Cancer stem cells: the lessons from pre‐cancerous stem cells

• Introduction • Stem cells and cancer stem cells ‐ Properties of stem cells ‐ Cancer stem cell hypothesis • Development of pre‐cancerous and cancer stem cells ‐ Origin of pre‐cancerous stem cells and cancer stem cells ‐ Initiation and progression of pre‐cancerous stem cells ‐ Clonal evolutionary relationship of pre‐cancerous stem cells to cancer stem cells • Characteristics of pre‐cancerous versuscancer stem cells • Are there demarcations between pre‐cancerous and cancer stem cells ‐ Mainstay of pre‐cancerous stem cells: the potential for both benign and malignant differentiation ‐ Conserved versusvolatile phenotypes for pre‐cancerous and cancer stem cells ‐ Genetic instability of pre‐cancerous and cancer stem cells ‐ Subverted expression of embryonic and germ line stem cell genes in pre‐cancerous stem • Contribution of pre‐cancerous and cancer stem cells to tumour malignancy ‐ Can pre‐cancerous and cancer stem cells serve as the precursors of tumour stromal cells tumour vasculogenic stem/progenitor cells (TVPCs)? ‐ Does frequency of pre‐cancerous and cancer stem cells in tumours determine prognostic outcome of cancer? ‐ Are pre‐cancerous and cancer stem cells associated with metastatic cancer? • Clonal evolution underlies the development of tumour‐initiating cell (TIC) → pre‐cancerous stem cell (pCSC) → cancer stem cell (CSC) ‐ Tumour initiation (TIC → pCSC): epigenetic alterations precede genetic mutations ‐ Tumour progression (pCSC → CSC): additional dynamic genetic alterations ‐ Clonal evolution and niche effect • Molecular pathways for the development of pre‐cancerous and cancer stem cells ‐ Expression of embryonic, germ line, and adult tissue stem cell‐related genes in pre‐cancerous and cancer stem cells ‐ Molecular pathways for self‐renewal of pre‐cancerous and cancer stem cells ‐ Role of piwil2 in the development of pre‐cancerous and cancer stem cells ‐ Do embryonic stem cell‐related genes confer upon pre‐cancerous stem cells the capacity of transdifferentiation? • Experimental models for pre‐cancerous and cancer stem cell research ‐ Roadblock for discrimination of human pre‐cancerous and cancer stem cells ‐ Approaches to establishing clonal pre‐cancerous and cancer stem cell lines ‐ Phenotypic characterization and functional verification of pre‐cancerous and cancer stem cells • Clinical implications: early detection, prevention and treatment via targeting of pre‐cancerous and cancer stem cells ‐ A novel strategy i