An area of research that has been recently gaining attention is the relationship between cancer stem cell (CSC) biology and chemo-resistance in colon cancer patients. It is well recognized that tumor initiation, growth, invasion and metastasis are promoted by CSCs. An important reason for the widespread interest in the CSC model is that it can comprehensibly explain essential and poorly understood clinical events, such as therapy resistance, minimal residual disease, and tumor recurrence. This review discusses the recent advances in colon cancer stem cell research, the genes responsible for CSC chemoresistance, and new therapies against CSCs.
Keywords
Cancer stem cellsChemoresistanceColon cancer
Introduction
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, and the 5-year relative survival rate is only 8% [1] despite diagnostic and therapeutic advances. Tumor recurrence and metastasis are two critical survival-influencing factors of CRC. Many researchers have observed that some cancer cells (such as breast cancer, colon cancer, etc.) acquire the characteristics of cancer stem cells through the epithelial-mesenchymal transition (EMT) [2-4], which is responsible for promoting the invasion of CRC cells into the basement membrane and the surrounding microenvironment, including the lymph and blood vascular systems, a phenomenon that contributes to the intra- and/or extravasation of the tumor [5,6].
As a result of the EMT, the epithelial cells in a tumor, which normally interact with the basement membrane via their basal surface, are polarized, causing multiple biochemical changes, including enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of extracellular matrix (ECM) components [7]. This complex process (dedifferentiation) was observed in an in vivo experimental model of differentiating spermatogonia, which generate germinal stem cells [8], as well as in mammary luminal cells, which convert to mammary stem cells upon the overexpression of Sox9 and Slug [9]. Chronic inflammation promotes the transition of epithelial cells to mesenchymal cells via the expression of transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) [10,11].
A subpopulation of basal-like human mammary epithelial cells that show spontaneous conversion into cancer stem cell-like cells in vitro was recently reported [12]. It was also demonstrated in a genetic model of intestinal tumor initiation that epithelial non-stem cells can re-express stem cell markers and be converted into tumor-initiating cells. This phenomenon is strictly dependent on the degree of Wnt activation and is only observed when Wnt signaling is markedly elevated [13].
Cancer stem cells
Evidence suggests that a small sub-population of tumor cells, termed cancer stem cells (CSCs), are responsible for propagating cancer in a highly efficient manner [14]. This malignant clonal population constitutes 0.1-10% of all tumor cells [15] of which only some have the ability to form tumors [16].
Compared to normal stem cells, CSC are thought to show no restraint with respect to cell number (i.e., proliferation); however, their slow rate of cycling plays a role in resistance to treatment (chemotherapy and radiotherapy) and tumor recurrence [17,18]. Also, the ability of CSCs to initiate new tumors may be of critical importance for metastatic colonization. In fact, the ability of a cancer cell to seed an entire tumor following experimental implantation and the ability of these cells to seed a macroscopic growth following metastatic dissemination appear to be very similar processes, leading to the notion that metastasis-forming ability is limited to CSCs [3,19].
Recently, studies have shown that growth factors such as epidermal growth factor (EGF), insulin-like growth factor-1 receptor (IGF-IR), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF) or cytokines (TGF-β, TNF-α, IL-6) among others produced by a microenvironment can revert differentiated cells to a more stem cell – like state. Many studies have suggested that the EGF signaling pathway regulates intestinal epithelial cell and stem/progenitor cell growth and differentiation [20]. However, there is little knowledge concerning the role of growth factors in mediating proliferation and self-renewal of colon CSC.
Properties of cancer stem cells
The properties of CSCs include infinite self-renewal potential and the capacity to differentiate into the diverse populations of cells that comprise a tumor.
Self-renewal refers to the ability to form new stem cells with an identical and intact potential for proliferation, expansion, and differentiation, thus maintaining the stem cell pool. Self-renewal mechanisms that allow stem cells to persist consistently involve proto-oncogenic pathways, such as the Wnt/β-catenin and Notch pathways. Another regulator of self-renewal in the context of embryogenesis is the sonic hedgehog (Hh) signaling pathway (reported in multiple myeloma); however, little is known about the role of this pathway in adult stem cells and CSCs [21]. The preferential expression of Hh in CSCs was first published in a pancreatic cancer xenograft model [22], and evidence that the Hh pathway is aberrantly activated in a number of solid tumors, including colon cancer, has also been published [23].
A variety of signals have been shown to promote the self-renewal capacities of colon CSCs, including the Wnt pathway and the prevention of β-catenin-dependent transcription. In addition, DLL4 stimulates Notch receptors on neighboring cells and, together with β-catenin, directs an immature transcription profile that promotes self-renewal. BMP4 is also known to counteract this self-renewal activity of CSCs by binding to BMP receptors, thereby interfering with Wnt signaling and subsequently promoting differentiation. Last, hepatocyte growth factor (HGF) has been shown to maintain colon CSCs in a stem-cell state and prevent differentiation [24].
