Therapeutic implications of cancer stem cells
Introduction
Recent evidence has demonstrated that in leukemia and solid tumors only a minority of cancer cells have the capacity to proliferate extensively and form new tumors. These tumorigenic, or tumor-initiating cells (TICs), have been identified and enriched on the basis of their expression of cell-surface markers. Upon transplantation, TICs give rise to tumors comprising both new TICs as well as heterogeneous populations of non-tumorigenic cells reminiscent of the developmental hierarchy in the tissues from which the tumors arise. Most adult tissues are maintained over the lifetime of the host by normal stem cells that undergo expansion and differentiation to yield the functional elements of the organ. Through the tightly regulated process of self-renewal, stem cells are able to function over the lifespan of the host. The genetic constraints on self-renewal restrict the expansion of stem cells in normal tissues. Breakdowns in the regulation of self-renewal is likely a key event in the development of cancer as demonstrated by the fact that several pathways implicated in carcinogenesis also play a key role in normal stem cell self-renewal decisions. Thus, malignant tumors can be viewed as an abnormal organ in which a minority population of tumorigenic cancer cells have escaped the normal constraints on self-renewal giving rise to abnormally differentiated cancer cells that have lost the ability to form tumors. This new model for cancer has important implications for the study and treatment of malignancies.
Section snippets
What is a stem cell?
Normal tissue stem cells are defined by three common properties: first, the presence of an extensive capacity for self-renewal that allows maintenance of the undifferentiated stem cell pool over the lifetime of the host; second, strict regulation of stem-cell number; and third, the ability to undergo a broad range of differentiation events to clonally reconstitute all of the functional elements within the tissue. Importantly, the stem cells in each tissue differ with respect to their intrinsic
Self-renewal and cancer
Self-renewal is a cell division in which one or both of the resulting daughter cells remain undifferentiated and retain the ability to give rise to another stem cell with the same capacity to proliferate as the parental cell. Proliferation, unlike self-renewal, does not require either daughter cell to be a stem cell nor to retain the ability to give rise to a differentiated progeny. The committed progenitor cell is destined to stop proliferating as with each cell division its potential to
Cellular origin of cancer stem cells
The term ‘cancer stem cell’ is an operational term defined as a cancer cell that has the ability to self-renew giving rise to another malignant stem cell as well as undergo differentiation to give rise to the phenotypically diverse non-tumorigenic cancer cells. The cell-of-origin for cancer stem cells remains unclear: they may or may not be derived from their normal stem cell counterpart. The fact that multiple mutations are necessary for a cell to become cancerous [18] has implications for the
Implications of the stem cell model for cancer
There are major implications for the way we study, diagnose and treat cancer if the same populations of cancer cells are tumorigenic in humans and the xenograft model. If only a rare subset of tumor stem cells drives tumor formation then the goal of therapy should be to identify this population and then develop therapies that target it. Current therapeutic strategies fail to account for potential differences in drug sensitivity or target expression between the TICs and the more frequent
Conclusions
It is becoming increasingly clear that cancer is a stem-cell disorder. In addition, our ability to identify pathways involved in both normal and malignant self-renewal will be important in furthering our knowledge of the events that lead to the development of cancer. The ability to prospectively identify, isolate and study cancer stem cells will significantly alter the way we think about, study, and treat cancer.
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
Acknowledgements
We would like to thank Laurie Luzynski for help in the preparation of this manuscript.
References (45)
- et al.
Cell-intrinsic differences between stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity
Neuron
(2002) - et al.
A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells
Blood
(1997) - et al.
The oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus
Nature
(1999) - et al.
Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization
Blood
(1998) - et al.
Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties
Genes Dev
(2002) - et al.
CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells
Blood
(1997) - et al.
Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast
Differentiation
(1998) - et al.
Preferential induction of apoptosis for primary human leukemic stem cells
Proc Natl Acad Sci USA
(2002) - et al.
The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype
Nat Med
(2001) - et al.
Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis
Blood
(2003)