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Abstract

For many years, cancer research has focused on the adult stem cells present in malignant tumors. It is believed that current cancer treatments sometimes fail because they do not target these cells. According to classic models of carcinogenesis, these events can occur in any cell. In contrast, the cancer stem cell (CSC) hypothesis states that the preferential targets of oncogenic transformation are tissue stem cells or early progenitor cells that have acquired the potential for self-renewal. These tumor-initiating cells, or CSCs, in turn, are characterized by their ability to undergo self-renewal, a process that drives tumorigenesis and differentiation, which contributes to the cellular heterogeneity of tumors. Herein, we discuss the definitions and properties of CSCs in the major human cancers.

Keywords

Cancer stem cell (CSC)Adult stem cells Tumor-initiating cells Self-renewal

Background and Definitions

Stem cells are found in many different somatic tissues and are important participants in their physiology (Fig. 1). Stem cells have three distinctive properties: (a) self-renewal, (b) the capability to develop into multiple lineages, and (c) the potential to extensively proliferate. The combination of these three properties makes stem cells unique. The attribute of self-renewal is especially notable because its subversion is highly relevant to oncogenesis and malignancy (1,57). Aberrantly increased self-renewal, in combination with the intrinsic growth potential of stem cells, may account for much of what is considered a malignant phenotype.

Figure 1.

Stem cells physiology, for examples in adult somatic tissues. (A) Hematopoietic stem cells generate all types of mature blood cells. (B) Neural stem cells generate brain tissue. (C) Lung stem cells generate lung tissue.

CSCs are found in tumors or hematological cancers and possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample; therefore, these cells are tumorigenic, in contrast to other nontumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis. Therefore, the development of specific therapies targeted at CSCs could improve the survival and quality of life of cancer patients, especially in cases of patients with metastatic disease.

The first conclusive evidence for the existence of CSCs was reported in 1997. Bonnet and Dick (5) isolated a subpopulation of leukemic cells that expressed the CD34 surface marker, but lacked the CD38 marker. This CD34⁺/CD38^- subpopulation was capable of initiating tumors that were histologically similar to the donor in NOD/SCID mice (48).

In cancer research experiments, tumors can be established by the injection of tumor cells into an experimental animal. Disease progression is then followed over time, and novel drugs can be tested for their ability to inhibit tumor growth; however, efficient tumor formation requires the introduction of thousands or tens of thousands of cells. Traditionally, this feature has been explained by poor methodology (i.e., the tumor cells lose their viability during transfer) or the critical importance of the tumor microenvironment (i.e., the particular biochemical surroundings of the injected cells). Supporters of the CSC paradigm argue that only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia (AML), the frequency of these cells is less than 1 in 10,000 (5).

Further evidence for this hypothesis has been provided by histological studies of tumors. Many tumors are heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained during the metastasis of tumors. This implies that the cell that produced them had the capacity to generate multiple cell types; that is, it possessed multidifferentiation potential, a classical hallmark of stem cells (5).

The identification of leukemic stem cells prompted further research into other types of cancer, leading to the identification of CSCs in several solid tumors, including cancers of the brain (64), breast (2), lung (40), colon (53,55), ovary (72), pancreas (45), and prostate (42,47).

Cancer Stem Cells in the Hematopoietic System

The hematopoietic system is the best characterized somatic tissue with respect to stem cell biology. Over the past several decades, many of the physical, biological, and developmental features of normal hematopoietic stem cells have been defined (41,63), and useful methods for studying stem cells in almost any context have been established (49). Hematopoietic cell cancers, such as leukemia, are clearly different from solid tumors, but certain aspects of hematopoietic stem cell biology are relevant to our understanding of the broad principles of CSC biology (57). CSCs have been unequivocally identified in various types of leukemia, and several biologic properties of these stem cells have direct implications for therapy (21,30,37,69).

