Moving toward an understanding of the metastatic process in hepatocellular carcinoma

摘要: Clinical factors contributing to the therapeutic challenge of hepatocellular carcinoma (HCC) are manifold: tumors arise often in patients with compromised liver function, therefore limiting options; symptoms develop only at later stages tumor progression, and tend invade normal structures or occur multiple locations simultaneously. Ninety percent larger than 5 cm will have synchronous intrahepatic metastases time presentation. In majority undergoing partial hepatectomy for HCC, intra-hepatic distant occur[1]. Likewise, about fifty who die within five years after transplantation intra- extrahepatic recurrences cause death[2]. Tumor characteristics predicting recurrence HCC following resection include portalvein invasion, metastasis, extratumoral spread, high mitotic index [3-5], a sarcomatous phenotype[6]. Such observations demonstrate that cells easily invading tissues achieve access circulation harbor greatest risk recurrence. The molecular events promoting invasiveness still widely unknown. Further understanding these processes is urgently needed development rational strategies prevention treatment metastatic disease HCC. Investigations different types murine models cancer depict characteristic cascade necessary successful dissemination from primary tumor. After malignant transformation initial growth, first step towards metastasis formation initiation vascularization tumor, process known as angiogenic switch. While progresses, new genetic changes leading ① reduced cell-cell adhesion, and, ② alterations interaction cell extracellular matrix, allowing invasion into surrounding including blood vessels (which mediated by integrin expression activation proteolytic enzymes). reaching must developed mechanisms suppress anoikis, which programmed death caused disruption cell-substrate adhesion. At sites, need leave migrate sites favorable conditions. Here, angiogenesis again initiated progression continues. It obvious this sequence be dependent on (e.g. stroma immune competent) cells. Some been characterized HCC. So far, agreement data other types, there evidence proliferative (as measured PCNA Ki-67 expression) associated differentiation might predictive resection[7-9]. several signalingpathways candidates driving proliferation, mainly those related growth factor receptors, Met, receptor hepatocyte factor/scatter facter (HGF/SF) epidermal (EGFR)[10,11]. enhanced proliferation an important during tumorigenesis, increases mobility generation metastases. has demonstrated signaling through Ras/MAPK pathway confers signals EGFR Met), could cooperate TGF-β signal transduction switch epithelial mesenchymal phenotype cells, rendering them significantly more mobile invasive[12]. vitro lines support possibility, it enhances lines[13]. Disassembly protein complexes involved adhesion consequence signaling[14]. Accordingly, loss cell-adhesion molecule E-cadherin nuclear its binding partner β-catenin, occurs frequently high-grade correlates poor prognosis[15]. There also strong indeed activates angiogenesis. For example, vascular endothelial (VEGF), promoter angiogenesis, was found upregulated HCC[16]. A recent prospective study 100 correlation between serum concentration (VEGF) microscopic invasion[17]. same study, levels were presence disease-free survival. As indicated, can facilitated proteases allow physiologic barriers, e.g. basement membranes. Indeed, experiments using revealed membrane-type 1 matrix metal loproteinase confer promote metastases[18]. addition, urokinase-type plasminogen activator (uPA), uPA (uPAR) inhibitor type-1 (PAI-1) mouse model human HCC[19]. Overall, suggest consistent solid tumors. However, most circumstantial correlative, reflecting lack appropriate systems. As Li et al describe issue World Journal Gastroenterology, systems available lend insight underlying authors generated two clonally line derivatives MHCC97 show dramatic differences their potential. Notably, used vivo selection included orthotopic xenografts livers mice, thus simulating clinical situation closely possible. potential mirrored significant phenotypical differences. These morphologic well faster invasiveness, increased alpha-fetoprotein (AFP) production highly derivative compared less counterpart. findings expected H CC exciting see results analyses Particularly, differential gene expression, cDNA arrays, revealing analysis profiles tumors[20]. Identification differentially expressed genes represents toward disease. pinpoint culprits process. transgenic created liver-specific oncogenes, Cyclin D1, c-myc, TGF-a, Met leads consistently HCC-like tumors[21,11,22]. Interestingly, occurring invasive phenotype. next rebuild full mice modified combinations genes. Based models, approaches tested.