Current Cancer Therapy Reviews - Volume 4, Issue 3, 2008

Recent advances in stem cell biology have highlighted the “cancer stem cell hypothesis”. This hypothesis constitutes two important related concepts. The first is that cancers arise from the mutational transformation of normal stem cells or restricted progenitors/differentiated cells that acquire self-renewal potential. The second is that cancers contain a small subset with stem cell like properties that are responsible for the growth, progression, and invasion of cancer [1-3]. The AACR Cancer Stem Cells Workshop in 2006 reported that the consensus definition of cancer stem cells is those cells within a tumor that have the capacity to self-renew and to bring about the heterogeneous lineages of cancer cells, and that such a definition needs experimentally conclusive evidence to recapitulate the generation of a continuously growing tumor [4]. The existence of cancer stem cells was first proven in the context of acute myelogenous leukemia [5,6] and subsequently verified in brain and breast tumors, using cell surface markers specific for the normal stem cells of the same organ [7,8]. The tumorigenicity and the “stemness” of these cells have been confirmed by performing in vitro clonogenicity and in vivo tumorigenicity. Recently, the identification of cancer stem cells has also been reported in prostate, ovary, pancreas and nasopharynx cancers [9-12]. The stem cell niche, a specialized microenvironment in which stem cells reside, plays an essential role in the self-renewal and maintenance of stem cells and also organizes interaction between stem cells and their niche thorough several signaling pathways, at least in the hematopoietic, intestinal, and hair follicle systems [13]. It is possible that cancer stem cells may also signal to their niche to allow it to induce proliferation and progression of a tumor [4]. Currently, a body of evidence indicates that bone marrow-derived stem cells can engraft and differentiate into nonhematopoietic cells of ectodermal, mesodermal, and endodermal tissues other than hematopoeitic tissues. These stem cells also contribute to cancer stroma in mouse models [3]. Moreover, gastric cancer originating from bone marrow derived cells has also been reported in a murine model [14]. However, University of Florida News reported that ”bone marrow stem cells mimic cancer but do not initiate it“ in human cancers [15] Several signaling pathways that confer the self-renewal of stem cells, contribute to proliferation of cancer cells. The WNT, sonic hedgehog (SHH), Notch, PTEN and the BMI1 pathways have all been shown to promote the self-renewal of normal stem cells as well as proliferation of cancer cells in the same tissues [1,13]. In addition to these positive signals, transforming growth factor-beta (TGF-beta) and TGF-beta-related proteins, such as bone morphogenetic protein (BMP) act as key regulators of stem cell renewal and differentiation [16]. BMP signaling mediated by BMP receptor BMPR1a directly inhibits stem cell proliferation in the niches of intestine and skin and indirectly regulates hematopoietic stem cells through control of its niches [13,16]. Mutations in the BMPR1a and Smad4 induce juvenile intestinal polyposis and Cowden disease, respectively [17]. The interplay between BMP negative signal and the Wnt positive signal regulates the homeostatic balance of stem cell self-renewal and ongoing regeneration. If this balance is disrupted by loss of BMP signaling or abnormal activation of Wnt signaling, unusual proliferation of stem cells occurs, leading to tumorigenesis [18]. Telomeres and telomerase are also implicated in stem cell biology and cancer. Telomerase expression is restricted to germ cells, stem/progenitor cells of the adult normal tissues and the vast majority of cancer cells. Recent data on loss-of-function and gain-of-function mouse models for telomerase indicate that the effects of telomerase length and telomerase activity on different stem cell compartments (hematopoietic stem cells, epidermal stem cells and neural stem cells) are cell autonomous and that these effects are intrinsic to the stem cells and do not depend on physiological niche micro-environments [19]. The fact that telomerase is specifically expressed in highly proliferative stem/progenitor compartments as well as in cancer cells suggests that telomerase may be regarded as a stem cell factor [19]. The concept of cancer stem cells also has implications for the development of targeted therapies for cancer. Normal stem cells, including haematopoietic stem cells, characteristically express drug-resistance proteins, such as the MDR1 and APC transporters [1]. Just as normal stem cells are resistant to the induction of apoptosis by cytotoxic agents and radiation therapy, cancer stem cells display increased resistance to these agents compared with more differentiated cancer cells, and thus they remain in patients after cancer therapy.

