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. Author manuscript; available in PMC: 2012 Jun 1.
Published in final edited form as: Stem Cell Rev. 2011 Jun;7(2):307–314. doi: 10.1007/s12015-010-9205-7

The Tissue-Specific Stem Cell as a Target for Chemoprevention

Sophia L Maund 1, Scott D Cramer 1,✉
PMCID: PMC3074006  NIHMSID: NIHMS265281  PMID: 21086069

Abstract

While cancer treatment modalities are gradually improving due to increased knowledge about tumor heterogeneity and the cancer stem cell hypothesis, there remains a disconnect between tumor detection and mortality rates. The increasing knowledge of stem cell biology and its contribution to cancer progression illuminates the potential for chemopreventative regimens that effectively target the tissue-specific stem cell. Several signaling pathways have emerged that are critical for regulating stem cell self-renewal and multilineage differentiation over a range of tissue types, including Wnt, Hedgehog, and Notch signaling. Dysregulation of these genes can lead to cancer, which supports the cancer stem cell hypothesis. Several known chemopreventative agents have recently been shown to impact these and other pathways in the stem cell population, suggesting that their efficacies may be attributed in part to maintaining homeostasis of tissue-specific stem cells. Further understanding of the mechanisms of action of chemopreventative agents and of stem cell biology will generate better chemoprevention regimens that can be recommended especially to those in high-risk populations.

Keywords: Stem cell, Chemoprevention, Cancer stem cell, Self-renewal, Differentiation

Introduction

Over 100 years ago scientists observed similar characteristics between tumor tissue and embryonic tissue, which inspired the proposal that cancer arises from an undifferentiated cell [1]. Tumor-initiating cells have properties that overlap with normal tissue-specific stem cells: the ability to self-renew and to differentiate. These tumor-initiating or tumor stem cells give rise to a heterogeneous tumor and are the source of metastatic outgrowths and tumor relapses. The origin of the tumor stem cell may be from a normal tissue stem cell or from a more differentiated progenitor cell that acquires stem cell characteristics. New insights into the biology of the cancer stem cell (or tumor-initiating cell) and its putative roles in tumor initiation and maintenance are changing the way we approach cancer treatment. The rationale and strategies behind targeting the cancer stem cell in therapeutic regimens have been reviewed extensively for several tumor types [2–11]. Cancer development is a multi-step process, and the complexity behind tumor biology and cancer treatment increases with each discovery. We posit that targeting cancer at the earliest step in its development will be the most effective approach. While the fight to cure the disease continues, we need to emphasize the significant importance of cancer prevention research and practice. Here we discuss the potential role of the tissue-specific stem cell in chemoprevention strategies and the emerging data supporting its efficacy as a chemoprevention target.

The Biology of Tissue-Specific Stem Cells

Adult somatic stem cells were first discovered in the hematopoietic system, and they have since been characterized in numerous tissues including the brain, breast, lung, prostate, ovary, liver, pancreas, and colon [12–20]. Adult tissue-specific stem cells constitute minute, quiescent cell populations that serve to regenerate injured tissue and maintain tissue homeostasis over time. They are thought to reside in a stem cell niche within the tissue microenvironment that is necessary for providing cellular signals and interactions to maintain stem cell functions. Characterization of tissue-specific stem cells requires proof of both self-renewal and multilineage differentiation (Fig. 1). Self-renewal occurs when a stem cell undergoes asymmetrical division to produce one daughter cell and one identical stem cell. Multilineage differentiation is the ability of a tissue-specific stem cell to give rise to daughter cells that are multipotent progenitors with the capacity to differentiate along tissue-specific cell lineages. A major aim in stem cell biology is to identify the molecular signaling networks within the cells and the stem cell niche that regulate self-renewal and multilineage differentiation. Some signaling pathways have already been characterized, and they are targets for cancer treatment and prevention.

Figure 1.