Homeostasis (i.e., CSC maintenance and proliferation) of the intestinal epithelium is tightly controlled and depends on the spatial organization of signals that emanate from supportive mesenchymal cells, the stromal environment, and differentiated epithelial progeny, although it remains unclear how these latter cells are integrated into the organization of intestinal cancers [25].
Increased numbers of CSCs may occur in poorly differentiated tumors (through asymmetric cell division and damaged stem cells) as well as advanced tumors where the tumor microenvironment promotes EMT, resulting in CSC expansion. Furthermore, activation of these pathways in stem cells over the life span of an organism may predispose these cells to neoplastic transformation and homeostatic proliferation.
Differentiation is defined as the ability to develop into a heterogeneous progeny of cells, which progressively diversifies and specializes according to a hierarchical process, constantly replenishing the tissue of short-lived, mature elements [26]. Recent reports about colon cancer have suggested that individual tumors, at the histopathological level, are relatively undifferentiated and may contain higher proportions of CSCs than their more differentiated counterparts, which have a significantly worse clinical prognosis [27,28].
Homeostatic control is the ability to modulate and balance differentiation and self-renewal [26]. Recently, it was shown that differentiated cells in the intestinal epithelium reside in the intestinal crypts as at least two types of stem cells leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) and B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), which serve to maintain the regenerative capacities of this tissue under homeostatic conditions [29]. Lgr5 expressing cells are the more active stem cell type and serve to maintain the regenerative capacities of these tissues under homeostatic conditions. In addition, Lgr5 expressing cells are actively proliferating and extremely sensitive to Rspo1-mediated Wnt stimulation and Dkk1-mediated Wnt inhibition. In contrast, Bmi-1-expressing cells are less affected by environmental stress (i.e., not sensitive to Wnt modulation), normally quiescent and are held in reserve for “special occasions”, in which they give rise to progeny that clonally repopulate multiple contiguous crypt-villus axes during subsequent intestinal regeneration [30]. However, the homeostasis of tumoral epithelial tissues is governed by a complex program, which is controlled by niche-dependent signals that involve the subepithelial stroma (VEGF, platelet-derived growth factor, TGF-β, Nuclear factor kB), adjacent epithelial cells (Notch, Hedgedog), natural enteric flora, as well as intracellular transcription factors and the activation of signaling networks associated with the epithelium (i.e., Wnt-β-catenin). As previously reported, Wnt proteins and the Notch pathway are crucial for maintaining stem cell homeostasis, as these signals have the potential to maintain the phenotype of CSCs in the tumor mass [31]. However, the equilibrium that regulates the growth and maintenance of tumors is poorly understood.
CSC markers
The discovery of CSC antigens is not based on the overexpression of typical tumor antigens but on the presence of antigens on populations of cells that have stem cell-like properties. However, it is important to note that variable expression levels of antigens on CSCs and their frequent co-expression on normal stem cells have made CSC antigen distinction difficult [15]. CD133, CD44, CD24, CDCP1, CXCR4, and CD26 have been identified as colon CSC surface antigens, but it is not well defined which are the best markers to identify a tumor stem cell [32,33] due to the variability found among individuals with the same tumor type [31]. A better understanding of the origin of CSCs during carcinogenesis would aid in the search for better markers [34].
Malignant transformation of colon cancer
Tumorigenesis occurs when cells acquire six hallmarks: self-sufficiency in growth signaling, insensitivity to anti-growth signaling, evasion of apoptosis, unlimited replicative potential, sustained angiogenesis and tissue invasion. An initial event of cancer involves genetic defects that cause DNA instability activation followed by less tumor suppressor gene or gatekeeper pathway. The idea that the key tumorigenic mutations occur in a few cells that can self-renew and reside in tissues in the long-term is a major shift in thinking and has implications in the ability of adenomas to progress to carcinoma, and finally, in treatment failure [35,36].
Model of colon carcinogenesis
The model of carcinogenesis begins with an expression increase in intracellular β-catenin in normal colon epithelial tissue, which results in the prolonged activation of the Wnt pathway, β-catenin stabilization, and C-terminal binding protein 1 (CtBP1). In addition, APC inactivation contributes to adenoma initiation as the first step. KRAS activation and β-catenin nuclear localization act synergistically to promote the progression of adenoma to carcinoma [37]. Also, the loss of p53 and the heterozygosity of chromosome 18q [38] are frequently observed in advanced colorectal cancer (only the TP53 mutation is generally believed to occur at the time of transition of an adenoma to cancer). Mutations in the transforming growth factor-beta receptor (TGFBR) and phosphatidylinositol 3-kinase (PIK3CA) genes are reported to be factors involved in tumor progression [39]. In addition, recent studies have indicated that the cellular origin of CRC initiation might involve the normal stem cells of the intestine, rather than progenitors or differentiated cells. It has been hypothesized that transformed stem cells progress to intestinal adenomas (Figure 1).
