Review Article

CD133: beyond a cancer stem cell biomarker

Amir Barzegar Behrooz Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, MalaysiaView further author information

Amir Syahir Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, MalaysiaCorrespondenceamirsyahir@upm.edu.my
View further author information

Syahida Ahmad Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, MalaysiaView further author information

Review Article

CD133: beyond a cancer stem cell biomarker

Abstract
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Abstract

CD133 (prominin-1), a pentaspan membrane glycoprotein, is one of the most well-characterized biomarkers used for the isolation of cancer stem cells (CSCs). The presence of CSCs is one of the main causes of tumour reversal and resilience. Accumulating evidence has shown that CD133 might be responsible for CSCs tumourigenesis, metastasis and chemoresistance. It is now understood that CD133 interacts with the Wnt/β-catenin and PI3K-Akt signalling pathways. Moreover, CD133 can upregulate the expression of the FLICE-like inhibitory protein (FLIP) in CD133-positive cells, inhibiting apoptosis. In addition, CD133 can increase angiogenesis by activating the Wnt signalling pathway and increasing the expression of vascular endothelial growth factor-A (VEGF-A) and interleukin-8. Therefore, CD133 could be considered to be an ‘Achilles’ heel’ for CSCs, because by inhibiting this protein, the signalling pathways that are involved in cell proliferation will also be inhibited. By understanding the molecular biology of CD133, we can not only isolate stem cells but can also utilise it as a therapeutic strategy. In this review, we summarise new insights into the fundamental cell biology of CD133 and discuss the involvement of CD133 in metastasis, metabolism, tumourigenesis, drug-resistance, apoptosis and autophagy.

Keywords:

CD133 apoptosis autophagy Wnt PI3K-Akt nitric oxide

The rise of prominin-1/CD133

Prominin-1 was first identified in 1997 in two independent research studies examining murine neuroepithelial (NE) cells and human haematopoietic stem cells. Weigmann and his colleagues [1] showed that prominin-1 is localised in microvilli on the apical surface of various epithelial cells, such as the brain ependymal layer and the brush border membrane of kidney tubules in the adult mouse. Prominin-1 is not only located on plasma membrane protrusions such as filopodia, lamellipodia and microspikes but also contains targeting information allowing it to be targeted to these plasma membrane protrusions rather than to the planar cell surface [2,3]. In 2000, a study examining the presence of prominin-1 in the microvilli revealed that it is located in the cholesterol-based lipid microdomains that exist in the apical plasma membrane, and therefore may be a novel marker for these cholesterol-based lipid rafts [3,4].

The expression of prominin-1 is not confined to stem cells; it is also expressed in epithelial cells in numerous tissues including the mammary gland, testis, digestive tract, trachea and placenta. Prominin-1 can also be found in non-epithelial cells, for example, rod photoreceptor cells, as well as in many types of cancers including gastric [5], breast [5], melanoma [5], lung [5] ovarian [5], pancreatic [5], colon [5], prostate [5], glioma and hepatocellular cancers [5–7]. Since its identification over 20 years ago, various roles have been proposed for prominin-1, including that of a stem cell and a cancer stem cell (CSC) biomarker, in the organisation of plasma-membrane protrusions, maintenance of the apical-basal polarity of epithelial cells, biogenesis of the photoreceptive disc and mechanism of multi-drug resistance, and the capacity for self-renewal and tumour formation [3,4,9]. In this review, we summarise new findings concerning the biological function of prominin-1 in cancer cells.

Prominin-1/CD133 structure

Prominin-1, also known as CD133, contains five transmembrane domains with two large glycosylated extracellular loops and two smaller intracellular loops that comprise ∼250 and 20 amino acid residues, respectively [10,11]. Prominin-1 has a molecular weight of ∼115/120 kDa and comprises 850–865 amino acids [4,12]. The N-terminus of prominin-1 is exposed to the extracellular milieu, whereas the C-terminus is exposed to the cytoplasm [12]. The human gene encoding prominin-1 is located on chromosome 4 and contains at least 37 exons.

In summary, as shown in Figure 1, prominin-1, a plasma membrane cholesterol-binding pentaspan glycoprotein (lipid microdomain), is specifically located to plasma membrane protrusions and accumulates in membrane lipid microdomains [4,13] (Figure 1).

Figure 1. Topological model of Prominin-1/CD133. (The name prominin originates from the Latin word ‘prominere’ meaning to protrude.) aa: amino acid.