Figure 1

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The tissue-specific stem cell undergoes asymmetric division resulting in self-renewal and multilineage differentiation. Transformation is a multi-step process that gives rise to a heterogeneous tumor. Conventional therapies do not eradicate the stem cell population, which can result in disease relapse at primary and metastatic sites. Development of chemoprevention strategies that target the tissue-specific stem cell and keep self-renewal and differentiation in check is a goal for effective cancer prevention and adjuvant therapy

Identification of tissue-specific stem cells has occurred in parallel to observations that they have the potential for transformation and can give rise to tumors. Many aberrant genetic signatures and signaling pathways involved in carcinogenesis have normal counterparts in adult stem cells that are necessary for maintenance of self-renewal and differentiation capabilities. Examples of these critical genes and signaling pathways include Wnt, Hedgehog, Notch, and TGFβ. Mutations and altered expression patterns of these genes have been identified in numerous tumor types including hematopoietic, gastrointestinal, breast and prostate [6, 11, 21–25]. These observations support the cancer stem cell hypothesis that a transformed stem cell gives rise to a tumor. An alternative hypothesis is that intermediate progenitor cells, not stem cells, are the cellular targets of mutations that lead to tumor formation. These hypotheses are not mutually exclusive. In fact, they may explain the differences between well-differentiated tumors (those that arose from a progenitor cell) and poorly-differentiated tumors (those that arose from a stem cell) (Fig. 1). A classic example of this is in skin cancer, where the stage of differentiation of the cell of origin along the cell lineage dictates the tumor type and severity [26]. Generally, a well-differentiated tumor has a better prognosis than a poorly-differentiated tumor. This emphasizes the importance of targeting the tumor-initiating stem cell at its earliest point along the lineage, which is the aim of chemoprevention.

The origin of the cancer stem/progenitor cell is still a matter of debate. One school of thought is that the cancer stem cell arises from a transformed adult tissue-specific stem cell, as discussed above. This was first demonstrated in the hematopoietic system when the cell of origin for acute myeloid leukemia in NOD/SCID mice was the transformed leukemic stem cell [27]. The other school of thought is that the cancer stem cell arises when a differentiated cell acquires mutations that cause “de-differentiation” and gives the cell stem-like properties of self-renewal which, when not properly regulated, can lead to tumor formation. This has also been demonstrated in the hematopoietic system: overexpression of the MLL fusion gene in a progenitor cell confers stem-like self-renewal capabilities and results in leukemia [28]. These two hypotheses may be tested in other systems by infecting a stem cell and a differentiated or progenitor cell with an observable marker and mutating genes involved in key self-renewal signaling pathways such as Wnt and Hedgehog, and then tracing their growth patterns in vivo and analyzing their self-renewal and differentiation potentials. There is evidence for both hypotheses, and both scenarios support the concept of a rare tumor-initiating cell population that is an important therapeutic and chemopreventative target.

An earlier model of carcinogenesis is Berenblum’s initiation-progression model of skin cancer which originated in the 1940’s [29]. In this model, DNA damage or another somatic mutation in the skin cell causes initiation, and a second cellular stress such as a wound or an additional mutation can instigate cancer progression. The time lapse between initiation and progression can span weeks to years, suggesting that the skin cell, which normally has a limited lifespan, was immortalized upon initiation. However, Berenblum speculated that tumor promotion was the result of “delayed maturation” of initiated skin stem cells, which would explain the stem-like ability of the initiated cells to survive in dormancy before promotion occurred [30]. The somatic mutation hypothesis for cancer initiation and progression in non-stem cells is still viable, but there is increasing support for and overlap with the cancer stem cell hypothesis across a wide range of systems.

Implications of the Cancer Stem Cell Hypothesis on Chemoprevention

The reasons behind targeting the cancer stem cell in the therapeutic setting also support the argument for targeting the tissue-specific stem cell for chemoprevention.

Resistance to Therapy

It has been documented in several tumor types that the cancer stem cell (or the tumor-initiating cell population) is resistant to both radiation therapy and chemotherapy and is the cause of disease relapse at primary and metastatic sites [11]. This is due to intrinsic properties of the stem cell that are important for its protection such as a slow cycling rate, increased drug efflux pumps, and, likely, niche localization. Therefore, instead of trying to overcome these natural barriers to kill the transformed cancer stem cell, a chemo-preventative approach would ideally help maintain stem cell homeostasis without antagonizing these properties. For example, a chemopreventative approach could take advantage of the slow-cycling or quiescent state of the stem cell during early stages of transformation to prevent dysregulated cell growth. Our group has recently shown that 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), the metabolically active form of vitamin D3, can induce senescence of prostate progenitor/stem cells [31]. Inducing senescence in the stem cell population is one mode of keeping cell growth in check, particularly in the face of environmental and genetic risk factors for prostate cancer that can lead to transformation of the prostate stem cell. Furthermore, chemopreventative strategies that target the stem cell populations could be used in the adjuvant setting to prevent tumor relapse.

