Cancer stem cells in solid tumors

https://doi.org/10.1016/j.copbio.2007.10.007Get rights and content

Cancer stem cells (CSCs) are cells that drive tumorigenesis, as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor, but that lack tumorigenic potential. CSCs have been identified in a variety of human tumors, as assayed by their ability to initiate tumor growth in immunocompromised mice. Further characterization studies have demonstrated that gene expression profiles in breast cancer correlate with patient prognosis, and brain CSCs are specifically resistant to radiation through DNA damage repair. In addition, specific signaling pathways play a functional role in CSC self renewal and/or differentiation, and early studies indicate that CSCs are associated with a microenvironmental niche. Thus the biological properties of CSCs are just beginning to be revealed, and the continuation of these studies should lead to the development of CSC-targeted therapies for cancer treatment.

Introduction

The cancer stem cell (CSC) model of tumor development and progression states that tumors, like normal adult tissues, contain a subset of cells that both self renew and give rise to differentiated progeny. As in other tissues, the stem cells are a minority of the whole organ, and are the only cells that can maintain tumor growth indefinitely. The remaining cells, though actively proliferating and making up the majority of the cells in the tumor, are also differentiating and destined to die. The self renewal properties of the CSCs are thus the real driving force behind tumor growth. The identification of markers that allow the prospective isolation of CSCs from whole tumor tissues will allow us to develop an understanding of several important biological properties of CSCs: first, what is the cell of origin for a given tumor? Second, what are the signaling pathways that drive self renewal and/or differentiation of CSCs? Third, are there molecules uniquely expressed on CSCs, regardless of whether they are functional, that will allow targeted therapies to be developed? Fourth, what are the mechanisms by which CSCs escape conventional therapies and can we defeat these mechanisms? Answers to these questions should lead to the development of therapies that target the CSC population and eliminate the ‘engine’ that drives tumors to grow, invade, and seed metastatic lesions. The challenges involved in identifying a CSC population from a solid tumor, and recent successes in this area are described in this review, as well as early studies that represent the first steps toward understanding the biological properties of these cells.

Section snippets

Identification of markers for the prospective isolation of cancer stem cells

A recent AACR workshop stated that ‘cancer stem cells can … only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor’ [1]. The most widely accepted assay to validate a candidate CSC population is therefore tumor initiation and serial transplantation in immunocompromised mice, where the tumor that grows in the mice recapitulates the heterogeneity of the primary patient tumor. This was first achieved for human acute myeloid leukemia (AML). The

Understanding the biological properties of CSC

Once CSCs have been identified, the real work begins, which is the characterization of their molecular and biological properties, in hopes of identifying ways to specifically target and eradicate these cells in cancer patients. This is a new field in which we have barely begun to scratch the surface because of the only very recent ability to prospectively isolate CSCs from various tumors. Some of the approaches towards gaining a deeper understanding of CSC biology that have been reported are

Conclusions

The CSC field, particularly in the area of solid tumors, is a very young one. A model of solid tumor stem-cell biology is shown in Figure 1, highlighting the properties that are currently viewed as important for tumor growth, and that may represent therapeutic targets. We are still in the very technically challenging stage of identifying the methods that will allow us to prospectively isolate CSCs from various solid tumors, and most importantly, to demonstrate in vivo that the populations we

Conflict of interest

ILW has stock in Amgen, Inc., was a member of the Amgen scientific advisory board, and is a cofounder and member of the Board of Directors of Cellerant, Inc., and Stem Cells, Inc.

Acknowledgements

This work was supported in part by National Institutes of Health Grants R01CA086017 and R01CA086065 and an anonymous gift fund for Cancer Stem Cell research at Stanford University. In addition LEA is a recipient of a Stanford Comprehensive Cancer Center Developmental Research Award.

References (56)

  • M.F. Clarke et al.

    Cancer stem cells  perspectives on current status and future directions: AACR workshop on cancer stem cells

    Cancer Res

    (2006)
  • C.M. Baum et al.

    Isolation of a candidate human hematopoietic stem-cell population

    Proc Natl Acad Sci U S A

    (1992)
  • N. Uchida et al.

    HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells

    Proc Natl Acad Sci U S A

    (1998)
  • D. Bonnet et al.

    Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell

    Nat Med

    (1997)
  • T. Miyamoto et al.

    AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation

    Proc Natl Acad Sci U S A

    (2000)
  • Majeti R, Park CY, Weissman IL: Identification of a hierarchy of multipotent hematopoietic progenitors in human cord...
  • C.H. Jamieson et al.

    Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML

    N Engl J Med

    (2004)
  • K.J. Hope et al.

    Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity

    Nat Immunol

    (2004)
  • 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)
  • 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)
  • C. Li et al.

    Identification of pancreatic cancer stem cells

    Cancer Res

    (2007)
  • P. Dalerba et al.

    Phenotypic characterization of human colorectal cancer stem cells

    Proc Natl Acad Sci U S A

    (2007)
  • C.A. O’Brien et al.

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

    Nature

    (2007)
  • L. Ricci-Vitiani et al.

    Identification and expansion of human colon-cancer-initiating cells

    Nature

    (2007)
  • S. Tamaki et al.

    Engraftment of sorted/expanded human central nervous system stem cells from fetal brain

    J Neurosci Res

    (2002)
  • N. Uchida et al.

    Direct isolation of human central nervous system stem cells

    Proc Natl Acad Sci U S A

    (2000)
  • H.D. Hemmati et al.

    Cancerous stem cells can arise from pediatric brain tumors

    Proc Natl Acad Sci U S A

    (2003)
  • Cited by (0)

    View full text