CSCs are readily evident in chronic myelogenous leukemia (CML) (34) and acute myelogenous leukemia (AML) (5,43), and they have also been implicated in acute lymphoblastic leukemia (ALL) (8,13,16). CML stem cells have a well-described stem cell phenotype and a quiescent cell cycle status. Similarly, AML stem cells are mostly quiescent (29,31,33,67), suggesting that conventional antiproliferative cytotoxic regimens are unlikely to be effective against them. AML stem cells have surface markers, such as the interleukin-3 receptor α chain, that are not present on normal stem cells (36). These markers may be useful for antibody-based (38) or other related therapeutic regimens (6,26). Early efforts have demonstrated the usefulness of antibodies against the CD33 antigen in the treatment of AML (32,44), and recent reports indicate that CD33 is expressed on some leukemic stem cells (66). These observations warrant the continued development of immunotherapy strategies against stem cell-specific antigens.

Cancer Stem Cells in the Brain

Brain tumors are the leading cause of cancer mortal-ity in children and are difficult to treat despite advances in surgery and adjuvant therapy. Most current brain tumor research is focused on the molecular and cellular analysis of the tumor mass. Brain tumors are typically comprised of morphologically diverse cells that express a variety of neural lineage markers. Analysis of the basic morphology and phenotype of brain tumors has yielded a limited amount of knowledge with respect to the clinical behavior of the tumor, as brain tumors that share a similar morphology and phenotype can have a very different prognosis and response to treatment.

The determination of key cells in the tumor population that maintain the tumor will provide an insight into the mechanism of brain tumorigenesis and allow us to identify the cell of origin in the normal brain. There is overwhelming evidence in other malignancies, such as leukemia, that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation (5,61). Rare stem cells within the leukemic population possess extensive proliferative and self-renewal capacities that are not observed in the majority of leukemic cells. Fractionation and functional analysis of leukemic stem cells indicated that they are necessary and sufficient to induce leukemia (5,43).

We have isolated normal neural stem cells in culture (as clonally derived neurospheres, each of which arise from a single stem cell) for the analysis of human pediatric brain tumors (62). Analysis of neurosphere cells were used to functionally characterize the populations of tumor cells. We purified and characterized a cell from primary human brain tumors with different phenotypes; this cell type had a marked capacity for proliferation, self-renewal, and differentiation. This cell represented a minority of the tumor cell population and was identified by the expression of the cell surface marker CD133. This CD133⁺ cell, which we have termed the brain tumor stem cell (BTSC) (43), lacked the expression of neural differentiation markers and was necessary for the proliferation and self-renewal of the tumor in culture. This cell was also capable of differentiating in vitro into the cell types found in the tumor in situ. The marker phenotype of the BTSC was similar to that of normal neural stem cells, in that it expressed CD133 and nestin, and was the same in patients with the same pathological type of tumor and in patients with different pathological subtypes. This suggests that brain tumors with a very similar phenotype can be generated from BTSCs. Further cellular and molecular studies of BTSCs would be required for better understanding of brain tumor biology. Comparison of normal neural stem cells and BTSCs will aid in finding the normal brain cell that is the source of the tumor.

Cancer Stem Cells in the Breast

Breast CSCs have been definitively identified by Al-Hajj et al. in specimens from patients with advanced stages of metastatic breast cancer. They demonstrated that cells with a specific cell-surface antigen profile (CD44⁺/CD24^-) could successfully establish themselves as tumor xenografts (2). Recent studies have provided definitive evidence for the existence of CSC populations within breast cancer cell lines. Charafe-Jauffret et al. used 33 cell lines derived from human breast cancers and nontransformed breast cells to study the expression of the stem cell marker aldehyde dehydrogenase (ALDH) (9). ALDH is a detoxifying enzyme that oxidizes intracellular aldehydes, and it is thought to play a role in the differentiation of stem cells via the metabolism of retinal to retinoic acid (11). ALDH activity, as assessed by the fluorescent ALDEFLUOR assay, has been successfully used to isolate CSCs from multiple myeloma and acute myeloid leukemia as well as from brain tumors (10,15). ALDH activity can be used to isolate a subpopulation of cells that display stem cell properties from normal human breast tissue and breast carcinomas (27). The majority of breast cancer cell lines contain an ALDE FLUOR-positive population with a distinct molecular profile that displays CSC properties (9). These studies have important implications for the interpretation of data using cell lines and suggest that these lines may be useful for elucidating the regulatory pathways of CSCs.

