Moving toward an understanding of the metastatic process in hepatocellular carcinoma

P.0.Bex 2345 Bejing 000230 CluruWorld J Catenetrol, 2001 ;7(6) 77788Fox: + 86-1085381893E-mail; wcjd@ pubie . bta . net.en www. wl .w.w.on.cnConigu e 2001 by TDe WC Prese ISSN 1007 - 9327●INVITED COMMENTARY●Moving toward an understanding of the metastaticprocess in hepatocellular carcinomaW. Michael Korn见57A.Division of Gastroenterology and Comprehensive Cancer Center,invasion into surrounding issues including blood vessels ( which areUniversity ofUniveriy of Clfola San Fanic. San Fandico, CA 94143 -mediated by changes in integrin expression and activation of0128，!Correspondence to : UCSF Comprehensive Cancer Center, 2340 Sutter St.proteolytic enzymes) . Tumor cells reaching the circulation must haveSan Francisco, CA 94115, USA. mlkormn@ cc . ucsf. edudeveloped mechanisms to suppess anoikis, which is programmed cellTelephone: +1-415 - 502-2844，Fax: +1- 415 - 502 -3179death caused by disruption of cell- substrale adhesion, At distart sites,Received 2001-10-12 Accepted 2001-11-03turmor cells need to leave tbhe circulation and migrate to sites withfavorable conditions. Here, angiogenesis is again initiated and cellSee article omLi Y, Tang ZY, Ye SL, Liu YK, ChenJ, Xue Q,progression of the metastasis continmues. It is obvious that this|Chen J, Gao DM, Bao WH. Establishment of cell clones with|sequence of events will be dependent on multiple molecular factors indiffcrcat metastatic potential from the metastatic bepatocellularmalignant and normal (e.g. stroma and immunc competent) cells.carcinoma cell line MHCC97. P World J Gaslroenlerol, 2001 ;7(5):Some of these factors have been characterized in HCC. So far, and in63)- 636agreement with data from other tumor types. there is evidence that ahigh proliferative index (as mcasured by PCNA or Ki- 67 expression)is associated with reduccd tumor differeniation and might beSubject headingscarcinoma. bepatocellular/predictive of recurrence after tumor resection'In HCC, severalpathology; clone cells; tumor cells， cultured; neoplasmssignaling pathways are candidates for driving this proliferation, mainlymetastasishuse related to growth factor receptors. including Met, the reepturKorn WM. Moving Toward an Understanding of the Melastaitic Process infor the hepatocyte growth factor/ scatter faxcter ( HGF/SF) andHepatocellular Cardinoma. World J Gestroeruerod, 2001 ;7(6):777 - 778cpidcnmal growh factur rcepor ( EGFR )While enhancedpruliferation is an important step during oumorigenesis. increascs ininvasiveness and cell mobility are necessary for the generation 0INTRODUCTIONmelasases. It has been demonstrated that signaling through the Ras/Clinical factors contributing to the therapeuic challenge 0MAPK pathway ( which confers signals from growth factor recepturs,heatocllular carcinoma (HCC) are manifold; tumors arise often inincluding EGFR and Met), could cooperate with the TGF-β signalpatients with compromised liver function， therefore limingtransduction patbway in promoting the swich from a epithelial totherapeutic options; symptoms develop only at later stages of tumormecsenchymal pbenotype in cancer cells, rendering them significantlyprogression, and tumors tend to invade normnal structures or occur inmore mobile and invasivelll. In vitro data from HCC cell linesmultiple locations simultaneously. Nincty" percent of patients withsuppont this posibility, as it has becn dermonstrated hal TGF-Btumors larger than 5 cm will have synchronous intrahepatic metastasessignaling enhanccs proliferation of HCC cell lines! 