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Cancer stem cells: the lessons from pre-cancerous stem cells.

Gao JX - J. Cell. Mol. Med. (2007)

Bottom Line: Both pCSC and CSC might also serve as precursors of tumor stromal components such as tumor vasculogenic stem/progenitor cells (TVPCs).The embryonic stem (ES) cell and germline stem (GS) cell genes are subverted in pCSCs.As cancer stem cell research is yet in its infancy, definitive conclusions regarding the role of pCSC can not be made at this time.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, Medical Center, Ohio State University, Columbus, OH 43210, USA. Jian.Xin.Gao@osumc.edu

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 precancerous 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 respects to their phenotype, differentiation and tumorigenic capacity during initiation and progression. Both pCSC and CSC might also serve as precursors of tumor stromal components such as tumor vasculogenic stem/progenitor cells (TVPCs). Thus, the CSC hypothesis covers the developing process of tumor-initiating cells (TIC) --> pCSC --> CSC --> cancer, a cellular process that should parallel the histological process of hyperplasia/metaplasia (TIC) --> precancerous lesions (pCSC) --> malignant lesions (CSC --> cancer). The embryonic stem (ES) cell and germline stem (GS) cell genes are subverted in pCSCs. Especially the GS cell protein piwil2 may play an important role during the development of TIC --> pCSC --> 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 can not 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.

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Establishment of clonal pCSC and CSC lines. Single tumour cells are cultured in regular or conditioned medium until tumour cells grow out and demonstrate a stable cell line. Then the cells are cloned by limiting dilution. The cloned cell lines are analysed phenotypically by flow cytometry, and the Lin – CD44+ cells with ambiguous stem cell markers are subjected to in vitro CFC assay and in vivo functional assay. SCID: SCID mice; BMR: lethally irradiated bone marrow-reconstituted mice; IC: immunocompetent mice.
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fig04: Establishment of clonal pCSC and CSC lines. Single tumour cells are cultured in regular or conditioned medium until tumour cells grow out and demonstrate a stable cell line. Then the cells are cloned by limiting dilution. The cloned cell lines are analysed phenotypically by flow cytometry, and the Lin – CD44+ cells with ambiguous stem cell markers are subjected to in vitro CFC assay and in vivo functional assay. SCID: SCID mice; BMR: lethally irradiated bone marrow-reconstituted mice; IC: immunocompetent mice.

Mentions: A tumourigenic assay, therefore, is important for distinguishing pCSCs from CSCs (Table 1; Fig. 4). Three murine models, including severe combined immunodeficient disease (SCID), lethally irradiated bone marrow-reconstituted (BMR) and immunocompetent (IC) mice, may be useful and necessary for the assay [2]. SCID mice provide an environment defective in immunosurveillance [87], allowing pCSC expansion in vivo to form tumours; BMR mice provide a recovering immune system and regenerative niches to check pCSCs that are progressing to cancer cells and to drive pCSCs to replenish the regenerating tissues, respectively; and IC mice provide a fully competent immune system to combat the pCSCs that are progressing to CSCs. Thus, SCID mice are used to test the tumourigenic capacity of the tested cells; BMR mice can be used to determine the capacity of benign differentiation and self-renewal of pCSCs, and IC mice can be used to determine whether the cells tested are pCSCs or CSCs (Fig. 4). In fact, while pCSCs are checked by immunosurveillance [2], CSCs are able to evade immunosurveillance and develop into tumours in IC mice (L. Chen et al., unpublished data).


Cancer stem cells: the lessons from pre-cancerous stem cells.

Gao JX - J. Cell. Mol. Med. (2007)

Establishment of clonal pCSC and CSC lines. Single tumour cells are cultured in regular or conditioned medium until tumour cells grow out and demonstrate a stable cell line. Then the cells are cloned by limiting dilution. The cloned cell lines are analysed phenotypically by flow cytometry, and the Lin – CD44+ cells with ambiguous stem cell markers are subjected to in vitro CFC assay and in vivo functional assay. SCID: SCID mice; BMR: lethally irradiated bone marrow-reconstituted mice; IC: immunocompetent mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823473&req=5

fig04: Establishment of clonal pCSC and CSC lines. Single tumour cells are cultured in regular or conditioned medium until tumour cells grow out and demonstrate a stable cell line. Then the cells are cloned by limiting dilution. The cloned cell lines are analysed phenotypically by flow cytometry, and the Lin – CD44+ cells with ambiguous stem cell markers are subjected to in vitro CFC assay and in vivo functional assay. SCID: SCID mice; BMR: lethally irradiated bone marrow-reconstituted mice; IC: immunocompetent mice.
Mentions: A tumourigenic assay, therefore, is important for distinguishing pCSCs from CSCs (Table 1; Fig. 4). Three murine models, including severe combined immunodeficient disease (SCID), lethally irradiated bone marrow-reconstituted (BMR) and immunocompetent (IC) mice, may be useful and necessary for the assay [2]. SCID mice provide an environment defective in immunosurveillance [87], allowing pCSC expansion in vivo to form tumours; BMR mice provide a recovering immune system and regenerative niches to check pCSCs that are progressing to cancer cells and to drive pCSCs to replenish the regenerating tissues, respectively; and IC mice provide a fully competent immune system to combat the pCSCs that are progressing to CSCs. Thus, SCID mice are used to test the tumourigenic capacity of the tested cells; BMR mice can be used to determine the capacity of benign differentiation and self-renewal of pCSCs, and IC mice can be used to determine whether the cells tested are pCSCs or CSCs (Fig. 4). In fact, while pCSCs are checked by immunosurveillance [2], CSCs are able to evade immunosurveillance and develop into tumours in IC mice (L. Chen et al., unpublished data).

Bottom Line: Both pCSC and CSC might also serve as precursors of tumor stromal components such as tumor vasculogenic stem/progenitor cells (TVPCs).The embryonic stem (ES) cell and germline stem (GS) cell genes are subverted in pCSCs.As cancer stem cell research is yet in its infancy, definitive conclusions regarding the role of pCSC can not be made at this time.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, Medical Center, Ohio State University, Columbus, OH 43210, USA. Jian.Xin.Gao@osumc.edu

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 precancerous 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 respects to their phenotype, differentiation and tumorigenic capacity during initiation and progression. Both pCSC and CSC might also serve as precursors of tumor stromal components such as tumor vasculogenic stem/progenitor cells (TVPCs). Thus, the CSC hypothesis covers the developing process of tumor-initiating cells (TIC) --> pCSC --> CSC --> cancer, a cellular process that should parallel the histological process of hyperplasia/metaplasia (TIC) --> precancerous lesions (pCSC) --> malignant lesions (CSC --> cancer). The embryonic stem (ES) cell and germline stem (GS) cell genes are subverted in pCSCs. Especially the GS cell protein piwil2 may play an important role during the development of TIC --> pCSC --> 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 can not 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.

Show MeSH
Related in: MedlinePlus