Characterization of Cancer Stem-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Transformed by Tumor-Derived Extracellular Vesicles

Several studies have shown that cancer niche can perform an active role in the regulation of tumor cell maintenance and progression through extracellular vesicles-based intercellular communication. However, it has not been reported whether this vesicle-mediated communication affects the malignant transformation of normal stem cells/progenitors. We have previously reported that the conditioned medium derived from the mouse Lewis Lung Carcinoma (LLC) cell line can convert mouse induced pluripotent stem cells (miPSCs) into cancer stem cells (CSCs), indicating that normal stem cells when placed in an aberrant microenvironment can give rise to functionally active CSCs. Here, we focused on the contribution of tumor-derived extracellular vesicles (tEVs) that are secreted from LLC cells to induce the transformation of miPSCs into CSCs. We isolated tEVs from the conditioned medium of LLC cells, and then the differentiating miPSCs were exposed to tEVs for 4 weeks. The resultant tEV treated cells (miPS-LLCev) expressed Nanog and Oct3/4 proteins comparable to miPSCs. The frequency of sphere formation of the miPS-LLCev cells in suspension culture indicated that the self-renewal capacity of the miPS-LLCev cells was significant. When the miPS-LLCev cells were subcutaneously transplanted into Balb/c nude mice, malignant liposarcomas with extensive angiogenesis developed. miPS-LLCevPT and miPS-LLCevDT, the cells established from primary site and disseminated liposarcomas, respectively, showed their capacities to self-renew and differentiate into adipocytes and endothelial cells. Moreover, we confirmed the secondary liposarcoma development when these cells were transplanted. Taken together, these results indicate that miPS-LLCev cells possess CSC properties. Thus, our current study provides the first evidence that tEVs have the potential to induce CSC properties in normal tissue stem cells/progenitors.

[1]  D. Salomon,et al.  Cancer stem cells maintain a hierarchy of differentiation by creating their niche , 2013, International journal of cancer.

[2]  Kristen Jepsen,et al.  Identification of Liver Cancer Progenitors Whose Malignant Progression Depends on Autocrine IL-6 Signaling , 2013, Cell.

[3]  A. Lazar,et al.  Heterogeneity and immunophenotypic plasticity of malignant cells in human liposarcomas. , 2013, Stem cell research.

[4]  Cristian Coarfa,et al.  SOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteo-adipo lineage. , 2013, Cell reports.

[5]  J. Li,et al.  Krüppel-Like Factor 4 Acts as an Oncogene in Colon Cancer Stem Cell-Enriched Spheroid Cells , 2013, PloS one.

[6]  G. Raposo,et al.  As we wait: coping with an imperfect nomenclature for extracellular vesicles , 2013, Journal of extracellular vesicles.

[7]  Zhihua Liu,et al.  Peroxisome Proliferator-activated Receptor γ Agonists Induce Cell Cycle Arrest through Transcriptional Regulation of Krüppel-like Factor 4 (KLF4)* , 2012, The Journal of Biological Chemistry.

[8]  L. Dodd Update on Liposarcoma: A review for cytopathologists , 2012, Diagnostic cytopathology.

[9]  Ken-ichi Yoshioka,et al.  Induction of Cancerous Stem Cells during Embryonic Stem Cell Differentiation* , 2012, The Journal of Biological Chemistry.

[10]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[11]  M. Hendrix,et al.  A Model of Cancer Stem Cells Derived from Mouse Induced Pluripotent Stem Cells , 2012, PloS one.

[12]  Dina Lev,et al.  MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances β-catenin signaling. , 2012, Cancer research.

[13]  A. Pandiella,et al.  Sox2 expression in breast tumours and activation in breast cancer stem cells , 2012, Oncogene.

[14]  Jung Ah Cho,et al.  Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. , 2011, International journal of oncology.

[15]  S. Orkin,et al.  Sox2 maintains self-renewal of tumor initiating cells in osteosarcomas , 2011, Oncogene.

[16]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[17]  M. Kolonin,et al.  An isoform of decorin is a resistin receptor on the surface of adipose progenitor cells. , 2011, Cell stem cell.