Figure 1
Carcinogenesis of colon cancer. Progression of colon normal epithelium to invasive carcinoma goes through several stages. The invasive carcinoma stage involves epithelial cells losing their polarity and detaching from the basement membrane altering cell-ECM interactions and signaling networks producing changes in stem cells that generate cancer stem cells. Malignant phase of tumor growth can progress from this stage to metastatic cancer, also involving invasion of tissue by feed blood vascular systems.
Cancer stem cells and carcinogenesis
Cancer stem/progenitor cells and their progeny attain more malignant phenotypes during primary cancer progression via three distinct pathways of genomic instability: the chromosomal instability, microsatellite instability, and CpG island methylator phenotype pathways [40]. However, carcinoma develops a decade after the appearance of polyps. Without prophylactic colostomy, colon cancer appears in 100% of these patients [39].
The tumorigenic pathways cooperate to activate different downstream signaling effectors leading to carcinogenesis, including PI3K/Akt/molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-kB), mitogen-activated protein kinases (MAPKs), Myc and polycomb group (PcG) proteins, such as B lymphoma Mo-MLV insertion region 1 homolog (BMI-1). Cooperation between these signal transduction elements, in turn, plays a critical role in the high self-renewal ability, sustained proliferation, survival, invasion and metastasis of cancer stem/progenitor cells and their progeny [39,41-47].
During the transformation process, defects in the DNA mismatch repair (MMR) system result in microsatellites in the genome that are either longer or shorter than those in the parent cell. This phenomenon is termed microsatellite instability (MSI). These are present in two copies in most individuals and are responsible for 15%–20% of colon cancer cases [48]. Inactivation of MMR enzymes can occur either through the aberrant methylation of promoter CpG islands in the MLH1 gene or through point mutations in MMR family genes. The majority of these inactivation events are due to the epigenetic silencing of MLH1 gene expression by promoter hypermethylation [49-52]. Aberrant hypermethylation involves the covalent attachment of a methyl group to the 5´ position of cytosine and takes place in repetitive CG dinucleotides or CpG-rich stretches of DNA within the promoter region, resulting in transcriptional silencing. In addition, other secondary pathways that regulate cellular proliferation, differentiation, senescence, and apoptosis (RAS/RAF/MAPK) have been reported [27,39].
Crypt progenitors divide every 12–16 h, generating approximately 300 cells per crypt each day [53]. The committed transit-amplifying (TA) cells are responsible for building tissue mass. TA cells typically undergo a limited number of cell divisions, after which they terminally differentiate into either secretory (goblet, paneth and enteroendocrine) cells or enterocytes. Their proliferation is balanced by apoptosis and cell shedding at the other end of the epithelial conveyor belt, the tip of the villus. However, in the tumor process, it is assumed that CSCs originate from normal stem cells after the accumulation of mutations, and growth-promoting signals change the microenvironment or niche for CSCs undergoing uncontrolled proliferation [54,55]. In recent years, CSCs have received intense interest as key tumor-initiating cells that may also play an integral role in recurrence following chemotherapy, particularly because of their ability to proliferate [56] and self-renew [57] after chemotherapy, irradiation or both [58]. As a result, a number of mechanisms for the chemoresistance of CSCs have been identified [59].
Chemoresistance
Treatment with CRC-based chemotherapeutic regimens principally includes 5 fluorouracil (5FU), oxaliplatin and/or leucovorin or 5-FU, leucovorin and irinotecan (FOLFIRI). However, drug failure occurs in 90% of metastatic cancers and is attributed to therapeutic resistance, which is associated with increased aerobic glycolysis, fatty acid synthesis, and glutamine metabolism, resulting in decreases in drug-induced apoptosis [60]. In addition, drug efflux transporter proteins (or ABC transporters) are generally found to be overexpressed in drug-resistant cancer cells [61].
Cancer stem cells and chemoresistance
Chemotherapeutic drugs display antitumor effects in part by inducing oxidative damage, which increases glycolysis and results in high levels of NADPH (an antioxidant), an event that can be associated with cancer chemoresistance; however, increased ATP can activate ABC transporters to increase drug efflux [61] and upregulate HIF-1α signaling, inducing hypoxia-associated drug resistance. Specifically, HIF-1α induces the expression of genes that promote survival through anti-apoptotic signaling (survivin, Bcl-XL, Mcl-1) or other survival mechanisms, such as autophagy by BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) or BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L) [62-65]. Also, HIF-1α expression decreases pro-apoptotic signaling by inducing the expression of decoy receptors, such as DcR2, that compete for pro-apoptotic signaling factors, such as tumor necrosis factor-related apoptosis-inducing ligand, thereby decreasing productive signaling through apoptosis-inducing receptors, including DR4 and DR5 [66-69]. This attenuation of pro-apoptotic signaling allows cells to tolerate a higher level of chemotherapeutic insult before inducing cellular death pathways.