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Prominin-1/CD133 and neuroepithelial cell differentiation

The development of the mammalian central nervous system (CNS), neurons, astrocytes and oligodendrocytes arise from a pool of NE cells, which are neural progenitor cells. Although NE cells are found in association with the basal lamina membrane, other NE cells undergo mitosis at the apical (ventricular) membrane [14,15]. In the early stages of growth before neurogenesis, NE cells are mainly found in the neural plate and neural tubes, and proliferate to produce more NE cells. At this stage, the proliferative divisions are completely symmetric, meaning that one NE mother cell gives rise to two equal NE daughter cells. However, when neurogenesis begins, proliferative cell division switches to differentiating cell division, which is thought to be asymmetric [4,16,17]. This change in cell division type is accompanied by two events (1) changes in the distribution of membrane components, such as proteins and junctional complexes, and (2) the release of membrane particles that contain prominin-1/CD133 [3,4,18].

During the transition from the neural plate to the neural tube, the following events occur (1) tight junctions lose their function and the expression of occludin is downregulated [18], (2) in parallel, the expression of ZO-1 and N-cadherin is upregulated [19], (3) there is a decrease in the length of the primary cilium and a redundancy in the apical microvilli (notable features of the apical plasma membrane of NE cells are broad vicinity about distending subdomains, for example, the microvilli, the primary cilium and the midbody [19], (4) there is a downregulation of Wnt and sonic hedgehog (shh) signalling [19], (5) there is a decrease in the size of the NE apical membrane, (6) the expression of CD133 is maintained in the microvillar membrane (this retention is due to the presence of a new cholesterol-based membrane microdomain in which CD133 interacts directly with plasma membrane cholesterol) [4,20], (7) release of membrane particles containing CD133 (this appears to help cell differentiation by diminishing or modifying those creations from stem). Furthermore, progenitor cell-characteristic microdomains inside the apical plasma membrane [3,4,21].

The primary cells (neurons, oligodendrocytes and astrocytes) that make up the brain come from neural stem cells (NSCs) [22]. These cells are present in both embryonic and adult cells and transform from NE cells to radial glial cells and astrocyte cells [22–24]. NSCs make up various cell types under different signalling pathways. One of the most substantial signalling pathways in the development of the CNS is Wnt/β-catenin [26]. The differentiation and proliferation of brain cells affected by the interaction between Wnt pathway proteins with other related components (adenomateous polyposis coli (APC), glycogen synthase kinase-3β (GSK-3β), axin and conductin in this signalling pathway [27,28]. The activation of the Wnt signalling pathway leads to the inhibition of the GSK-3β pathway [29]. By inhibiting this pathway, the amount of β-catenin increases in the cytoplasm.

The β-catenin molecule then enters the nucleus and forms a complex with T-cell factors (TCFs) and lymphocyte enhance factors (LEFs) [30]. β-Catenin–TCF–LEF complex increases expression of basic helix–loop–helix (bHLH) proteins family, neurogenin 1 (Ngn 1) and Ngn 2, by activating the promoter of Ngn 1 and Ngn 2, and ultimately increase neurogenesis [31–34]. When the Wnt signalling pathway is not active, β-catenin is phosphorylated by the axin–APC–GSK3β–conductin complex and degrades by the ubiquitin-proteasome system [32,34]. It is therefore suggested that CD133 activates the Wnt signalling pathway to promote growth and differentiation of nerve cells (Figure 2).

Figure 2. The involvement of Wnt/β-catenin signalling pathway in neurogenesis.

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Prominin-1/CD133 in normal and cancer cells

The precise physiological function of CD133 is not clear, but its ubiquitous presence indicates its importance. As discussed above, it is found in plasma membrane protrusions that contain cholesterol-rich membrane microdomains, and these protrusions are associated with the presence of prominosomes. Prominosomes are extracellular vesicles that are attached to the plasma membrane that contains prominin proteins and are often thought of as being organisers of the plasma membrane [4,35]. One of the most common uses for CD133 is in the identification and isolation of stem cells from body tissues, not only in normal cells such as brain [36], kidney [37], prostate [18], bone marrow [19], liver [6,20], sarcoma [20], pancreas [20] and skin [20] but also in cancer cells from brain [21], liver [11,20], pancreas [20], lung [20], skin [20], sarcoma [20], prostate [20,38], colon [36] and ovary [36]. In other words, CD133 is a biomarker that can be used to identify stem cells in both normal and cancerous tissues.