Scientists have tried for many years to understand cancer development and progression in the expectation of defining the therapeutic target. Emerging evidence has revealed that cancers contain a minority population, termed “Cancer stem cells (CSCs)”, which are responsible for sustaining the tumour as well as giving rise to proliferating cells. CSCs are thought share the three features with normal stem cells: self-renewal, the capability give rise to multiple lineages, the potential to proliferate extensively and therefore it has been proposed that they have their origin in normal stem cells. However, since there is evidence that genetic alterations occurring in committed progenitor cells can reactive their proliferative potential, the origin of CSCs still remains undecided. In this review, we discuss the current status of cancer stem cells in various tissues, the origin of some cancers from normal stem cells, the evidence for the existence of particular markers and aspects of their cell biology. Better understanding of the relation between adult stem cells and cancer stem cells in tumourigenesis may will provide novel therapeutic strategies against cancers.

New evidence has dramatically demonstrated that only a minority of cancer cells has the capacity to proliferate extensively and form new tumors; these cells are called “tumor-initiating cells” or “cancer stem cells”. In this review, we focus on recent molecular insights into the nature of cancer stem cells in leukemia, leukemic stem cells (LSCs). LSCs arise not only from primitive hematopoietic stem cells (HSCs) with self-renewal capacity but also from committed progenitor cells that normally lack the ability to self-renew. These latter cells gain stem cell properties by reactivating a gene expression program similar to that functioning in normal HSCs. The self-renewal and differentiation capacities of normal primitive hematopoietic cells are controlled by complex signaling pathways involving Wnt/β-catenin, Pu.1/JunB and PI3K/Akt. These same mediators also participate in the leukemogenesis. In mice, administration of drugs such as rapamycin and anti-CD44 antibody, which target properties unique to LSCs, can selectively deplete these cells in vivo. The goal for this field is to design successful human leukemia therapies based on the targeting or manipulation of features specific to LSCs.

An oncogenic stimulus in a cell primarily results in hyperproliferation. However, uncontrolled cell proliferation is sensed by the cell and triggers a fail-safe mechanism resulting in senescence, apoptosis, or differentiation. This phenomenon is considered to be a cellular fail-safe mechanism to eliminate undesirable cells from a population of healthy cells. The RUNX1/AML1 gene, one of the most frequently targeted genes in human leukemia, is induced by the Ras oncogene in hematopoietic stem/progenitor cells and required to maintain the fail-safe mechanism. The stem cell pool is thereby protected from oncogenic insults and cancer-initiating cells, which would become cancer stem cells after accumulation of sequential genetic changes, are eliminated. This fail-safe mechanism and the consequence of its disruption in oncogenesis seems to be a fundamentally important concept, but have not been fully recognized to date. Gaining a better understanding of this mechanism might lead to new strategies to treat cancer stem cell-associated resistance to chemotherapy which is the subject of intense discussion in recent years.

The TGF-β signaling pathway plays a significant role in various biological phenomena such as cell growth, embryogenesis, differentiation, morphogenesis and apoptosis. Gastrointestinal endodermal stem cells, influenced by TGF- β signals, undergo asymmetric cell division that leads to differentiation into tissue-specific functional cells such as hepatocytes and gut epithelial cells. Disruption of this process results in tissue-specific cancer development. This review illustrates the role of TGF-β signaling in normal and cancer stem cells. Through mouse studies targeting different members of this pathway, investigators will be able to better define mechanisms of malignant progression in order to develop and improve cancer therapeutics.

Both stem cells and cancer cells can proliferate indefinitely. In many case, cancers consist of the cells expressing tissue-specific stem cell markers and the cells expressing differentiation markers. Moreover, it has been revealed that many cancer cells express ATP-binding cassette (ABC) transporters, by which the cells pump out a specific fluorescence dyes as well as anti-cancer drugs. Thus these finding suggest that either cancer cells resemble stem cells or cancers contain stem cell-like cells. Using the common characteristics between brain cancer cells and neural stem cells, several research groups have succeeded to identify stem cell-like brain cancer cells (called “brain cancer stem cells”) in brain tumors and brain cancer cell lines. The brain cancer stem cells, but not the other cancer cells, self-renew, form tumors when transplanted in vivo, and are highly resistant for both anti-cancer drugs and irradiation. Together all, these recent progresses suggest that it is crucial to characterize brain cancer stem cells and identify targets for the therapy.