Cancer Stem Cells in the Lung

Bronchoalveolar stem cells (BASCs), which may be precursors of lung adenocarcinoma, have been identified using a mice model for lung cancer (40). BASCs were resistant to bronchiolar and alveolar damage and proliferated during epithelial cell renewal in vivo. BASCs exhibited self-renewal and were multipotent in clonal assays, highlighting their stem cell properties (3); furthermore, BASCs expanded in response to oncogenic K-ras in vitro and in lung tumor precursors in vivo (35). These data support the hypothesis that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinomas.

The K-ras, phosphatase and tensin homolog (Pten), phosphoinositide 3-kinase (PI3K), and cyclin-dependent kinase pathways have been implicated in the proliferation of these stem cells (70,71). The potential role of bronchoalveolar stem cells and other tumorigenic stem cell populations in the development and prognosis of human lung cancer and its resistance to drugs is an important area for future investigation.

Cancer Stem Cells in the Colon

Colon cancer is one of the best understood neoplasms from a genetic perspective (24,25,60), yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies (54,56). It has not been established whether every colon cancer cell possesses the potential to initiate and sustain tumor growth, or whether the tumor is hierarchically organized so that only a subset of cells (i.e., CSCs) possess such a potential (22,39,69). O'Brien et al. (55) used renal capsule transplantation in non-obese diabetic (NOD)/severe combined immunodeficient (SCID) to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133⁺; the CD133⁺ cells, which comprised the majority of the tumor, were unable to initiate tumor growth. CC-ICs within the CD133⁺ population were able to maintain themselves, differentiate, and reestablish tumor heterogeneity after serial transplantation. The identification of CSCs in the colon, which are distinct from the bulk of tumor cells, provides strong support for the hierarchical organization of human colon cancer. Their existence suggests that for therapeutic strategies to be effective, they must target the CSCs.

Cancer Stem Cells in the Ovary

In ovarian cancer, Bapat et al. (4) isolated two clones from patients' ascites that could organize anchorage-independent, spherical structures (spheroids) in vitro, similar to those observed in ascites in vivo (7). These clones formed xenografts in nude mice (with a histopathology similar to the parental human tumors), serially propagated in animals (4), and expressed the stem cell factor receptor CD117 (c-kit)—a well-known proto-oncoprotein (52). Another ovarian cancer study identified a subpopulation of dye-excluding cultured murine cells, representing membrane transporter-expressing putative stem cells, that were highly tumorigenic in mice when compared to dye-staining (i.e., non-effluxing) cells (65). To satisfy the CSCs' criterion of distinctive cell surface markers (18), the expression of CD117 (similar to the ascites study) and the hyaluronate receptor CD44 (also a marker for CSCs from several other solid tumors (14,19,45,59) was observed in these cultured murine cells.

Cancer Stem Cells in the Pancreas

Al-Hajj et al. (2) reported that a phenotypically distinct and relatively rare population of CD44⁺/CD24^-/epithelial-specific antigen-positive (ESA⁺) tumor-initiating cells was responsible for the propagation of human metastatic breast cancer specimens in NOD/SCID mice. Li et al. identified a highly tumorigenic subpopulation of CD44⁺/CD24⁺/ESA⁺ pancreatic cancer cells in a xenograft model of primary human pancreatic adenocarcinomas grown in immunocompromised mice (45). CD44⁺/ CD24⁺/ESA⁺ pancreatic cancer cells (0.2—0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential when compared to nontumorigenic cancer cells. Fifty percent of animals injected with 100 CD44⁺/CD24⁺/ESA⁺ cells formed tumors that were histologically indistinguishable from the human tumors from which they were derived. The enhanced ability of CD44⁺/CD24⁺/ESA⁺ pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44⁺/CD24⁺/ESA⁺ pancreatic cancer cells possessed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and the increased expression of the developmental signaling molecule sonic hedgehog (SHH). The identification of pancreatic CSCs and the elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.

Cancer Stem Cells in the Prostate

The cellular origins of prostate cancer are still undecided. It has been suggested that prostate cancers arise from terminally differentiated luminal cells (20,51) because the bulk population of tumor cells, in the most common form of prostate cancer, express luminal cell-specific markers (cytokeratins (CK) 8 and 18, androgen receptor (AR), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)), but lack the expression of basal cell markers, such as p63. Moreover, cells that solely express basal cell markers, such as CK5 and CK14, are rarely observed. This has led to the speculation that prostate cancers are derived from intermediate progenitors that have acquired the ability for self-renewal (68).