Tumor Heterogeneity

A common characteristic of tumors that supports the cancer stem cell hypothesis is cellular heterogeneity. If a tumor arises from a transformed epithelial cell, it is expected to be phenotypically and genotypically similar, with the exception of randomly acquired mutations. No tumor is entirely homogeneous, but generally the less heterogenic the tumor is, the greater the therapeutic success rate. If a tumor arises from a transformed stem cell, it has the capacity to generate a tumor composed of heterogeneous cell lineages that are genotypically different and more difficult to treat. Combination therapies are most successful in these cases, and they are prevalent in cancer treatment today. However, even combination therapies do not eradicate the tumor-initiating cells, not only because of the stem cell’s intrinsic protective barriers, but also because of genetic disparities from the bulk of the tumor that are impervious to the therapeutic strategy. These genetic disparities are difficult to anticipate and are the main argument for tumor genotyping and personalized treatment. While we try to find a personalized cocktail of drugs that will target every type of cell in a tumor, we can promote a chemopreventative approach that focuses on the tumor-initiating stem cell population, which may help prevent the need for such an expensive and toxic cocktail.

Tumor Detection

Advances in tumor detection have occurred in the past 20 years, but a disconnect remains between detection and survival rates [32, 33]. Unfortunately, most cancers are detected once they are palpable, and even if they are classified as early-stage tumors, millions of cancer cells are likely to have already shed from the tumor and disseminated into the bloodstream [34]. The chance that one of these circulating tumor cells has the capacity to metastasize is very low, but it is there nonetheless. In fact, assessing circulating tumor cell levels may be an independent prognostic factor for tumor response to treatment and/or recurrence after treatment [35, 36]. If the metastatic cell is a tumor stem cell, as proposed by the cancer stem cell hypothesis, it can remain quiescent at the metastatic site (likely in a stem cell niche) for long periods of time, remaining invisible to current detection methods but maintaining the threat of exiting quiescence and causing disease relapse. Relapse at the primary site may be caused by the residual cancer stem cells that were not killed during therapy.

A common example of relapse at the primary site is androgen-independent prostate cancer recurrence, in which the prostate cancer stem cell is hypothesized to play a role. The prostate stem cell is androgen receptor (AR)-negative, yet it has been shown to be responsive to androgens [37–39]. Upon differentiation, the progenitor cell expresses AR, as do the transformed prostate progenitor cells that give rise to the AR-positive prostate tumor. When a patient receives hormone ablation therapy, the AR-expressing cells die and the tumor regresses, but the minute population of AR-negative prostate cancer stem cells remain, undetected. These cells are hypothesized to be the source of the inevitable regeneration of a tumor that is resistant to androgen ablation therapy. A chemoprevention regimen that targets the AR-negative prostate stem cell and keeps it from transforming may also work as adjuvant therapy to help prevent androgen-independent tumor relapse. Targeting the source of a tumor when it is still undetectable is a critical advantage of chemoprevention.

Chemoprevention Strategies Targeting the Tissue-Specific Stem Cell

The concept of differentiation therapy has been used in cancer treatment since the 1980’s with varying success depending on the tumor type. Differentiation therapy is based on the idea of administering agents that induce the differentiation of a transformed cell that has acquired aberrant growth capabilities, or has become “de-differentiated.” This would sensitize the cell to additional cytotoxic agents or otherwise impede cell survival. The most successful example is treatment of acute promyelocytic leukemia with the differentiating agent all-trans-retinoic acid [40]. More recently, all-trans-retinoic acid has been shown to reduce the mammary stem cell population as well as hematopoietic stem cells by inducing their differentiation [41, 42]. In light of the cancer stem cell hypothesis, differentiation therapy may be more successful when applied to chemoprevention strategies. The adult tissue-specific stem cell is inherently susceptible to differentiation cues from the microenvironment, so this property should be exploited during chemoprevention.