Signals of chemoresistance
Another mechanism of CSC drug resistance is the preferential activation of pro-survival signaling. For example, CD44, a receptor for hyaluronan (HA), is a major marker for CSCs in a variety of cancers. The binding of CD44 by HA can lead to the association of CD44 with epidermal growth factor receptor (EGFR) [63,64]. This association activates MAP kinase and other cellular signaling pathways, promoting cell survival in response to antineoplasic treatments, such as cisplatin, methotrexate, and adriamycin [70]. Furthermore, the HA-CD44 interaction activates EGFR-elicited cellular signaling pathways without engagement of the ligand EGF [70-72], which leads to resistance to targeted anti-EGFR therapy [71].
Another signaling mechanism involves CD47. CD47 is a widely expressed transmembrane protein, a receptor for thrombospondin family members, and the ligand for signal regulatory protein alpha (SIRPα). The CD47/SIRPα interaction has been attributed as a mechanism that provides the cell with an anti-phagocytic signal. Tumor cells express high levels of CD47 to avoid phagocytosis by tumor-associated macrophages, and CD47 expression has been shown to be required for the survival, growth and metastasis of hematopoietic and solid tumors [72].
Finally, the failure of conventional treatment regimens, particularly chemotherapy [73,74] and radiotherapy [75], can be attributed to CSCs. In fact, CSCs can be segregated from a cell population by selecting for cells that exhibit resistance to standard cancer treatments [76]. New strategies are being sought to address this problem, including a chemotherapy response assay that evaluates the chemosensitivity of a tissue sample (in vitro) and the design of compounds against CSCs.
Perspectives on treatment
Recently several compounds and drugs have been discovered selectively against CSC [77]. Some of these are microbe-derived and plant-derived biomolecules [78,79], small molecule inhibitors that target key components of the intrinsic signaling pathways of CSCs, some classical drugs, such as metformin, tranilast, and thioridazine [77], monoclonal antibodies (mAbs) and antibody constructs that are directed against CSC-specific cell surface molecules, such as the CD44, CD47, EpCAM, CD123, GD2, Lgr5, IGF-IR, Dll4 and FZD receptors [15,80], or antibody derivatives. Technologies such as antibody PEGylation [81] polysialylation [82] and albumin can be used to engineer a longer blood half-life for use against target signaling pathways and/or molecules that selective operate in CSCs, some of which are also capable of killing subpopulations of cancer cells that do not display CSC properties. Therapeutic approaches with mAbs [83-90], antibody constructs and novel therapeutic strategies against colon CSCs [91,92] are summarized in Table 1, and some of these methods are reviewed in detail below.
Table 1
Monoclonal antibodies and nanocarriers against human colon cancer stem cells
Target
Compound
Class
Status
Reference
anti-EpCAM/anti-CD3
MT110 (solitomab)
BITE; human recombinant single chain bispecific bifunctional mAb construct
Preclinical, in vitro, xenograft mice Phase I clinical study, advanced solid tumors
Triomab; recombinant chimeric two half antibody, each with one light and one heavy chain from mouse IgG2a and rat IgG2b isotypes. Bispecific, trifunctional mAb construct
Colon CSCs that are resistant to 5FU or oxaliplatin can be sensitized with an interleukin-4 blocking antibody. The autocrine stimulation of interleukin-4 receptors on CSCs has been suggested to contribute to their stemness, including their drug-resistant phenotype [76,93]. Another study demonstrated that the anti-EREG antibody (epiregulin, epidermal growth factor family) is efficacious against tumor metastasis [94]. This antibody showed only moderate activity against established xenograft tumors in mice NOG (NOD/Shi-scid/IL-2Rcnull) but exhibited a stronger efficacy in a metastatic model tested in this study, suggesting that the anti-EREG antibody is efficacious in the early stage of cancer development when cancers are rich in CSCs [94].
Other authors have reported the use of antibody constructs that target CSCs, which are more effective when combined with conventional cytostatic drugs [77,88]. Combinations or cocktails of antibodies against bulk tumor targets and CSC targets can sometimes destroy the whole tumor as well as the resilient CSC population, preventing relapse [95]. Also, the design of bi-specific antibodies that recognize both CSC markers (which are co-expressed on normal stem cells) and tumor antigens could be used as a novel treatment to increase the specificity of CSC targeting [96].
Nanotechnology and cancer stem cells
Today, nanotechnology is encountered in many aspects of our daily lives. The growing field of biotechnology requires new tools that can easily interact with proteins in even smaller sizes. Nanonization can be applied to drugs for pharmaceutical use as a drug delivery system, resulting in the effective and selective delivery of treatment against tumor cells [97].
Drug delivery systems can be optimized with respect to drug extrusion, low aqueous solubility and stability, and high nonspecific toxicity using nanocarriers, such as nanoparticles (NPs), liposomes, micelles, nanotubes and nanogels, which have high penetrability. For example, polymeric micelles with a core-shell structure can be formed by the self-aggregation of polymeric amphiphile for the delivery of cytotoxic agents after intravenous administration in solid tumors providing a significant advantage against tumor by increased the enhanced permeability and retention effect of the cytotoxic compounds [97]. A novel micelle formulation of oxaliplatin encapsulated in a chitosan vesicle (CSO-SA/OXA micelles) [92] shows an excellent internalization ability that targets the tumor cell nucleus and increases the oxaliplatin concentration in tumor cells, which was shown to eliminate CSCs in vitro and in vivo.
