Recent advances in cancer stem cells

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The theory of cancer stem cells states that a subset of cancer cells within a tumor has the ability to self-renew and differentiate. Only those cells within a tumor that have these two properties are called cancer stem cells. This concept was first demonstrated in the study of leukemia where only cells with specific surface antigen profiles were able to cause leukemia when engrafted into immunodeficient mice. In recent years solid tumors were studied utilizing similar techniques in mice. Human tumors where evidence of cancer stem cells has been published include tumors of the breast, brain, pancreas, head and neck, and colon. If this difference in tumorigenicity of cancer cells also occurs in patients, then the ability to enrich for cancer stem cells lays an important groundwork for future studies where mechanisms involved in cancer stem cells can now be investigated.

Introduction

In recent years, numerous cancers have been described as having a ‘cancer stem cell’ compartment. Alternative terminologies to cancer stem cells are cancer initiating cells [1, 2, 3•] and tumorigenic cancer cells [4]. Tumors recently described as having such populations of cells include cancers of the blood [1, 5••], breast [6••], brain [7], pancreas [8], head and neck [9], and colon [2, 3•, 10•]. The purpose of this article is to bring attention to parallels between in vivo methods first used in hematopoietic stem cell research and recent publications in the solid tumor ‘cancer stem cell’ field. By doing so we hope to shed light onto why stem cell biologists view cancers from a ‘developmental paradigm’ and thus use certain nomenclatures such as the term ‘cancer stem cells.’ Viewing cancers from a developmental perspective has led to insights into tumor biology that otherwise would not be possible.

A ‘developmental paradigm’ of cancers emphasizes the hierarchy of cells present within a tumor [11]. This hierarchy by necessity implies cellular heterogeneity. Heterogeneity here does not refer to invasive endothelial cells, hematopoietic cells, or other non-cancer cells that infiltrate the tumor environment. Rather, it refers to differences in cancer cells within a single tumor. An example of one such difference is with surface antigen expression where cancer cells of a tumor do not all express the same antigens. More importantly, functional assays show that only a specific subset of cells within a tumor is able to propagate tumor growth in immunodeficient mice whereas other cells are unable to propagate tumor growth. It appears that cancer cells responsible for tumor propagation are able to self-renew as well as give rise to cells that cannot propagate tumor growth. Thus, the ‘cancer stem cell theory’ states that these tumor forming cells have two main properties that of self-renewal and differentiation [12, 13].

Section snippets

Normal hematopoietic stem cell markers and leukemia

Methods used in the isolation of ‘adult’ stem cell populations play a pivotal role in the definition of these cells. The best developed methods come from isolation of the hematopoietic stem cell (HSC) and the resultant hematopoietic lineage map [14]. Crucial methods for the in vivo study of hematopoiesis have been the ability to collect different hematopoietic cell populations by staining with various antibodies of interest in concert with sorting by magnetic bead and/or fluorescence activated

Solid tumor cancer studies

Utilizing concepts developed in the study of normal hematopoiesis and leukemic stem cells, solid tumors were also investigated. The first solid tumor to be studied utilizing methods described earlier was human breast cancer [6••]. Human breast tumor samples were analyzed for the expression of CD44 and CD24. As in AML, breast tumor cells were found to be heterogeneous in surface antigen expression. On the basis of the differences in surface antigen expression, human breast cancer cells were

Mouse modeling of mammary development and breast cancer

Insights to leukemogenesis were obtained through the study of normal mouse hematopoiesis and transgenic mouse leukemia models [24, 25, 26, 27, 28, 29, 30]. Recently, normal mouse breast stem and progenitor cells have been partially characterized. It has been known for some time that transplanting mouse breast tissue into recipient mice with surgically cleared mouse breast fat pads allows for regeneration of the lost fat pads [31, 32, 33]. Recently, it was shown that a single breast stem cell

Relevance of cancer stem cells to human disease

Possible implications of cancer stem cells to human disease are in the roles they play in tumor growth, metastasis, and relapse as all three are closely related to patient survival. It is not difficult to imagine a situation where a cancer stem cell escapes the primary tumor and imbeds itself at a distant site to initiate a metastatic tumor. Recent evidence suggests that leukemic stem cells are relatively resistant to standard cytotoxic treatments [43, 44], suggesting that these cells may lead

Conclusion

The theoretical advantage that isolation of cancer stem cells offers is the ability to study processes responsible for tumor propagation separately from the mechanisms present in the non-tumor forming cells. It remains to be seen whether known pathways already characterized in other stem cell systems have applicability to cancer stem cells. However, early evidence suggests that some pathways involved in normal stem cell self-renewal are important in cancer stem cells. An example of this is

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (52)

  • C.A. O’Brien et al.

    A human colon cancer cell capable of initiating tumour growth in immunodeficient mice

    Nature

    (2007)
  • Cho RW, Wang X, Diehn M, et al.: Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine...
  • T. Lapidot et al.

    A cell initiating human acute myeloid leukaemia after transplantation into SCID mice

    Nature

    (1994)
  • M. Al-Hajj et al.

    Prospective identification of tumorigenic breast cancer cells

    Proc Natl Acad Sci U S A

    (2003)
  • S.K. Singh et al.

    Identification of human brain tumour initiating cells

    Nature

    (2004)
  • C. Li et al.

    Identification of pancreatic cancer stem cells

    Cancer Res

    (2007)
  • M.E. Prince et al.

    Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma

    Proc Natl Acad Sci U S A

    (2007)
  • P. Dalerba et al.

    Phenotypic characterization of human colorectal cancer stem cells

    Proc Natl Acad Sci U S A

    (2007)
  • M.F. Clarke et al.

    Stem cells and cancer: two faces of eve

    Cell

    (2006)
  • M. Al-Hajj et al.

    Self-renewal and solid tumor stem cells

    Oncogene

    (2004)
  • P. Dalerba et al.

    Cancer stem cells: models and concepts

    Annu Rev Med

    (2007)
  • B.T. Tan et al.

    The cancer stem cell hypothesis: a work in progress

    Lab Invest

    (2006)
  • G.J. Spangrude et al.

    Purification and characterization of mouse hematopoietic stem cells

    Science

    (1988)
  • A.D. Garcia et al.

    GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain

    Nat Neurosci

    (2004)
  • F.T. Merkle et al.

    Radial glia give rise to adult neural stem cells in the subventricular zone

    Proc Natl Acad Sci U S A

    (2004)
  • C. Blanpain et al.

    Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche

    Cell

    (2004)
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