13]. Disasembly ofa the time of presentation. In the majurity of patients undergoingprotein complexes involved in cell-cell adhesion has beenpartial bepatectomy for HCC，intra-bepauic or distant metastases willdcmonstrated as a consequence of TGFB and Ras/MAPKoccurl. Likewise, in about fly percent of the patients who diesignalingl4l. Accordingly, loss of expression of the cell- adhesionwithin five years aftcr liver transplantation for HCC，. intra- andmolccule E-cadherin and nuclear expression of its binding partner βextrahepatic recuncnces are the cause of deathl2.. Tumorcatcnin，occuTs frequenly in high-grade HCC and correlates with acharactcristics predicting recurence of HCC fllowing resectionpoor prognosish151. There is also strong evidence that HCC indeedinclude purtal vein invasion, intrahepatic metastasis, extratumoralactivates angiogenesis. For example， vascular endothelial growthspread，high mitotic index- ”， and a sarcomatous phenotypel6.factor ( VEGF)，a promoter of angiogenesis. was found to beSuch observations demonstrate that tumor cells that are easily invadingupregulared in HCCl6.. A reccn prospective studly in 100 palientsnormal tsses and achieve access to the circulation harbor the greatestundergoing resection of HCC demonstrated a strong correlationrisk of tumor rccurrence. The molecular events promotingbetween serum concentration of vascular endothelial growth factorinvasiveness of HCC clls arc still widely unknown. Further(VEGF) and microscopic vascular invasion[171. In the same study.understanding of thcse processes is urgenly needed for theigh serum levels were associated also with the presence ofdevelopment of rational sturategies for prevention and treatment 0intrabepatic metastases and reduced disease-free survival. Asmetastatic disease in HCC.indicated. successful invasion into surrounding tissues can also befacilitatedt by proleases that allow malignant cells to migrate throughInvestigaions in differenttumor types and murine models ofphysiolog“ 中国煤化工ns Ided cxrinerscancer depict a characteristic cascade of events necessary for a tumorusing-nembrune-type 1 matrixto achieve successful dissemination of metastases from a primarymetalloprnd promote intrahepaticYHCNMH Gand pooetumor. After malignant transformation and initial tumor growth，thefirst step towards metastasis formation is the initiation oactivator (uPA)，uPA reeptor ( uPAR) and plasminogen activatorvasularization of the tumor, a process known as the angiogenicinbibitor type-1 (PAI-1) was found 10 be associated with numorswitch. While the umor progresses, new genetic changes occurinvasiveness in a mouse model of HOC and human HCC9. . Overall,leading l0➊a reduced cell-cell adhesion, and, ②alterations in thethese data suggest that mechanisms of metastasis in HCC that areinteraction of序户数据ell with the extracellular matrix, alowingconsistent with data in oher lypes of solid tumors. However, most of778 ISSN 1007 - 9327CN 14- 1219/ RWorld J GastroenterolDecember 15, 2001 Volume 7 Number 6the evidence is circumstantial and correlative, reflccting a lack ofKuroda N, Takata M, Maeda s, Masushila K, Uemalsu K, Okanoto E.Cinicopatbologic analysis of sage I 0 hepaocellulara carcinoma showingappropriate modcl systems .early massive recurence afer liver resetion. J Gasroenternol Heputol,200;15:1192- 1198AsLi et al. describe in this isue of the World Jourmal ofGastrocntcrology, new model systems might be available thar couldYoshida K, Ashida K, Ohguchi S, Tsuji T. Proliferaing cell muclearlend insight into the mochanisms underlying the metastatie process inantigen and grade of malignanty in small hepatocelular carcinona-evabuation in US guidel specimens. Hepxungastrenterology, 1997 :44:245HCC. The authors generated two conally related cell line derivaivesfrorm human HCC cell line MHCC97 that show dramatic differences in8 Wu PC, Fang JW, Lau VK, Lai CL, Lo CK, Lan JY. Cassification o[their metastatic potential. Notably， the authors used an in vivohepatocellular carcinoma accordting to hepatoellular and biliarydiferentiation markers. Clinical and biological implications. An J Pathwl,selection process bat incluxded the orthotopic transplantation ol1996;149:1167- 1175 .xenografts into the livers of mice, thus simulating the clinical situation9 Suchimn T, Matsunata T, lasaku