integrin expression and activation of proteolyt ic enzymes). Tumor cells reaching the circulation must have developed mechanisms to suppress anoikis, which is programmed cell death caused by disruption of cel l-substrate adhesion. At distant sites, tumor cells need to leave the circulati o n and migrate to sites with favorable conditions. Here, angiogenesis is again in itiated and cell progression of the metastasis continues. It is obvious that thi s sequence of events will be dependent on multiple molecular factors in malignan t and normal (e.g. stroma and immune competent) cells. Some of these factors hav e been characterized in HCC. So far, and in agreement with data from other tumor types, there is evidence that a high proliferative index (as measured by PCNA o r Ki-67 expression) is associated with reduced tumor differentiation and might b e predictive of recurrence after tumor resection[7-9]. In HCC, several s ignaling pathways are candidates for driving this proliferation, mainly those related to growth factor receptors, including Met, the receptor for the hepatocyte growth factor/scatter facter (HGF/SF) and epidermal growth factor receptor (EGFR)[ 10,11 ]. While enhanced proliferation is an important step during tumorigenesis, in cre ases in invasiveness and cell mobility are necessary for the generation of metastases. It has been demonstrated that signaling through the Ras/MAPK pathway (whi ch confers signals from growth factor receptors, including EGFR and Met), could cooperate with the TGF-β signal transduction pathway in promoting the switch f ro m a epithelial to mesenchymal phenotype in cancer cells, rendering them signific antly more mobile and invasive[12]. In vitro data from HCC cell line s support th is possibility, as it has been demonstrated that TGF-β signaling enhances prol if eration of HCC cell lines[13]. Disassembly of protein complexes involved in cell -cell adhesion has been demonstrated as a consequence of TGF-β and Ras/MAPK s ign aling[14]. Accordingly, loss of expression of the cell-adhesion molecul e E-cadhe rin and nuclear expression of its binding partner β-catenin, occurs frequently i n high-grade HCC and correlates with a poor prognosis[15]. There is als o strong evidence that HCC indeed activates angiogenesis. For example, vascular endotheli al growth factor (VEGF), a promoter of angiogenesis, was found to be upregulated in HCC[16]. A recent prospective study in 100 patients undergoing resec tion of HCC demonstrated a strong correlation between serum concentration of vascular en dothelial growth factor (VEGF) and microscopic vascular invasion[17]. In the sam e study, high serum levels were associated also with the presence of intrahepati c metastases and reduced disease-free survival. As indicated, successful invasi o n into surrounding tissues can also be facilitated by proteases that allow malig nant cells to migrate through physiologic barriers, e.g. basement membranes. Ind eed, experiments using HCC cell lines revealed that membrane-type 1 matrix meta l loproteinase confer invasiveness and promote intrahepatic metastases[18] . In addition, expression of urokinase-type plasminogen activator (uPA), uPA receptor ( u PAR) and plasminogen activator inhibitor type-1 (PAI-1) was found to be associ at ed with tumor invasiveness in a mouse model of HCC and human HCC[19]. Ov erall, t hese data suggest that mechanisms of metastasis in HCC that are consistent with data in other types of solid tumors. However, most of the evidence is circumstantial and correlative, reflecting a lack of appropriate model systems.
      As Li et al. describe in this issue of the World Journal of Gastroenterology , new mo del systems might be available that could lend insight into the mechanisms underlying the metastatic process in HCC. The authors generated two clonally related cell line derivatives from human HCC cell line MHCC97 that show dramatic differe nces in their metastatic potential. Notably, the authors used an in vivo sel ecti on process that included the orthotopic transplantation of xenografts into the l ivers of mice, thus simulating the clinical situation as closely as possible. Th e differences in metastatic potential were mirrored by significant phenotypical differences. These included morphologic differences as well as faster proliferat ion, enhanced in vitro invasiveness, and increased alpha-fetoprotein (AFP) prod u ction of the highly malignant derivative compared to its less metastatic counter part. These findings are consistent with the expected metastatic phenotype of H CC and it will be most exciting to see results from molecular analyses of these cells. Particularly, analyses of differential gene expression, e.g. using cDNA e xpression arrays, will be revealing and could be compared to results from the an alysis expression profiles in human tumors[20].
      Identification of di fferentially expressed genes represents an important step toward understanding m etastasis in this disease. However, genetic evidence will be necessary to pinpoi nt the culprits in this process. So far, transgenic mouse models of HCC have bee n created in which liver-specific expression of potential oncogenes, including C yclin D1, c-myc, TGF-a, and Met leads consistently to the development of HCC- lik e tumors[21,11,22]. Interestingly, tumors occurring in these models lack a highl y invasive or metastatic phenotype. A next step is to rebuild the full phenotype of HCC in mice using modified transgenic models that include combinations of gr owth and metastasis promoting genes. Based on these models, rational therapeutic approaches could be developed and tested.

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