[18]  Rong Wang,et al.  Glioblastoma stem-like cells give rise to tumour endothelium , 2010, Nature.

[19]  Luigi Biancone,et al.  Exosomes/microvesicles as a mechanism of cell-to-cell communication. , 2010, Kidney international.

[20]  H. Ishii,et al.  Properties and identification of cancer stem cells: A changing insight into intractable cancer , 2010, Surgery Today.

[21]  Crislyn D'Souza-Schorey,et al.  Microvesicles: mediators of extracellular communication during cancer progression , 2010, Journal of Cell Science.

[22]  Nicolò Riggi,et al.  EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. , 2010, Genes & development.

[23]  M. Ratajczak,et al.  Lung cancer secreted microvesicles: Underappreciated modulators of microenvironment in expanding tumors , 2009, International journal of cancer.

[24]  Nicolò Riggi,et al.  Identification of cancer stem cells in Ewing's sarcoma. , 2009, Cancer research.

[25]  V. Rotter,et al.  Cancer cells suppress p53 in adjacent fibroblasts , 2009, Oncogene.

[26]  M. Panaro,et al.  Membrane microvesicles as actors in the establishment of a favorable prostatic tumoral niche: a role for activated fibroblasts and CX3CL1-CX3CR1 axis. , 2009, Cancer research.

[27]  Paolo Malatesta,et al.  SOX2 Silencing in Glioblastoma Tumor‐Initiating Cells Causes Stop of Proliferation and Loss of Tumorigenicity , 2009, Stem cells.

[28]  Cameron P Bracken,et al.  MicroRNAs as regulators of epithelial-mesenchymal transition , 2008, Cell cycle.

[29]  C. Ballantyne,et al.  Expression, activation, and function of integrin alphaMbeta2 (Mac-1) on neutrophil-derived microparticles. , 2008, Blood.

[30]  Douglas D. Taylor,et al.  Exosomal microRNA: a diagnostic marker for lung cancer. , 2008, Clinical lung cancer.

[31]  A. Shiau,et al.  Oct-3/4 expression reflects tumor progression and regulates motility of bladder cancer cells. , 2008, Cancer research.

[32]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[33]  E. Nakakura,et al.  Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas , 2008, Modern Pathology.

[34]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[35]  A. Guha,et al.  Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells , 2008, Nature Cell Biology.

[36]  J. Friedman,et al.  Transcriptional regulation of adipogenesis by KLF4. , 2008, Cell metabolism.

[37]  M. Biffoni,et al.  Identification and expansion of the tumorigenic lung cancer stem cell population , 2008, Cell Death and Differentiation.

[38]  T. Ichisaka,et al.  Generation of germline-competent induced pluripotent stem cells , 2007, Nature.

[39]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[40]  William E. Grizzle,et al.  Tumor Exosomes Inhibit Differentiation of Bone Marrow Dendritic Cells1 , 2007, The Journal of Immunology.

[41]  Irving L Weissman,et al.  Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. , 2006, Cancer research.

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

[43]  Linheng Li,et al.  Normal stem cells and cancer stem cells: the niche matters. , 2006, Cancer research.

[44]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[45]  Michael Lehrke,et al.  The Many Faces of PPARγ , 2005, Cell.

[46]  Li Zhong,et al.  Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4. , 2005, Blood.

[47]  F. DiMeco,et al.  Erratum: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma (Cancer Research (October 2004) 64 (7011-7021) , 2004 .

[48]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.

[49]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[50]  Michael F. Seldin,et al.  A Gene for a Novel Zinc-finger Protein Expressed in Differentiated Epithelial Cells and Transiently in Certain Mesenchymal Cells* , 1996, The Journal of Biological Chemistry.

[51]  M. Greaves,et al.  Expression of the CD34 gene in vascular endothelial cells. , 1990, Blood.

[52]  G. Mechtersheimer Towards the phenotyping of soft tissue tumours by cell surface molecules , 2005, Virchows Archiv A.

[53]  Michael Lehrke,et al.  The many faces of PPARgamma. , 2005, Cell.

[54]  R. Lovell-Badge,et al.  Multipotent cell lineages in early mouse development depend on SOX2 function. , 2003, Genes & development.