Loss of telomere DNA in normal somatic cells is a major alteration upon ageing. Stem cells and progenitor cells also lose telomere DNA, but at a slower rate than normal cells due to activation of a low level of telomerase activity. Embryonic stem cells exhibit strong telomerase activity, maintain telomere length, and are resistant to DNA damage. In contrast, hematopoietic stem cells, which have weak telomerase activity, are sensitive to DNA damage. The shelterin complex is involved in t-loop formation, a mechanism thought to protect chromosome ends from DNA damage that induces telomere dysfunction. Telomere dysfunction in stem cells brought on by ageing as well as DNA damage has been shown to partake in various age-related diseases. This review illustrates the importance of the telomere end protection mechanism in normal, stem cells and cancer stem cells.

The phosphoinositide 3-kinase (PI3K)/AKT pathway plays an important role in cancer development and progression. Mammalian target of rapamycin (mTOR) is a downstream effector of this pathway and is responsible for various cellular functions including mRNA translation, cell cycle progression and cellular proliferation. Activation of the PI3K/AKT pathway plays an important role in normal and neoplastic T and B cell proliferation. Abnormal activation of this pathway is seen in various hematologic malignancies. This knowledge has lead to an interest in evaluating the use of mTOR inhibitors in hematologic malignancies. The prototype mTOR inhibitor is rapamycin. Three other drugs are being evaluated in clinical trials. This review focuses on the biologic function of the PI3K/AKT/mTOR pathway and the mTOR inhibitors that are in clinical development for treatment of hematological malignancies.

Unresectable or metastatic hepatocellular carcinoma (HCC) carries a poor prognosis. Hepatic reserve often dictates the therapeutic options. There have been multitudes of negative systemic therapy trials for advanced HCC unsuitable for surgical and locoregional therapy up until now. Hormonal drugs, such as tamoxifen or immune response modifiers such as interferon and thalidomide are mostly ineffective. Recently, long-acting octreotide has shown to improve the survival and quality of life in somatostatin receptors positive patients with advanced HCC. It should be verified in well designed controlled trials. In general, efficacy of conventional cytotoxic chemotherapy is poor. Growth factors and their corresponding receptors are commonly overexpressed or dysregulated in many cancers. There is a strong rationale for the drug inhibition of molecular components of proliferative and angiogenic components of signaling pathways in HCC, a hypervascularized neoplasm. Recently, in a randomized, placebo controlled trial, sorafenib, an oral multikinase inhibitor (Tab Nexavar® 200mg, in a dose 400 bid), has been found safe and effective for the first time in prolonging survival of patients with advanced HCC and preserved liver function (compensated cirrhosis). This effect is clinically meaningful and established sorafenib as first-line treatment for these patients. After this landmark study, several molecularly targeted therapies, alone or combined with chemotherapy or locoregional attempts, are currently under evaluation for advanced HCC. Nevertheless, the side effect profile of each regimen must be carefully considered in patients with advanced liver disease.

Mammalian target of rapamycin (mTOR) is a cytoplasmic kinase that is a downstream component of the phosphatidylinositol 3-kinase (PI3K)/Akt kinase cascade. Together with its associated proteins, it can affect mRNA transcription, protein translation, protein degradation and changes in the actin cytoskeleton. Since mTOR has the ability to influence cell proliferation and apoptosis, it plays an important role in carcinogenesis. The existence of specific inhibitors of mTOR in the form of the antibiotic rapamycin, and its analogs, make the mTOR signaling pathway an attractive target for anti-cancer therapy. Rapamycin (sirolimus, Wyeth Pharmaceuticals, Philadelphia, PA) is a macrocyclic lactone that forms a complex with the intracellular immunophilin FKBP12 and inhibits mTOR. Rapamycin derivatives that are being evaluated in clinical trials include CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573. Rapamycin inhibits T-cell proliferation and is thus used as an immunosuppressive agent. Temsirolimus (Wyeth Pharmaceuticals, Philadelphia, PA) has been evaluated in renal cell carcinoma (RCC), endometrial carcinoma, glioblastoma, breast cancer and mantle cell lymphoma. Everolimus (Novartis, East Hanover, NJ) is a macrolide derivative of rapamycin that has been evaluated in patients with imatinibrefractory gastrointestinal stromal tumors. AP23573 (ARIAD Pharmaceuticals, Cambridge, MA) is an intravenous (iv) mTOR inhibitor that has demonstrated antitumor activity against sarcomas. These examples illustrate the fact that mTOR inhibition is a viable therapeutic option in the treatment of solid tumors and further development of this new class of antineoplastic drugs should be pursued.