title: Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A-HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC-prone microenvironment. Here, we have identified and validated an A-HSC-specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue-related, A-HSC-specific gene expression is associated with recurrence and poor survival. Analyses of A-HSC-specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A-HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A-HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation.
  
  
  CONCLUSIONS
  A-HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse.
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.|Department of Pathology, Medical School of Nantong University, Nantong, China.
authors.forename: Juling
authors.initials: J
authors.lastname: Ji
authors.affiliation: Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eggert
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Budhu
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Marshonna
authors.initials: M
authors.lastname: Forgues
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takai
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Hien
authors.initials: H
authors.lastname: Dang
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Systems Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002450:Cell Communication; D002465:Cell Movement; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor
references.citation: F1000Prime Rep. 2014 Mar 03;6:13
references.pmid: 24669294
references.citation: Ann Surg Oncol. 2009 Sep;16(9):2555-64
references.pmid: 19548033
references.citation: Am J Clin Pathol. 2009 Apr;131(4):498-510
references.pmid: 19289585
references.citation: Gastroenterology. 2007 May;132(5):1937-46
references.pmid: 17484886
references.citation: Cancer Res. 2008 Mar 1;68(5):1451-61
references.pmid: 18316609
references.citation: J Immunol. 2013 Jan 15;190(2):794-804
references.pmid: 23248262
references.citation: N Engl J Med. 2008 Nov 6;359(19):1995-2004
references.pmid: 18923165
references.citation: Hepatology. 2012 Jul;56(1):332-49
references.pmid: 22331624
references.citation: Cancer Res. 2010 Dec 15;70(24):10202-12
references.pmid: 21159642
references.citation: Cell. 2010 Mar 19;140(6):883-99
references.pmid: 20303878
references.citation: Front Biosci (Schol Ed). 2013;5:217-30
references.pmid: 23277047
references.citation: Hepatology. 2004 Sep;40(3):667-76
references.pmid: 15349906
references.citation: Hepatology. 2014 Mar;59(3):1060-72
references.pmid: 24481979
references.citation: Hepatology. 2009 Sep;50(3):799-807
references.pmid: 19551844
references.citation: Cancer Res. 2005 Jun 1;65(11):4728-38
references.pmid: 15930291
references.citation: Hepatology. 2013 Feb;57(2):829-39
references.pmid: 23081697
references.citation: Gastroenterology. 2009 Mar;136(3):1012-24
references.pmid: 19150350
references.citation: J Exp Clin Cancer Res. 2013;32:22
references.pmid: 23601182
references.citation: J Hepatol. 2013 Sep;59(3):528-35
references.pmid: 23665041
references.citation: Nat Commun. 2013;4:2823
references.pmid: 24264436
references.citation: Gastroenterology. 2014 Sep;147(3):577-594.e1
references.pmid: 25066692
references.citation: Cancer Res. 2009 Sep 15;69(18):7385-92
references.pmid: 19723656
references.citation: J Clin Invest. 2013 May;123(5):1902-10
references.pmid: 23635788
references.citation: Genes Immun. 2005 Jun;6(4):319-31
references.pmid: 15789058
references.citation: Hepatology. 2011 Aug;54(2):707-13
references.pmid: 21520207
references.citation: Cancer Res. 2012 May 15;72(10):2533-42
references.pmid: 22419664
references.citation: Ann Surg. 2000 Jul;232(1):10-24
references.pmid: 10862190
references.citation: J Immunol. 2014 Apr 15;192(8):3858-67
references.pmid: 24639350
references.citation: Gastroenterology. 2004 Apr;126(4):1005-14
references.pmid: 15057740
references.citation: Cancer Immunol Immunother. 2013 Sep;62(9):1439-51
references.pmid: 23760662
references.citation: Nat Med. 2003 Apr;9(4):416-23
references.pmid: 12640447
references.citation: Cancer Sci. 2009 Apr;100(4):646-53
references.pmid: 19175606
references.citation: Nat Rev Cancer. 2004 Jul;4(7):540-50
references.pmid: 15229479
references.citation: Cell. 2013 Apr 11;153(2):449-60
references.pmid: 23562644
references.citation: Gastroenterology. 2008 Jul;135(1):234-43
references.pmid: 18485901
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Cell. 2008 Aug 22;134(4):657-67
references.pmid: 18724938
references.citation: Cancer. 2001 Apr 15;91(8):1479-86
references.pmid: 11301395
references.citation: Hepatology. 2012 May;55(5):1443-52
references.pmid: 22105560
references.citation: J Clin Invest. 1993 Oct;92(4):1674-80
references.pmid: 8408620
references.citation: Gut. 2005 Jan;54(1):142-51
references.pmid: 15591520
references.citation: Cancer Cell. 2006 Aug;10(2):99-111
references.pmid: 16904609
references.citation: J Leukoc Biol. 2006 Dec;80(6):1197-213
references.pmid: 16946019
references.citation: Gastroenterology. 2012 Oct;143(4):1073-83.e22
references.pmid: 22750464
references.citation: Nat Rev Cancer. 2003 Apr;3(4):276-85
references.pmid: 12671666