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Keywords:

  • tumour-initiating cells;
  • pre-cancerous stem cells;
  • cancer stem cells;
  • tumour development;
  • clonal evolution;
  • genetic instability;
  • Piwil2;
  • tumour vasculogenesis;
  • common cancer biomarker;
  • embryonic stem cell genes;
  • immunoprevention;
  • tumour vaccine
  • • 
    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) [RIGHTWARDS ARROW] pre-cancerous stem cell (pCSC) [RIGHTWARDS ARROW] cancer stem cell (CSC)
    • - 
      Tumour initiation (TIC [RIGHTWARDS ARROW] pCSC): epigenetic alterations precede genetic mutations
    • - 
      Tumour progression (pCSC [RIGHTWARDS ARROW] 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 integrating early detection and prevention for the cure of cancer
    • - 
      Potential of piwil2 for early detection of cancer
    • - 
      Potential of pre-cancerous and cancer stem cells as a target for immunoprevention
    • - 
      Potential of pre-cancerous and cancer stem cells for the development of tumour vaccines
  • • 
    Concluding remark

Abstract

How a cancer is initiated and established remains elusive despite all the advances in decades of cancer research. Recently the cancer stem cell (CSC) hypothesis has been revived, challenging the long-standing model of ‘clonal evolution’ for cancer development and implicating the dawning of a potential cure for cancer [1]. The recent identification of pre-cancerous stem cells (pCSCs) in cancer, an early stage of CSC development, however, implicates that the clonal evolution is not contradictory to the CSC hypothesis but is rather an aspect of the process of CSC development [2]. The discovery of pCSC has revealed and will continue to reveal the volatile properties of CSC with respect to their phenotype, differentiation and tumourigenic capacity during initiation and progression. Both pCSC and CSC might also serve as precursors of tumour stromal components such as tumour vasculogenic stem/progenitor cells (TVPCs). Thus, the CSC hypothesis covers the developing process of tumour-initiating cells (TIC) [RIGHTWARDS ARROW] pCSC [RIGHTWARDS ARROW] CSC [RIGHTWARDS ARROW] cancer, a cellular process that should parallel the histological process of hyperplasia/metaplasia (TIC) [RIGHTWARDS ARROW] pre-cancerous lesions (pCSC) [RIGHTWARDS ARROW] malignant lesions (CSC [RIGHTWARDS ARROW] cancer). The embryonic stem (ES) cell and germ line stem (GS) cell genes are subverted in pCSCs. Especially the GS cell protein piwil2 may play an important role during the development of TIC [RIGHTWARDS ARROW] pCSC [RIGHTWARDS ARROW] CSC, and this protein may be used as a common biomarker for early detection, prevention, and treatment of cancer. As cancer stem cell research is yet in its infancy, definitive conclusions regarding the role of pCSC cannot be made at this time. However, this review will discuss what we have learned from pCSC and how this has led to innovative ideas that may eventually have major impacts on the understanding and treatment of cancer.