Several lines of evidence support the hypothesis that prostate cancer stem cells arise from normal stem cells. Advanced prostate cancers are androgen independent and basal cells can be phenotypically identified in the majority of metastases (46). Craft et al. showed that advanced androgen-independent tumors arise from the clonal expansion of AR^- cells that are present at a frequency of 1/10⁵-10⁶ AR⁺ cells (17). Recent studies have found that only the most primitive cells (a2β1^hi/CD133⁺/CD44⁺), which were phenotypically identical to normal prostate stem cells, could self-renew in vitro (14). Under differentiating conditions, AR⁺/PAP⁺/CK18⁺ luminal cells could be identified in these cultures, suggesting that they were derived from the more primitive cell population. In support of this finding, the CD44⁺ population from xenograft tumors and cell lines had enhanced proliferative potential and tumor-initiating ability in vivo compared to CD44⁺ cells (58). The CD44⁺ cells were AR^- and expressed higher mRNA levels of “stemness” genes, such as OCT3/4 and BMI1. By using clonally derived human prostate cancer epithelial cells expressing human telomerase reverse transcriptase (hTERT), Gu et al. demonstrated that these lines could regenerate tumors in mice that resembled the original tumor (with respect to the Gleason score) in patients (28). The tumors contained luminal, basal, and neuroendocrine cells, implying that the clone of origin could differentiate into the epithelial cell lineages of the prostate. In this case, the tumor-initiating cell was AR^-/p63^- and expressed the stem cell genes Oct-4, Nanog, Sox2, nestin, CD44, CD133, and c-kit. Moreover, Sca-1-sorted cells, en-righed for cells with prostate-regenerating activity, showed evidence of a basal and luminal lineage.

Conclusion

CSCs were the first identified in acute myeloid leukemia as cells expressing the furface antigen phenotype CD34+/CD38^-, which have the capacity to reproduce the complete leukemic hierarchy following xenoengraftment (5). The epithelial linings of most tissue surfaces undergo continuous turnover and are organized according to a stem cell hierarchy, similar to the hematopoietic system (18,50). CD24^-/CD44+ cells that could be serially propagated in animals and recapitulate their original phenotype were isolated from human breast tumors (2). CSCs have also been identified in numerous other epithelial malignancies (melanoma, lung, head/neck, pancreas, prostate, and colon cancers) (14,19,23,40,45,59). A consensus of five defining criteria has been established to affirm the existence of CSCs: (a) self-renewal, (b) restriction to a small minority of the total tumor population, (c) reproducible tumor phenotype, (d) multipotent differentiation into nontumorigenic cells, and (e) expression of distinctive cell surface markers permitting consistent isolation (12,18).

Some types of cancer, when identified at an early stage, can be successfully treated; however, advanced cancers and a number of other cancer types, such as pancreatic cancer, still have dismal survival rates. Other cancers, such as head and neck cancers, are often resistant to current therapies, making less-invasive treatments more difficult. In addition, current chemotherapeutic regimens cause severe side effects because they target all rapidly dividing cells.

Existing cancer treatments have mostly been developed using animal models, where therapies that were able to promote tumor shrinkage were deemed effective. However, animals do not provide a complete model of human disease. Tumor relapse is exceptionally difficult to study in mice because they have a short life span that does not usually exceed 2 years. The study of CSCs is still in its early stages, primarily taking place in the laboratory. No standard treatments have yet been developed as a result of research on CSCs. The next step is to understand CSC activity and to identify drugs that target the stem cells without harming normal cells. Treatments that specifically target CSCs would cause fewer side effects for patients.

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An Overview of Concepts for Cancer Stem Cells

Abstract

Keywords

Background and Definitions

Cancer Stem Cells in the Hematopoietic System

Cancer Stem Cells in the Brain

Cancer Stem Cells in the Breast

Cancer Stem Cells in the Lung

Cancer Stem Cells in the Colon

Cancer Stem Cells in the Ovary

Cancer Stem Cells in the Pancreas

Cancer Stem Cells in the Prostate

Conclusion

References