In another example, solid lipid nanoparticles (SLNs) were utilized for the release of 5-FU inside the colonic medium for the local treatment of colon cancer; however, these SLNs have not been evaluated in an in vivo model to date [98]. The uptake of nanovehicles may occur via endocytosis, in which the free drug is internalized into cancer cells by molecular diffusion. Using drug-loaded nanovehicles, the drug can be efficiently delivered via penetration of the cell membrane, especially in chemoresistant tumor cells.
Liu C. has described a method by which chemotherapy resistance in colon CSC can be overcome through the siRNA-mediated knockdown of the drug efflux protein MDR1, which often is overexpressed in CSCs. Utilizing a moderate-throughput approach, the authors generated libraries of lipid nanocarriers composed of varying ratios of cationic polyethylenimine (PEI1200), polyethylene glycol (PEG) and a biodegradable lipid crosslinker such as 1,2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA). The electrostatic complexes formed by mixing with siRNA were screened for knockdown efficiency, and the optimized nanocarrier formulations were found to achieve >90% silencing. It has also been reported that treatment of colon CSCs with lipid nanocarriers containing MDR1-directed siRNA leads to efficient MDR1 knockdown and sensitizes cells to subsequent paclitaxel treatment tested in an in vitro model using CHOK1 cells [89].
In vitro assays have shown that nickel zinc ferrite nanoparticles produce cytotoxicity in epithelial cancer cells [99], and silver nanoparticles have been demonstrated to induce apoptosis in human colon cancer cells (HCT-116) dependent on the p53 expression [100]. Silver nanoparticles can be dissolved in solution, which prevents their agglomeration, or entrapped in a matrix. These kinds of particles represent interesting candidates for research as broad-spectrum bactericidal and virucidal compounds due to their effectiveness at small doses as well as their minimal toxicity and side effects [94]. Thus, the administration of silver nanoparticles (Table 1) during chemotherapy treatment in cancer patients could protect against the recurrent infections caused by chemotherapy agents. Nonetheless, conclusive safety has not been extensively demonstrated in animal models, and therefore, additional testing of silver nanoparticles is required before they can be used in clinical applications.
Conclusion
A better understanding of how tumor-initiating cells, such as CSCs, escape chemotherapy, the establishment of appropriate biomarkers, and the definition of novel clinical endpoints for monitoring the efficacy of combined and multimodal therapeutic strategies will be a challenge to improving future colon cancer treatment.
Notes
Abbreviations
CRC:
Colorectal cancer
CSC:
Cancer stem cells
EMT:
Epithelial mesenchymal transition
ECM:
Extracellular matrix
Lgr5:
Leucine-rich repeat containing G protein-coupled receptor 5
TNF-α:
Tumor necrosis factor-alpha
TNF-β:
Transforming growth factor-beta
Hh:
Hedgehog
HGF:
Hepatocyte growth factor
CTBP1:
C-terminal binding protein 1
PI3K:
Phosphatidylinositol 3-kinase
Bmi-1:
B lymphoma Mo-MLV insertion region 1 homolog
VEGF:
Vascular endothelial growth factor
IGF-IR:
Insulin-like growth factor-1 receptor
FGF-2:
Fibroblast growth factor-2
TGFBR:
Transforming growth factor-beta receptor
BNIP3:
BCL2/adenovirus E1B 19 kDa interacting protein 3
BNIP3L:
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like
Formulation of oxaliplatin encapsulated in a chitosan vesicle
DLin-DMA:
1,2-dilinoleyloxy-3-dimethylaminopropane
Declarations
Acknowledgements
This work was partially supported by CONACYT, Mexico. Register No. CB2012-178641 M.