Dietary Chemopreventative Agents

Several of the existing dietary chemopreventative agents that have been supported by epidemiological and clinical observations may already act by targeting the tissue-specific stem cell. Sulforaphane, a natural compound derived from cruciferous vegetables such as broccoli, has long been studied for its anti-tumor benefits [43]. Recently, sulforaphane was reported to inhibit breast cancer stem cell growth in vitro and in vivo through inhibition of Wnt-regulated self-renewal [44]. Importantly, sulforaphane specifically targeted the cancer stem/progenitor cell population rather than the bulk tumor cells. This finding may explain the efficacy of sulforaphane as a chemopreventative agent for breast cancer in accordance with the cancer stem cell hypothesis, but definitive studies on the chemopreventative effects of sulforaphane on the breast stem cell in the clinical setting will take many years to complete. Regardless, these findings support the concept of targeting the tissue-specific stem cell during chemoprevention.

Vitamin D is another example of a promising chemo-preventative agent that likely acts in part on the stem cell population. Epidemiological and laboratory studies have pointed to a role for vitamin D3 in prevention of breast, prostate, colon, and ovarian cancers [45, 46]. 1,25(OH)2D3 has more recently been shown to exert anti-proliferative and pro-differentiating effects on a variety of stem and progenitor cells, including hematopoietic, skin, and prostate [47–50]. We have demonstrated that treating prostate progenitor/stem cells with 1,25(OH)2D3 induces G1 and G2 arrest and leads to expression of AR and prostatic acid phosphatase among other differentiation-related genes [31]. Genistein, a soy derivative, has been shown to act synergistically with 1,25(OH)2D3 to inhibit growth of prostate cells, and it has also been shown to regulate genes involved in stem cell self-renewal [48, 51, 52]. These findings support the use of vitamin D3 in addition to genistein in targeting the prostate stem cell population during chemoprevention, among other tissue types.

Curcumin, a polyphenol derivative of turmeric, exhibits anti-tumor properties in breast, prostate, pancreatic, and colon cancers [52–55]. In addition to its anti-inflammatory mechanism of action, it also acts by downregulating the Hedgehog, Wnt and Notch signaling pathways. A recent report showed that curcumin, in addition to piperine, can inhibit Wnt signaling in mammary stem cells, inhibiting their self-renewal capability [56]. Furthermore, curcumin preferentially targeted the self-renewal capacity of the stem cells instead of inducing overall cellular toxicity, so it is not detrimental to the general cell population. Another group recently showed that curcumin, in combination with the therapeutic cocktail of leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX), eliminated the colon cancer stem cell population [57]. These preliminary findings support the use of curcumin as a promising chemopreventative agent for breast and colon cancers, among others.

Quercetin and epigallocetechin-galleate (EGCG) are polyphenol compounds that occur naturally in apples and green tea, respectively. Both have long been recommended as chemopreventative agents due to their antioxidant and anti-inflammatory properties [58, 59]. They have also been shown to inhibit Wnt and Hedgehog signaling in colon, breast, and prostate cancer cells, suggesting putative roles for quercetin and EGCG in inhibiting the self-renewal capacity of the cancer stem cell [52, 60, 61]. A recent study showed that quercetin and sulforaphane synergistically inhibited pancreatic cancer stem cell growth in vitro and in vivo [62]. Vitamin E is another known antioxidant that exhibits anti-tumor effects in a wide variety of tumors. One of its isoforms, gamma tocotrienol (γ-T3), is particularly effective in inhibiting prostate cancer cell proliferation and invasion and sensitizing prostate cancer cells to chemotherapy [63, 64]. γ-T3 has recently been shown to target the prostate tumor initiating cell population in vitro and in vivo [65]. The effects of γ-T3, quercetin, and EGCG have yet to be tested in normal stem cell populations or in tumor progression models, but these findings support the cancer stem cell hypothesis as well as the hypothesis that targeting the stem cell population may be an effective preventative strategy against tumor relapse.

