3.0 MS-Stem_Cell-FINAL-FINAL.pdf

Stem Cells What is Stem Cell? Types of Stem Cells Embryonic and Adult Stem Cell Embryonic vsAdult Stem Cells Characteristics of Embryonic Stem (ES) CellsUndifferentiated andnon-committerSelf renewal Pluripotency Characteristics of Adult Stem Cells Adult Stem Cells Plasticity and Type Plastici...

Stem Cells What is Stem Cell? Types of Stem Cells Embryonic and Adult Stem Cell Embryonic vsAdult Stem Cells Characteristics of Embryonic Stem (ES) CellsUndifferentiated andnon-committerSelf renewal Pluripotency Characteristics of Adult Stem Cells Adult Stem Cells Plasticity and Type Plasticity is the ability of stem cells from one adult tissue to generate differentiated types of another tissues§Hematopoietic§Mesenchymal§Neuronal Potential Alternatives to ES Cells Individual Pluripotent Stem (iPS) Cells For Studying Human Diseases Key Challenges with Stem Cells Culture Potential Uses Current and Future Clinical Stem Cells Application Cancer stem cells (CSCs)First cancer stem cells were identified in acute myeloid leukemia (AML)CD34+, CD38-cells harbored serial leukemic transplantation potential CSCs can be derived from stem cells or evolve from differentiated cells to become CSCs Cancer stem cells (CSCs)1.Self-renewal capacity: cancer stem cells are capable of renewing themselvesthrough cell division and can give rise to new tumors2.Ability to generate heterogeneouscancer cells:they generate heterogeneous population of cancer cells but these cells cannot give rise to new tumors Characteristics of cancer stem cells (CSCs)1.Ability to give rise to new tumors (self-renewal) in serial transplants2.Expression of stem cell transcription factors (e.g. OCT3/4, NANOG, SOX2, etc.)3.Expression of CSC cell surface markers (e.g. CD133, CD44, CD24, CXCR4, etc.)4.High expression of ATP-binding cassette (ABC) family transporters(side population with rhodamine, resistant to chemotherapy drugs)5.High expression of ALDH (Aldehyde Dehydrogenase gene family)6.Many CSCs from different epithelial-or mesenchymal-derived tumors havethe ability to grow as spheroids (3-D culture) Serial transplantation of cancer stem cells (CSCs)Catherine AdellO'Brien et al. ClinCancer Res 2010;16:3113-3120 “Stemness” factors are critical for self-renewal in CSCs Autonomous or tumormicroenvironment can activatepathways to CSC self-renewal Catherine AdellO'Brien et al. ClinCancer Res 2010;16:3113-3120tumor microenvironment Wu et al., Cancer Research 2007; 67:8216-8222.More aggressive tumorshave greater number of CSCs: Hoechst33342 dye-excluding side population Ta m u r a e t a l . , B M J O p e n , 2 0 1 1-000179.CSCs have ability to grow as spheroids and spheroidsexpress higher levels of CSC cell surface markers DSRCT cells undergo sphere formation and spheroidsexpress higher levels of “Stemness” TF genesJN-DSRCT-1 cells05010 015 020 025 030 035 040 0monolayer4 da ys7 da ys10 d ay s14 d ay sOct405010 015 020 025 030 035 0monolayer4 da ys7 da ys10 d ay s14 d ay sNanogqRT-PCRRelative expression Isotypecontrol0 days0.06%0.04%0.11%CD133CD448.78%0.06%0.01%CD133+ cells are enriched in spheroids6 days5.25%0.36%1.04% P<0.001***P<0.001***untreatedCisplatin5mMEtoposide5nMCamptothecin50nMadherentsphereSpheroids are more resistant to chemotherapeutic drugs Spheroids have greater tumorigenic capacity