Authors’ Affiliations
(1)
Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León
References
Thomassen I, van Gestel YR, Lemmens VE, de Hingh IH. Incidence, prognosis, and treatment options for patients with synchronous peritoneal carcinomatosis and liver metastases from colorectal origin. Dis Colon Rectum. 2013;56(12):1373–80.View ArticlePubMedGoogle Scholar
Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A, et al. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs. 2005;179(1–2):56–65.View ArticlePubMedGoogle Scholar
Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5(9):744–9.View ArticlePubMedGoogle Scholar
Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820–5.View ArticlePubMed CentralPubMedGoogle Scholar
Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2(8):563–72.View ArticlePubMedGoogle Scholar
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.View ArticlePubMed CentralPubMedGoogle Scholar
Barroca V, Lassalle B, Coureuil M, Louis JP, Le Page F, Testart J, et al. Mouse differentiating spermatogonia can generate germinal stem cells in vivo. Nat Cell Biol. 2009;11(2):190–6.View ArticlePubMedGoogle Scholar
Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell. 2012;148(5):1015–28.View ArticlePubMed CentralPubMedGoogle Scholar
Reiman JM, Knutson KL, Radisky DC. Immune promotion of epithelial-mesenchymal transition and generation of breast cancer stem cells. Cancer Res. 2010;70(8):3005–8.View ArticlePubMed CentralPubMedGoogle Scholar
Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011;108(19):7950–5.View ArticlePubMed CentralPubMedGoogle Scholar
Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Goktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013;152(1–2):25–38.View ArticlePubMedGoogle Scholar
Puglisi MA, Tesori V, Lattanzi W, Gasbarrini GB, Gasbarrini A. Colon cancer stem cells: controversies and perspectives. World J Gastroenterol. 2013;19(20):2997–3006.View ArticlePubMed CentralPubMedGoogle Scholar
Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nat Rev Cancer. 2012;12(2):133–43.PubMedGoogle Scholar
Moore N, Lyle S. Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance. J Oncol. 2011;2011:1–11.View ArticleGoogle Scholar
Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, et al. Targeting notch to target cancer stem cells. Clin Cancer Res. 2010;16(12):3141–52.View ArticlePubMed CentralPubMedGoogle Scholar
Feng Y, Dai X, Li X, Wang H, Liu J, Zhang J, et al. EGF signalling pathway regulates colon cancer stem cell proliferation and apoptosis. Cell Prolif. 2012;45(5):413–9.View ArticlePubMedGoogle Scholar
Agarwal JR, Matsui W. Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis. Anti Cancer Agents Med Chem. 2010;10(2):116–20.View ArticleGoogle Scholar
Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–7.View ArticlePubMedGoogle Scholar
Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1(6–7):338–51.View ArticlePubMed CentralPubMedGoogle Scholar
Ong BA, Vega KJ, Houchen CW. Intestinal stem cells and the colorectal cancer microenvironment. World J Gastroenterol. 2014;20(8):1898–909.View ArticlePubMed CentralPubMedGoogle Scholar
Edelblum KL, Yan F, Yamaoka T, Polk DB. Regulation of apoptosis during homeostasis and disease in the intestinal epithelium. Inflamm Bowel Dis. 2006;12(5):413–24.View ArticlePubMedGoogle Scholar
Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007;58:267–84.View ArticlePubMedGoogle Scholar
Ashley N, Yeung TM, Bodmer WF. Stem cell differentiation and lumen formation in colorectal cancer cell lines and primary tumors. Cancer Res. 2013;73(18):5798–809.View ArticlePubMedGoogle Scholar
Merlos-Suarez A, Barriga FM, Jung P, Iglesias M, Cespedes MV, Rossell D, et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell. 2011;8(5):511–24.View ArticlePubMedGoogle Scholar
Tian H, Biehs B, Warming S, Leong KG, Rangell L, Klein OD, et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature. 2011;478(7368):255–9.View ArticlePubMed CentralPubMedGoogle Scholar
Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci U S A. 2012;109(2):466–71.View ArticlePubMed CentralPubMedGoogle Scholar
Panequin J, Joubet D, Hollande F. Intestinal Stem cells: From Homeostasis to Cancer. In: Hayat MA, editor. Stem Cells and Cancer Stem Cells.Therapeutic Applications in Disease and Injury. Vol 9. New York, USA: Springer; 2013. p. 219–26.Google Scholar
Du L, Wang H, He L, Zhang J, Ni B, Wang X, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14(21):6751–60.View ArticlePubMedGoogle Scholar
Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol. 2010;23(3):450–7.View ArticlePubMedGoogle Scholar
Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.View ArticlePubMedGoogle Scholar
Phelps RA, Chidester S, Dehghanizadeh S, Phelps J, Sandoval IT, Rai K, et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell. 2009;137(4):623–34.View ArticlePubMed CentralPubMedGoogle Scholar
Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol. 2007;13(28):3784–91.PubMedGoogle Scholar
Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer. Gastrointestinal Cancer Res. 2012;5(1):19–27.Google Scholar