Although their effects on stem cell populations have not yet been tested, additional known chemopreventative agents may target self-renewal and differentiation pathways in tissue-specific stem cells. For example, resveratrol, a natural compound found in grapes, exhibits anti-cancer effects in prostate, brain, liver, and colon cancer cell lines, among others [66]. Among its anti-tumor mechanisms, it has been shown to inhibit Hedgehog signaling in prostate cancer cell lines, suggesting that it may also effectively inhibit prostate stem cell self-renewal [52]. This remains to be tested in stem cells and cancer stem cells, and it is likely to apply to other cell types besides prostate. Lycopene is a carotenoid found in tomatoes that is especially promising for chemoprevention of prostate cancer. It can induce apoptosis of prostate cancer cell lines in vitro and in vivo, and it even shows promise in reducing BPH and prostate tumor burden in patients [67]. Lycopene can also induce cell cycle arrest at G1 in various cancer cell types, but it has yet to be tested in any stem cell population [68]. Stem cell biology is a relatively young field, and investigating the effects of both known and potential chemopreventative agents in stem cell populations is a new approach that will take time to validate in vivo, but these studies are laying the groundwork for further investigation.

Sulforaphane, curcumin, genistein, resveratrol, quercetin, EGCG, lycopene, and other dietary chemopreventative agents have been shown to regulate epigenetic mechanisms in addition to regulating classical signaling pathways [69]. Epigenetic regulation via DNA methylation, histone modification, and microRNAs can contribute to pathogenesis, and the proteins and networks associated with these actions are being investigated as therapeutic targets [70–72]. Epigenetic modification is a useful mode of genetic regulation due to its reversible nature. It is especially encouraging that environmental factors such as diet and exercise can induce these effects, minimizing the need for synthetic compounds with potential toxicities. Since epigenetic regulation is being investigated in the therapeutic setting, and since the natural compounds described above can impact epigenetic regulation, chemopreventative strategies targeting epigenetic regulation by these natural compounds may be developed. First, the modes of epigenetic regulation by these agents need to be examined in tissue-specific stem cells.

Natural chemopreventative agents are especially promising because of their newfound impacts on stem cell populations. Further insight into their mechanisms of action in tissue-specific stem cells, cancer stem cells, and the stem cell niche will help lead to more effective chemopreventative regimens that can be recommended especially to people at high risk for certain types of cancers. Furthermore, such mechanistic insight may lead to discovery of novel chemopreventative agents that are effective in tissue-specific stem cells.

Hormones

Hormones play important roles in breast and prostate cancer development and maintenance, and have thus been manipulated by cancer therapeutics. Hormones are also important for normal breast and prostate differentiation and function, including stem cell maintenance. For example, there are correlations among high birth weight (due to growth hormones), high numbers of mammary stem cells, and the risk for breast cancer [73, 74]. Insulin-like growth factor-1 (IGF-1) and estrogen levels in utero affect the number of mammary stem cells, affecting breast cancer risk. Aggressive basal-like breast cancers are enriched in Wnt/β-catenin activity, suggesting an enrichment of self-renewal activity in what is likely a stem cell-derived tumor that is more difficult to treat [75]. The mammary stem cell is therefore a promising target for both cancer treatment and prevention. While mammary stem cells do not express hormone receptors, they are responsive to hormone ablation. It was recently shown that hormone ablation by both ovariectomy and letrozole sufficiently reduced the mammary stem cell population while pregnancy transiently increased the number of mammary stem cells, which can lead to a short-term increase in breast cancer risk [76]. These findings may explain the decreased risk for breast cancer after anti-estrogen therapies, and they support the concept of targeting the mammary stem cell population for breast cancer chemoprevention.

Conclusion

The molecular mechanisms behind tissue-specific stem cell biology and the cancer stem cell hypothesis are still under investigation. Emerging data are pointing to the importance of the tissue-specific stem cell in tumor initiation and maintenance, and the cancer stem cell is becoming a critical target in the development of cancer therapeutics. With equal importance, chemoprevention strategies should be focusing on tissue-specific stem cell populations. Recent studies have revealed that known chemoprevention agents including sulforaphane, vitamin D3, curcumin, quercetin, genestein, vitamin E, and EGCG may attribute their success at least in part to regulating self-renewal and differentiation of tissue-specific stem cells. Other natural agents such as resveratrol and lycopene remain to be tested in tissue-specific stem cells. Further understanding of their mechanisms of action and of stem cell biology will help potentiate the chemopreventative effects of these natural compounds, promote their concomitant use with primary and adjuvant cancer therapies, and lead to new chemopreventative compounds that act on the tissue-specific stem cell.

Acknowledgements

The authors are supported by the American Foundation for Aging Research, NIH Training Grant 5T32CA079448-10, and RO1-CA150105

Footnotes

Conflicts of Interest The authors declare no conflicts of interest.

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