Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma.

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1-mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550-61. ©2016 AACR.

[1]  K. Nan,et al.  Association Between Expression of Cancer Stem Cell Markers and Poor Differentiation of Hepatocellular Carcinoma , 2015, Medicine.

[2]  E. Biskup,et al.  Co-expression of CXCL8 and HIF-1α is associated with metastasis and poor prognosis in hepatocellular carcinoma , 2015, Oncotarget.

[3]  Ying Wang,et al.  PDK4 Protein Promotes Tumorigenesis through Activation of cAMP-response Element-binding Protein (CREB)-Ras Homolog Enriched in Brain (RHEB)-mTORC1 Signaling Cascade*♦ , 2014, The Journal of Biological Chemistry.

[4]  Libin,et al.  The CD133+CD44+ precancerous subpopulation of oval cells is a therapeutic target for hepatocellular carcinoma. , 2014 .

[5]  Melinda J. Cromie,et al.  mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert , 2014, Nature.

[6]  Chi-Long Chen,et al.  Alternative Mammalian Target of Rapamycin (mTOR) Signal Activation in Sorafenib-resistant Hepatocellular Carcinoma Cells Revealed by Array-based Pathway Profiling* , 2014, Molecular & Cellular Proteomics.

[7]  W. Bamlet,et al.  SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells , 2013, Oncogenesis.

[8]  Jianzhu Chen,et al.  Human Fetal Hepatic Progenitor Cells Are Distinct from, but Closely Related to, Hematopoietic Stem/Progenitor Cells , 2013, Stem cells.

[9]  X. Wang,et al.  Cancer stem cells in the development of liver cancer. , 2013, The Journal of clinical investigation.

[10]  E. Wagner,et al.  Characterization of in vivo chemoresistant human hepatocellular carcinoma cells with transendothelial differentiation capacities , 2013, BMC Cancer.

[11]  Lei-bo Xu,et al.  Bmi1 gene silencing inhibits the proliferation and invasiveness of human hepatocellular carcinoma cells and increases their sensitivity to 5-fluorouracil. , 2013, Oncology reports.

[12]  D. Hwang,et al.  Osmotic Stress Regulates Mammalian Target of Rapamycin (mTOR) Complex 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor Protein Phosphorylation* , 2012, The Journal of Biological Chemistry.

[13]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[14]  K. Chan,et al.  CD133+ liver tumor‐initiating cells promote tumor angiogenesis, growth, and self‐renewal through neurotensin/interleukin‐8/CXCL1 signaling , 2012, Hepatology.

[15]  D. Steinemann,et al.  The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. , 2010, The Journal of clinical investigation.

[16]  M. Kurrer,et al.  A lymphotoxin-driven pathway to hepatocellular carcinoma. , 2009, Cancer cell.

[17]  Ge Guo,et al.  Nanog Is the Gateway to the Pluripotent Ground State , 2009, Cell.

[18]  S. Byers,et al.  Liver stem cells and hepatocellular carcinoma , 2009, Hepatology.

[19]  D. Waugh,et al.  The Interleukin-8 Pathway in Cancer , 2008, Clinical Cancer Research.

[20]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[21]  S. Thorgeirsson,et al.  A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells , 2006, Nature Medicine.

[22]  Michael Dean,et al.  Tumour stem cells and drug resistance , 2005, Nature Reviews Cancer.

[23]  H. Schrem,et al.  Liver-Enriched Transcription Factors in Liver Function and Development. Part II: the C/EBPs and D Site-Binding Protein in Cell Cycle Control, Carcinogenesis, Circadian Gene Regulation, Liver Regeneration, Apoptosis, and Liver-Specific Gene Regulation , 2004, Pharmacological Reviews.

[24]  B. Clurman,et al.  Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. , 1999, Genes & development.

[25]  S. Thorgeirsson,et al.  Expression of hepatic transcription factors during liver development and oval cell differentiation , 1994, The Journal of cell biology.

[26]  W I Wood,et al.  Structure and functional expression of a human interleukin-8 receptor. , 1991, Science.

[27]  R. Derynck,et al.  Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta‐thromboglobulin. , 1988, The EMBO journal.

[28]  L. Platanias,et al.  Intersection of mTOR and STAT signaling in immunity. , 2015, Trends in immunology.

[29]  Takuji Tanaka,et al.  The CD133+CD44+ precancerous subpopulation of oval cells is a therapeutic target for hepatocellular carcinoma. , 2014, Stem cells and development.

[30]  G. Dranoff,et al.  Cytokines in cancer pathogenesis and cancer therapy , 2004, Nature Reviews Cancer.

[31]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.