Birnie R, Bryce SD, Roome C, Dussupt V, Droop A, Lang SH, et al. Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions. Genome Biol. 2008;9(5):R83.1-R83.13.View ArticleGoogle Scholar
Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y, et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res. 2008;68(19):7742–9.View ArticlePubMedGoogle Scholar
Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008;27(12):1749–58.View ArticlePubMedGoogle Scholar
Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol. 2012;3(3):32–42.View ArticlePubMed CentralPubMedGoogle Scholar
Shiras A, Chettiar ST, Shepal V, Rajendran G, Prasad GR, Shastry P. Spontaneous transformation of human adult nontumorigenic stem cells to cancer stem cells is driven by genomic instability in a human model of glioblastoma. Stem Cells. 2007;25(6):1478–89.View ArticlePubMedGoogle Scholar
Venugopal C, Li N, Wang X, Manoranjan B, Hawkins C, Gunnarsson T, et al. Bmi1 marks intermediate precursors during differentiation of human brain tumor initiating cells. Stem Cell Res. 2012;8(2):141–53.View ArticlePubMedGoogle Scholar
Wang H, Wu J, Zhang Y, Xue X, Tang D, Yuan Z, et al. Transforming growth factor beta-induced epithelial-mesenchymal transition increases cancer stem-like cells in the PANC-1 cell line. Oncol Lett. 2012;3(1):229–33.PubMed CentralPubMedGoogle Scholar
Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis. 2008;29(4):673–80.View ArticlePubMedGoogle Scholar
Ahmed D, Eide PW, Eilertsen IA, Danielsen SA, Eknaes M, Hektoen M, et al. Epigenetic and genetic features of 24 colon cancer cell lines. Oncog. 2013;2:e71.View ArticleGoogle Scholar
Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology. 2000;119(4):921–8.View ArticlePubMedGoogle Scholar
Nakagawa H, Nuovo GJ, Zervos EE, Martin Jr EW, Salovaara R, Aaltonen LA, et al. Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res. 2001;61(19):6991–5.PubMedGoogle Scholar
Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10(9):917–23.PubMedGoogle Scholar
Marshman E, Booth C, Potten CS. The intestinal epithelial stem cell. Bioessays. 2002;24(1):91–8.View ArticlePubMedGoogle Scholar
Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457(7229):608–11.View ArticlePubMedGoogle Scholar
Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 2006;66(9):4553–7.View ArticlePubMedGoogle Scholar
Francescangeli F, Patrizii M, Signore M, Federici G, Di Franco S, Pagliuca A, et al. Proliferation state and polo-like kinase1 dependence of tumorigenic colon cancer cells. Stem Cells. 2012;30(9):1819–30.View ArticlePubMedGoogle Scholar
Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013;210(13):2851–72.View ArticlePubMed CentralPubMedGoogle Scholar
Zeuner A, Todaro M, Stassi G, De Maria R. Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell. 2014;15(6):692–705.View ArticlePubMedGoogle Scholar
Abdullah LN, Chow EK. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med. 2013;2(1):9.View ArticleGoogle Scholar
Wu CP, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol. 2008;1(2):93–105.View ArticlePubMed CentralPubMedGoogle Scholar
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.View ArticlePubMedGoogle Scholar
Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004;279(23):24218–25.View ArticlePubMedGoogle Scholar
Raspaglio G, Filippetti F, Prislei S, Penci R, De Maria I, Cicchillitti L, et al. Hypoxia induces class III beta-tubulin gene expression by HIF-1alpha binding to its 3' flanking region. Gene. 2008;409(1–2):100–8.View ArticlePubMedGoogle Scholar
Zeng L, Kizaka-Kondoh S, Itasaka S, Xie X, Inoue M, Tanimoto K, et al. Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions. Cancer Sci. 2007;98(9):1394–401.View ArticlePubMedGoogle Scholar
Chen N, Chen X, Huang R, Zeng H, Gong J, Meng W, et al. BCL-xL is a target gene regulated by hypoxia-inducible factor-1{alpha}. J Biol Chem. 2009;284(15):10004–12.View ArticlePubMed CentralPubMedGoogle Scholar
Flamant L, Notte A, Ninane N, Raes M, Michiels C. Anti-apoptotic role of HIF-1 and AP-1 in paclitaxel exposed breast cancer cells under hypoxia. Mol Cancer. 2010;9:191.View ArticlePubMed CentralPubMedGoogle Scholar
Sullivan R, Graham CH. Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1. Mol Cancer Ther. 2009;8(6):1702–13.View ArticlePubMedGoogle Scholar
Wen W, Ding J, Sun W, Wu K, Ning B, Gong W, et al. Suppression of cyclin D1 by hypoxia-inducible factor-1 via direct mechanism inhibits the proliferation and 5-fluorouracil-induced apoptosis of A549 cells. Cancer Res. 2010;70(5):2010–9.View ArticlePubMedGoogle Scholar
Wang SJ, Bourguignon LY. Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Arch Otolaryngol Head Neck Surg. 2006;132(7):771–8.View ArticlePubMedGoogle Scholar
Wang MT, Jiang H, Boral D, Nie D. Cancer Stem Cells in Resistance to Cytotoxic Drugs: Implications in Chemotherapy. In: Bonavida B, editor. Molecular Mechanisms of Tumor Cell Resistant to Chemotherapy. Resistance to Target Anti-Cancer Therapeutics. Vol 1. New York, USA: Springer; 2013. p. 151–61.View ArticleGoogle Scholar
