Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ “cancer stem cells,” such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000–50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-β-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf+/− mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-β signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf+/− mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-β signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-β pathway.

[1]  L. Mishra,et al.  Elf3 encodes a novel 200-kD β-spectrin: role in liver development , 1999, Oncogene.

[2]  Sean J. Morrison,et al.  Asymmetric and symmetric stem-cell divisions in development and cancer , 2006, Nature.

[3]  C. Deng,et al.  Disruption of Transforming Growth Factor-β Signaling in ELF β-Spectrin-Deficient Mice , 2003, Science.

[4]  M. Wigler,et al.  Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach , 2006, Cell.

[5]  P. van Eyken,et al.  Cytokeratin expression in hepatocellular carcinoma: an immunohistochemical study. , 1988, Human pathology.

[6]  E. Lesaffre,et al.  The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin , 2006, Histopathology.

[7]  T. Hirano,et al.  Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors , 2000, Oncogene.

[8]  S. Byers,et al.  The role of TGF-β and Wnt signaling in gastrointestinal stem cells and cancer , 2005, Oncogene.

[9]  Takafumi Yoshida,et al.  Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production , 2006, Oncogene.

[10]  T. Roskams.  Liver stem cells and their implication in hepatocellular and cholangiocarcinoma , 2006, Oncogene.

[11]  J. Massagué,et al.  Controlling TGF-β signaling , 2000, Genes & Development.

[12]  C. Deng,et al.  Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression , 2006, Oncogene.

[13]  R. Derynck,et al.  Transforming Growth Factor-ß Signaling in Stem Cells and Cancer , 2005, Science.

[14]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  N. Fausto,et al.  Production of hepatocellular carcinoma by oval cells: cell cycle expression of c-myc and p53 at different stages of oval cell transformation. , 1989, Cancer research.

[16]  M. Alison.  Liver stem cells , 2007, Stem Cell Reviews.

[17]  Lori J Sokoll,et al.  Quantification of fragments of human serum inter-alpha-trypsin inhibitor heavy chain 4 by a surface-enhanced laser desorption/ionization-based immunoassay. , 2006, Clinical chemistry.

[18]  E. Fuchs,et al.  Defining the Epithelial Stem Cell Niche in Skin , 2004, Science.

[19]  Tetsuhiro Chiba,et al.  Side population purified from hepatocellular carcinoma cells harbors cancer stem cell–like properties , 2006, Hepatology.

[20]  A. Roberts,et al.  Role of TGF-β in stem cells and cancer , 2005, Oncogene.

[21]  M. Makuuchi,et al.  Regeneration and function of hemiliver graft: right versus left. , 2006, Surgery.

[22]  P. Musiani,et al.  Coexpression of IL‐6 and soluble IL‐6R causes nodular regenerative hyperplasia and adenomas of the liver , 1998, The EMBO journal.

[23]  J. Cox,et al.  Itih‐4, a serine protease inhibitor regulated in interleukin‐6–dependent liver formation: role in liver development and regeneration , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  L. Olson,et al.  Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. , 2004, Carcinogenesis.

[25]  J. Lau,et al.  Hepatocellular carcinoma expressing both hepatocellular and biliary markers also expresses cytokeratin 14, a marker of bipotential progenitor cells. , 1999, Journal of hepatology.

[26]  J. Massagué,et al.  TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders , 2000, Cell.

[27]  Yi Lu,et al.  Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. , 2006, Cancer research.

[28]  A. Smith,et al.  Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. , 1998, Genes & development.

[29]  Ronald A. DePinho,et al.  Hepatocellular carcinoma pathogenesis: from genes to environment , 2006, Nature Reviews Cancer.

[30]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[31]  D. Levy,et al.  What does Stat3 do? , 2002, The Journal of clinical investigation.

[32]  P. Schirmacher,et al.  Hepatocellular hyperplasia, plasmacytoma formation, and extramedullary hematopoiesis in interleukin (IL)-6/soluble IL-6 receptor double-transgenic mice. , 1998, The American journal of pathology.

[33]  A. Brasier,et al.  Vascular inflammation and the renin-angiotensin system. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[34]  F. Valeriote,et al.  Growth characteristics of a mouse plasma cell tumor. , 1968, Cancer research.

[35]  Kevin R Coombes,et al.  Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  A. Brasier,et al.  STAT3 NH2-terminal acetylation is activated by the hepatic acute-phase response and required for IL-6 induction of angiotensinogen. , 2005, Gastroenterology.

[37]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[38]  C. Deng,et al.  Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. , 2000, Cytokine & growth factor reviews.

[39]  P. Schirmacher,et al.  Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis , 2001, Oncogene.

[40]  M. Netea,et al.  Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis , 2005, Annals of the rheumatic diseases.

[41]  A. Salsbury.  The significance of the circulating cancer cell. , 1975, Cancer treatment reviews.

[42]  S. Thorgeirsson,et al.  Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling , 2004, Hepatology.