Sci. Aging Knowl. Environ., 24 May 2006
Vol. 2006, Issue 9, p. pe12
[DOI: 10.1126/sageke.2006.9.pe12]

PERSPECTIVES

Stem Cell Aging and Cancer

Jennifer Fuller

The author is in the Immunology Program at the University of Michigan, Ann Arbor, MI 48109, USA. E-mail: jen6598{at}yahoo.com

http://sageke.sciencemag.org/cgi/content/full/2006/9/pe12

Key Words: stem cells • cancer stem cells • acute myeloid leukemia (AML) • breast cancer

Introduction

Human embryonic stem cells, derived from the undifferentiated inner mass cells of an embryo, are totipotent, meaning that they can differentiate into all the cell types of the adult body. Instead, adult or somatic stem cells are undifferentiated cells found in small numbers in most adult tissues. They are pluripotent or multipotent cells, meaning that they can differentiate into the various cellular components of the tissue in which they reside. By definition, a stem cell possesses three fundamental properties (1). First, it must be capable of self-renewal, whereby each round of cell division results in at least one daughter cell retaining the same developmental potential as the mother cell. This process differs from proliferation, or cell divisions that result in restricted progenitor cells (which are slightly more differentiated than true stem cells) and/or terminally differentiated cells. The second property of stem cells is the ability to differentiate into many different types of cells. Finally, stem cells must be capable of strictly regulated proliferation, resulting in a stable stem cell pool maintained over the life span of an individual. Loss of controlled proliferation, as a result of accumulated damage to DNA, may result in the transition from a stem cell to a neoplastic cell (2, 3). This Perspective explores the relationship between stem cell aging and cancer and the implications for cancer therapy.

Aging is evident in most tissues and organ systems, although the precise mechanisms involved have been difficult to delineate. It involves a progressive deterioration of tissue function, due in part to a reduction in new growth and a diminished capacity for tissue repair. These observations support the hypothesis that much age-related morbidity may be caused by diminished somatic stem cell self-renewal and proliferation. In addition, the aging process correlates with increased cancer rates in all tissues that contain stem cells (4). More specifically, a number of cancers, including those of the skin (5), bone marrow (6), colon (7), breast (8), prostate (9), and pancreas (6), disproportionately strike individuals 65 years of age and older.

Studies have identified similarities between somatic stem cells and some subsets of cancer cells known as cancer stem cells. Cancer stem cells are capable of self-renewal and giving rise to different types of cells (10, 11). Under normal circumstances, somatic stem cells continuously repopulate the mature differentiated cells of the organ system that they serve. Homeostatic pressures, such as contact with bone marrow stroma, growth factors, or cytokines, can affect whether a stem cell undergoes symmetric division to produce two daughter cells that are either both stem cells or both committed progenitor cells, which are capable of further differentiation and proliferation but lack the ability to self-renew. Alternatively, the stem cell divides asymmetrically, resulting in the formation of one stem cell and a committed progenitor. A cancer stem cell functions in a similar way to a somatic stem cell: it sustains the growth and spread of tumors by generating more stem cells, as well as repopulating the more differentiated cell types represented within the tumor. However, whereas proliferation of somatic stem cells is tightly constrained by intrinsic and external mechanisms, proliferation of cancer stem cells is dysregulated.

Do Stem Cells Age?

The ability of hematopoietic stem cells (HSCs) to maintain their numbers and continuously replenish blood cells throughout the life span of an organism implies that the HSC population does not age, but accumulating evidence indicates that HSCs display signs of aging and may have a limited functional life span. Competitive repopulation studies in which mice are implanted with bone marrow cells from young and old animals of several different mouse strains showed that HSCs from old mice do not establish normal multilineage hematopoeisis in their new host (a process known as engraftment) as well as do those from young mice (12-14). Age-associated differences in engraftment are even more pronounced when HSCs from fetal liver are compared with HSCs from young adult bone marrow (14). Studies using human HSCs from fetal liver, umbilical cord blood, and adult bone marrow showed similar age-related differences (15, 16).

A number of factors may contribute to the observed age-related decrease in HSC function, including oxidative damage to intracellular proteins (17, 18), chromosomal instability (19), and the accumulation of genomic DNA mutations (18, 20-22). The alterations occurring in aging HSCs mirror characteristics typically observed in tumor cells.

Are There Cancer Stem Cells?

The existence of cancer stem cells had been hypothesized for decades, but it was not until 1997 that they were sorted from patients with acute myeloid leukemia (AML) (23). In this study, Bonnet and Dick used cell-surface markers to distinguish a small subset of AML cells phenotypically similar to normal hematopoietic stem cells but with substantially greater proliferative potential. Normal stem cells are typically quiescent, but the subset of AML "stem cells" were, in comparison, highly proliferative, presumably due to an internal and/or external dysregulation. They also found that this subset of cells alone could produce AML when transplanted into immunodeficient mice. These data demonstrated that AML cells are inherently heterogeneous in both the expression of cell-surface molecules and in functional characteristics, including proliferation and possibly apoptosis. These characteristics ultimately define their ability to support and sustain the malignancy.

More recently, these so-called "cancer stem cells" were identified and purified from breast cancer tissue (24) and tumors of the central nervous system (25-27). In both cases, researchers sorted tumor cells into several distinct fractions on the basis of surface molecule expression patterns. They found that only a small subset of tumor cells that resembled somatic stem cells in their capacity for self-renewal and differentiation were capable of generating tumors when transplanted into immunodeficient mice. These findings suggest that solid tumors are made up of several types of cancer cells that can be organized into hierarchies from a less to a more differentiated phenotype, each originating from a rare population of cancer stem cells. These cancer stem cells have extensive proliferative potential compared with normal stem cells, and the ability to differentiate into cancer cells with even greater proliferative potential and which comprise the majority of the tumor cells. These more differentiated and highly proliferative cell types create the tumor mass.