Wang SJ, Bourguignon LY. Hyaluronan-CD44 promotes phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer. Arch Otolaryngol Head Neck Surg. 2006;132(1):19–24.View ArticlePubMedGoogle Scholar
Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, et al. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006;13(7):1238–41.View ArticlePubMedGoogle Scholar
Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10(2):R25.View ArticlePubMed CentralPubMedGoogle Scholar
Holtz MS, Forman SJ, Bhatia R. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia. 2005;19(6):1034–41.View ArticlePubMedGoogle Scholar
Todaro M, Perez Alea M, Scopelliti A, Medema JP, Stassi G. IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle. 2008;7(3):309–13.View ArticlePubMedGoogle Scholar
Naujokat C. Targeting Human Cancer Stem Cells with Monoclonal Antibodies. J Clin Cell Immunol. 2012;2012:1–15.Google Scholar
Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem. 2011;22(9):799–806.View ArticlePubMed CentralPubMedGoogle Scholar
Naujokat C, Fuchs D, Opelz G. Salinomycin in cancer: a new mission for an old agent. Mol Med Rep. 2010;3(4):555–9.View ArticlePubMedGoogle Scholar
Majeti R. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene. 2011;30(9):1009–19.View ArticlePubMedGoogle Scholar
Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003;2(3):214–21.View ArticlePubMedGoogle Scholar
Constantinou A, Epenetos AA, Hreczuk-Hirst D, Jain S, Deonarain MP. Modulation of antibody pharmacokinetics by chemical polysialylation. Bioconjug Chem. 2008;19(3):643–50.View ArticlePubMedGoogle Scholar
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G, et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009;69(5):1951–7.View ArticlePubMed CentralPubMedGoogle Scholar
Fischer M, Yen WC, Kapoun AM, Wang M, O'Young G, Lewicki J, et al. Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer Res. 2011;71(5):1520–5.View ArticlePubMedGoogle Scholar
Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A. 2012;109(29):11717–22.View ArticlePubMed CentralPubMedGoogle Scholar
Hart LS, Dolloff NG, Dicker DT, Koumenis C, Christensen JG, Grimberg A, et al. Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab. Cell Cycle. 2011;10(14):2331–8.View ArticlePubMed CentralPubMedGoogle Scholar
Herrmann I, Baeuerle PA, Friedrich M, Murr A, Filusch S, Ruttinger D, et al. Highly efficient elimination of colorectal tumor-initiating cells by an EpCAM/CD3-bispecific antibody engaging human T cells. PLoS One. 2010;5(10):e13474.View ArticlePubMed CentralPubMedGoogle Scholar
Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5(2):168–77.View ArticlePubMedGoogle Scholar
Liu C, Zhao G, Liu J, Ma N, Chivukula P, Perelman L, et al. Novel biodegradable lipid nano complex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel. J Control Release. 2009;140(3):277–83.View ArticlePubMedGoogle Scholar
Strohlein MA, Lordick F, Ruttinger D, Grutzner KU, Schemanski OC, Jager M, et al. Immunotherapy of peritoneal carcinomatosis with the antibody catumaxomab in colon, gastric, or pancreatic cancer: an open-label, multicenter, phase I/II trial. Onkologie. 2011;34(3):101–8.View ArticlePubMedGoogle Scholar
Ueno K, Hirata H, Hinoda Y, Dahiya R. Frizzled homolog proteins, microRNAs and Wnt signaling in cancer. Int J of cancer J Int du Cancer. 2013;132(8):1731–40.View ArticleGoogle Scholar
Wang K, Liu L, Zhang T, Zhu YL, Qiu F, Wu XG, et al. Oxaliplatin-incorporated micelles eliminate both cancer stem-like and bulk cell populations in colorectal cancer. Int J Nanomedicine. 2011;6:3207–18.PubMed CentralPubMedGoogle Scholar
Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1(4):389–402.View ArticlePubMedGoogle Scholar
Kobayashi S, Yamada-Okabe H, Suzuki M, Natori O, Kato A, Matsubara K, et al. LGR5-positive colon cancer stem cells interconvert with drug-resistant LGR5-negative cells and are capable of tumor reconstitution. Stem Cells. 2012;30(12):2631–44.View ArticlePubMedGoogle Scholar
Logtenberg T. Antibody cocktails: next-generation biopharmaceuticals with improved potency. Trends Biotechnol. 2007;25(9):390–4.View ArticlePubMedGoogle Scholar
Reid A, Vidal L, Shaw H, de Bono J. Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). Eur J Cancer. 2007;43(3):481–9.View ArticlePubMedGoogle Scholar
Junghanns JU, Muller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3(3):295–309.PubMed CentralPubMedGoogle Scholar
Yassin AE, Anwer MK, Mowafy HA, El-Bagory IM, Bayomi MA, Alsarra IA. Optimization of 5-flurouracil solid-lipid nanoparticles: a preliminary study to treat colon cancer. Int J Med Sci. 2010;7(6):398–408.View ArticlePubMed CentralPubMedGoogle Scholar
Al-Qubaisi MS, Rasedee A, Flaifel MH, Ahmad SH, Hussein-Al-Ali S, Hussein MZ, et al. Cytotoxicity of nickel zinc ferrite nanoparticles on cancer cells of epithelial origin. Int J Nanomedicine. 2013;8:2497–508.View ArticlePubMed CentralPubMedGoogle Scholar
Satapathy SR, Mohapatra P, Preet R, Das D, Sarkar B, Choudhuri T, et al. Silver-based nanoparticles induce apoptosis in human colon cancer cells mediated through p53. Nanomedicine. 2013;8(8):1307–22.View ArticlePubMedGoogle Scholar
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