Trends in Cell Biology
Cancer stem cells: lessons from leukemia
Introduction
A fundamental problem in cancer research is identification of the cell type capable of initiating and sustaining growth of the neoplastic clone in vivo. The key to solving this riddle lies in determining whether every cell within the neoplasm has tumor-initiating capacity, or whether only a rare subset of cells – so-called ‘cancer stem cells’ (CSCs) – is responsible for maintenance of the neoplasm. The existence of CSCs was first proposed over 40 years ago 1, 2, providing an explanation for the observed functional heterogeneity within tumors. However, proof of principle had to await the development of modern research tools for investigating the behavior of defined cell populations. The best evidence supporting the existence of CSCs has come from the study of hematological malignancies. Here, we review the historical developments that have led to our current understanding of normal and leukemic stem cell biology and demonstrate how these studies provide a paradigm for identification of CSCs from solid tumors.
Section snippets
Stem cells in normal tissues: the hematopoietic system as a paradigm
In the 1950s and 1960s, seminal studies in mice established fundamental concepts regarding the nature of the hematopoietic system and provided a foundation for later studies in human hematopoiesis (Box 1). In both mouse and human, hematopoietic cells are organized in a hierarchy that is ultimately sustained by a small population of long-lived, quiescent, pluripotent stem cells capable of self-renewal (Figure 1). Succeeding these cells are lineage-restricted, differentiated progenitors with
Stem cells in leukemia
Just as the fundamental concepts of normal stem cell biology were derived from early experiments in murine hematopoiesis, hematologic malignancies, in particular chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML), have served as important model diseases in the establishment of modern concepts of cancer development.
Cancer stem cells in solid tumors
Recent studies in solid tumors indicate that the concept of stem cells in cancer might have broader implications beyond the field of hematopoiesis. In breast cancer, a minor, phenotypically distinct tumor cell population has been isolated that is able to form mammary tumors in NOD/SCID mice, whereas cells with alternative phenotypes are nontumorigenic [46]. The tumorigenic cells can be serially passaged, demonstrating self-renewal capacity, and are able to generate tumor heterogeneity,
Concluding remarks
Based on these recent studies, the paradigm of cancer as a hierarchical disease whose growth is sustained by a rare population of stem cells is re-emerging on a much more solid footing since being proposed five decades earlier. These CSCs are self-renewing and retain remnants of normal developmental programs, giving rise to phenotypic and functional tumor heterogeneity. Implicit in this model of cancer development is the notion that CSCs are biologically distinct from other cells in the tumor
Glossary
- SCID & NOD/SCID (severe combined immune-deficient & non-obese diabetic/SCID):
- immune-deficient mouse strains used in xenotransplantation assays of human HSC
- CFU (colony-forming unit):
- committed hematopoietic progenitor
- LTC-IC (long-term culture-initiating cell):
- primitive hematopoietic progenitor assayed in vitro (more primitive than CFU)
- SRC (SCID-repopulating cell):
- primitive human hematopoietic progenitor capable of repopulating normal hematopoiesis in SCID or NOD/SCID mice
- SL-IC (SCID
References (66)
Identification of clonogenic common lymphoid progenitors in mouse bone marrow
Cell
(1997)Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment
Cell
(2005)- et al.
The biology of CML blast crisis
Blood
(2004) - et al.
The hallmarks of cancer
Cell
(2000) - et al.
Clonogenic cells in acute myeloblastic leukemia
Blood
(1986) Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo
Blood
(1997)- et al.
Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117)
Exp. Hematol.
(2000) Fluorouracil selectively spares acute myeloid leukemia cells with long- term growth abilities in immunodeficient mice and in culture
Blood
(1996)Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells
Blood
(2001)Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML)
Blood
(2003)