The failure of current cancer therapy regimes may be explained by their inability to target damaged somatic stem cells, which presumably become cancer stem cells. Standard cancer treatments target differentiated tumor cells by taking advantage of their rapid proliferation. Such therapies would be expected to shrink the tumor by killing the majority of cancer cells, but the relatively quiescent cancer stem cell would survive this treatment, causing the tumor to recur. Further characterization of the changing biology of somatic stem cells with advancing age could provide insights leading to more effective therapeutic approaches for cancer.

Where Do Cancer Stem Cells Come From?

The origins of cancer stem cells are not clear. One theory holds that cancer stem cells were originally normal somatic stem cells that acquired genetic mutations over time (Fig. 1). Normal stem cells that maintain adult tissues, such as bone marrow and skin, have long life spans and thus could accumulate cancer-causing mutations over decades. Another theory suggests that cancer stem cells are actually differentiated non-stem cells that acquired the ability to self-renew through genetic changes. In both scenarios, the buildup of mutations due to aging plays a role.


Figure 1
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Fig. 1. (A) Adult stem cells possess the ability both to self-renew and to differentiate into many different cell types in the body. When a stem cell divides, each new cell has the potential either to remain a stem cell (self-renewal) or to become another type of cell with a more specialized function. (B) Normal adult stem cells or progenitor cells may acquire age-related mutations transforming them into cancer stem cells. These cancer stem cells would be defined by their ability to generate new cancer stem cells (self-renewal) and their ability to generate the various components of the tumor mass, including benign cancer cells that may acquire further mutations to become highly malignant cells.

 
How do cancer stem cells support the growth of a tumor mass? One hypothesis discussed in this Perspective holds that within a tumor resides a small population of cancer stem cells that are responsible for the proliferation potential of the tumor. However, an alternative hypothesis could explain the heterogeneous potential of tumor cells to self-renew. In this model, all tumor cells have the potential to self-renew and to recapitulate tumorigenesis, but there is an extremely low probability that any particular tumor cell will enter the cell cycle at any one time. When the cell enters the cell cycle, it would acquire a different phenotype, detectable in changes in cell-surface markers.

To determine which of these two models is most relevant to cancer biology, it will be necessary to characterize and purify different populations of cells from tumors to conduct single-cell analysis. Recent developments in antibody technology for the ex vivo analysis of the hematopoietic system provide an invaluable tool for such research. Using these antibodies, researchers have identified a large number of phenotypic markers associated with defined lineages and developmental stages of hematopoietic cells, allowing the identification of heterogeneous populations of cancer cells. Another technical advance that greatly facilitates the characterization of leukemia and other cancer stem cells is the development of high-speed, multiparameter flow cytometry and sorting. Combining these techniques has allowed the prospective selection of specific cancer cells based on cell-surface marker expression patterns.

Scientists have identified a growing number of parallels between somatic and putative cancer stem cells. In addition, application of the knowledge acquired from the stem cell biology field to cancer has lead to a number of advances in our understanding of tumor biology. However, up to now, studies of cancer stem cells have used heterogeneous populations of cells. The true definition of a cancer stem cell is the emergence of a tumor from the implantation of a single cell that possesses the ability to self-renew and differentiate. Until studies are repeated at the single-cell level in vivo, any conclusions derived from them have critical limitations.

To gain an understanding of the mechanisms leading to the generation of cancer stems cells, it will be necessary to compare normal stem cells with their tumorigenic counterparts, specifically with respect to genetics and the activities of different signal transduction pathways thought to be important in self-renewal and the regulation of proliferation. Several signaling pathways involved in the regulation of normal stem cell self-renewal have been shown to cause tumor cell proliferation when they are dysregulated. Recently, pathways regulated by WNT (wingless-type MMTV integration site family), SHH (sonic hedgehog), Notch, PTEN (phosphatase and tensin homolog), and BMI1 (B lymphoma Mo-MLV insertion region-1), have been shown to promote self-renewal of somatic stem cells and, when dysregulated, to promote tumorigenesis in the same tissues. Thus, it seems that the genes responsible for regulating normal stem cell self-renewal must also regulate proliferation and maintain multipotentiality. Stem cells retain mechanisms to self-renew throughout adult life. Thus, the age-related changes in genes regulating stem cell self-renewal, proliferation, and cellular maintenance may also be associated with an increased incidence of cancers.

Conclusions

To the extent that some, or perhaps many, malignancies are derived from somatic stem cells, investigating cancer development may provide some of the strongest evidence to date in support of stem cell aging. But for now, the notion that stem cells show age-related decay in function remains controversial (28).

It will be important for future studies to elucidate the relationships of genes important to stem cell phenotypes, aging, and malignant transformation. What complicates such studies is the wide variation in the latency of cancer development and progression among different individuals and in mouse strains, even when the cancer is experimentally induced by the same genetic alteration. The identification and manipulation of putative modifier genes affecting the severity of disease represents an important but largely untapped approach to cancer therapy. Until now, sifting through the genome in search of modifiers and understanding the molecular pathways by which they exert their influence was difficult, if not impossible. With the completion of the human and mouse genomes, however, genetic tools for such studies are available. Just as understanding cancer development may provide insights into stem cell aging, understanding the mechanisms that regulate somatic stem cell behaviors may lead to identification of molecular pathways common to both normal and cancer stem cells. This information will increase the potential for developing more effective therapies to target tumors and for decreasing recurrences and metastases, which currently limit cancer treatment protocols.


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Citation: J. Fuller, Stem Cell Aging and Cancer. Sci. Aging Knowl. Environ. 2006 (9), pe12 (2006).








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