J Korean Med Assoc.  2013 Jul;56(7):611-624. 10.5124/jkma.2013.56.7.611.

Changing concepts of cancer stem cells and their application into targeted therapy for cancer

• Lee DS
• Kim SY

• KMID: 2193051
• DOI: http://doi.org/10.5124/jkma.2013.56.7.611

Abstract

Cancer stem cells (CSCs) are characterized by self-proliferation, an ability for symmetric/asymmetric division and an ability to propagate cancer in vivo. Contrary to our expectation, CSCs show a quiescent nature, the morphology of small resting cells, resistance to multiple drugs/radiation, and side-population phenotypes distinct from major cancer cells. Research has been focused on overcoming drug resistance, discovery of biomarkers for CSCs, and tailored treatment targeting CSCs. Recently changing concepts of CSCs reflect the genetic heterogeneity, hierarchy of cancer tissue, and evolving dynamic mutations within one tumor. First, multiple CSC clones with different mutations including initiating driver mutations can coexist within one tumor. Second, CSCs stand at the top of the tumor hierarchy during therapy or disease progression, and the proportions of these clones are changing dynamically, depending on the cancer progression. Third, tailored treatments should be not fixed, according to the initial situation at diagnosis, but appropriate treatment should be attempted in accordance with the dynamic properties of CSCs at each stage of cancer.

Keyword

Cancer stem cell; Genetic heterogeneity; Tumor hierarchy; Tailored treatment

MeSH Terms

Biomarkers
Clone Cells
Disease Progression
Drug Resistance
Genetic Heterogeneity
Neoplastic Stem Cells
Phenotype

Figure

• 

  Figure 1 The classical cancer stem cell (CSC) concept. Tumors are heterogeneous and hierarchically organized entities. Upon dissociation and transplantation into an immunocompromised animal, human CSCs can be functionally distinguished from non/poorly tumorigenic cell populations by their ability to reinitiate and grow a similar heterogeneous tumor in vivo. From Baccelli I, et al. J Cell Biol 2012;198:281-293, according to the Creative Commons license [4].

• 

  Figure 2 The dynamic classical cancer stem cell (CSC) concept. (A) Acquisition of new CSC clones. Although early stage tumors might be governed by a single CSC clone, advanced stage tumors might contain several distinct but related clones, either arising from the initial CSC clone or from its differentiated progeny via mutations or via induction by the CSC niche. Targeted therapy and/or chemotherapy eliminate the tumor mass, possibly including some of the CSCs. At least one resistant CSC clone is then responsible (possibly after acquiring additional mutations) for tumor relapse. (B) Flattening of CSC hierachy at late stages. Advanced stage tumors contain several distinct but related CSC clones. Some acquire enhanced self-renewal capabilities with simultaneously decreased differentiation. During tumor progression, the CSC clones compete with each other, leading to the dominance of at least one CSC clone with the subsequent loss of differentiated tumor progeny. Over time, this leads to a flattening of the hierarchical structure and to a selection of the most aggressive CSCs. Late stage tumors may thus be comprised almost exclusively of aggressive, multiresistant CSCs, a situation similar to the one proposed by the stochastic model. (C) CSC plasticity during dissemination. Carcinoma CSCs display a dynamic phenotype during systemic dissemination: they are able to at least partially lose epithelial traits through epithelial-to-mesenchymal transition (EMT). It is most likely that only a subset of such disseminating CSCs are able to survive in the systemic circulation, extravasate, and reacquire epithelial features (MET) to seed in a new microenvironment and to initiate metastasis. All three scenarios illustrated in A, B, and C occur in parallel and/or during different phases of tumor progression. From Baccelli I, et al. J Cell Biol 2012;198:281-293, according to the Creative Commons license [4].

• 

  Figure 3 The metastasis initiating cell (MIC) concept. Advanced stage primary tumors are heterogeneous and multi-hierarchical structures. Upon dissociation and transplantation in immunocompromised hosts, MICs can be functionally distinguished from classical cancer stem cell (CSC) clones by their metastatic ability in vivo (dissemination, survival in the systemic circulation, extravasation, seeding, and expansion in a new microenvironment, termed "metastatic niche"). MICs are adapted descendants and therefore subpopulations of CSCs with metastatic capacity and, possibly, organ specificity. From Baccelli I, et al. J Cell Biol 2012;198:281-293, according to the Creative Commons license [4].

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