H，Yamanoto K，Kawahara N,as closely as possible. The difeneces in mclastatic potential wereSugimachi K. Clinicopathologic features and prognosis of resectedmirured by significant phenotypical diferences. Thecse incoudedhepatocelolar carcinomas of vanied sizes with special reference toproliferuting cell nuclear antigen. Camcer, 1995;76:399 - 405morpholugic iferences as well as faster proliferation, enhanced in10 Harada K, Shiota G, Knwasaki H. Trunsfoming growth facor-apba andvitro invasiveness, and increased alpha-fetoprotcin ( AFP) productionepidermul grwth factor roceptor in chronie liver disease aund betoellularof the highly malignant derivative compured to its less metastaticcarcinoma. liver, 1999; 19:318 - 325counterpart. These findings are consistent with the expected metastutic11 Wang R, Ferell LD, Faouzi s. Maher J, Bisbop JM. Activation of beMet receptor by cell attachment induces and sustains hepatocellolarphenotype of HCC and it will be most exciting to see results fromcarcinonas in transgenic mice. J Cell Biol, 2001; 153: 1023 - 1034molecular analyses of these cells. Particularly 。amalyses of difenial12 0OftM, PeliJ, Rudaz C, Schwarz H, Beug H, Reichmann E. TCiF-hetalgene expression, e. g. uring cDNA expression aurays. will beand Ha-Ras collaborale in modulaing the phenotypic plasticity aunurevealing and could be compared to results from the analysisinvasiveness of epithelial tumor cells. Geners Dev, 1996; 10:2462 - 24Marsuzaki K, Date M, Funukawa F. Tahashi Y, Matsushita M, Sakitaniexpression profiles in human tumors0l.，Yaumushiki N, Scki T, Saito H, Nisbizawa M, Fujisawa J, InoucAutocrine stimulatary mechanismn by transforming growth factor beta inIdentification of iferentially exressed gencs represents alhurman bepaloellular carcinoma. Cwuer Res, 2000:60: 1394- 1402important step toward understanding metastasis in this discase.Chen Y, Lu Q, Schneberger E，Goodenough DA. Restoration of tightjunction struclure and burier function by down- regulation of the mitogen-However, genetic evidence will be nocessary to pinpoint the culpris inactivated protcin kinase pathway in mb- ransformed Madin-Darby caninethis process. So far. transgenic mouse moxlels of HCC have beenkidney cells. Mol Biol Cell. 2000;11:849 - 862created in which liverspcific expression of polential oncogenes,1S Endo K, Ueda T. eyama」，Oha T, Terada T. mmunoreactive Ecadhcrin, alpha-catenin， bela- calenin, and gamma- catenin proteins ininchuding Cyclin DI. c-myc, TGF-a， and Mct leads consistently tohepatoellulkur curinoma: relationships with tuoor grade. cliniooputbhologicthe development of HCC-like tumrs2.11.21. Interestingly, tumorsparamcters, and patients' survival. Hum Pathol.2000;31 :558- 565cuming in thesc models lack a highly invasive or metastatic. 16 Muca II, Miyazaki T，Kuroda M. Oka T, Machinami R. Kodunu Tphenoltype. A next step is to rebuild the full phenotype of HCC inShibuya M. Makuuchi M, Yazaki Y, Ohnishi S. Increased cxpression ofmice using modified transgenic modcls that include combinaions ofvascular endoLhelial growthr in humanbealollula carcinma.Henttol. 97:27:854-861growth and metastasis promoting genes. Based on these models.Poon RT. Ng l0, LauC. ZhuIX. Yu WC, Lo CM. Fan ST, Wong J.rational therapcutic approaches could be developed and tested.Scrum vascular endothelial growth lautofautoroditsvicnousinvasioinxiets venousinvasoounbeaollular carcinomu: a propective snudy. Ann Surg, 2001;233: 228 Munkaani K, Sakukawa R, Ikeda T. Matsmura T. Hasunura s, NaganoriREFERENCES5，Yamada Y, Saikci 1. Invasiveness of hepatocellulur camcinoma cell lincs:Ono T, Yamanoi A, Naznry E Assl O, Kothno H,contribution of menbrane-lype I matrix mealopropeinse.cheunotherapy after reseution of healocelolar carcinoma causes deteroration1999;1:424- 430of long-term prognosis in cirhbotic patients: noetanalysis of three19 Zheng Q, Tang ZY, Xue Q, Shi DR. Song HY, Tang HB. 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