The presence of CD133 is not only confined to NE progenitors, but it is also found in both epithelial and non-epithelial cell types. During the growth stages from the embryo stage to maturity, this protein is expressed in different parts of the body [37]. For example, at the embryonic stage, CD133 is expressed in trophoblasts [39], and is subsequently found in the epithelia of all three germinal layers [40]. In adults, CD133 can be found in the kidney [41], the epididymis [41,42], the ductus deferens [41], the seminal vesicle and the prostate [41]. On the basis of a study by Fargeas et al. [42] from 2004, CD133 was found to be expressed in the testis, and furthermore it was shown to have a role in the formation of epididymal stereocilia and the tail of the spermatozoa, and so therefore has a pivotal role in the biogenesis of spermatozoa. Studies have also demonstrated the presence of prominosomes in external body fluids such as saliva, urine, seminal fluid and lacrimal fluid [41]. The physiological role of these particles is not fully understood, but these small particles seem to be involved in interconnecting cells by transporting signalling molecules [3,19,21,35]. In epithelial cells, CD133 is found to be expressed only in the apical membrane domain [21,35,43].

CD133 is also found in non-epithelial cells, such as rod photoreceptor cells and bone marrow cells [9,35]. In this regard, it appears that CD133 plays a role in the formation of photoreceptor discs. Photoreceptors are specialised cells that are located in the retina and are involved in the process of visual phototransduction. These cells are divided into either cones or rods and are generally made up of the following parts: synaptic area, cell body, inner segment, transition zone and outer segment [39]. The discs are made from the base of the outer segment of these cells (membrane evaginations are located in the transition zone area and nascent discs are created from this region and from the connecting cilium) [39]. The precise mechanism of action of CD133 in disc morphogenesis is not clear but it appears to be involved in disc synthesis due to the presence of sufficient amounts of proteins and lipids, particularly, cholesterol [39]. Dystrophy of photoreceptors cells is one of the most common causes of blindness in the world and Stargardt (STGD) disease (macular degeneration) is caused by mutation of the CD133 gene, proving the important role of this protein in photoreceptors [44] (Figure 3).

Figure 3. The role of CD133 in disc morphogenesis in the photoreceptor.

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Grosse-Gehling et al. have shown that CD133 can regulate the expression of the angiogenic protein vascular endothelial growth factor (VEGF), thus indicating a role for CD133 in neovascularization and angiogenesis [45]. Mechanistically, CD133 activates the Wnt signalling pathway, which led to an increase in the expression of VEGF-A and interleukin-8 (IL-8) [46]. In response to an increase in these two factors, there is an increase in angiogenesis, and as a result, wound healing is accelerated [47,48].

It is suggested that CD133 activates the Wnt/β-catenin signalling pathway [49–51]. Following the activation of this pathway, the tumour cells grow as a result of CSC stemness. There is positive feedback mechanism between a stem and mature cells. As the stem cells grow, the adult cells also grow [52]. As the cells produce, food and oxygen are reduced. Cancer cells begin to compensate this deficiency by angiogenesis. However, tumour vessels due to abnormal formation of basement membranes are permeable. As the growth of tumour cells is very fast, pericyte cells do not entirely cover the vascular surface, and therefore the vessels become leaky, and loss of oxygen causes hypoxia [52–55]. The hypoxia increases the production of reactive oxygen species (ROS), and consequently, activates the nuclear factor-kappa beta (NF-kβ), and eventually activates epithelial–mesenchymal transition (EMT) [57,58].

Hypoxia also causes an increase of hypoxia-inducible 1-α (HIF-1α) in cancerous cells and subsequently by stimulation of glycolysis, increases the Warburg effect. According to this phenomenon, the amount of energy generated per glucose from the glycolysis is higher than the oxidative metabolism pathway because of high glycolytic rates in cancer cells, which provides growth advantages to the cells [59,60]. Moreover, hypoxia increases the production of nitric oxide (NO) with effect on endothelial cells, and NO activates Wnt/β-catenin signalling pathway [61,62]. In addition, hypoxia increases VEGF-A and consequently angiogenesis [63]. With rising of angiogenesis, tumour cells also grow, and hypoxia continues. Thus, we can consider this positive feedback as a ‘vicious cycle’ and the gain, proportional value that indicates the association between the extent of the input to the magnitude of an output signal at steady state ( $G a i n = \frac{C o r r e c t i o n}{E r r o r})$ [64] of this system (cancerous cells) is not high (Figure 4).

Figure 4. A proposed model of the ‘triangle of cancer’ (hypoxia-HIF-1α-angiogenesis), and the interplay of CD133 or prominin-1 and Wnt/β-catenin signalling pathway in glioblastoma CSCs. The expression of CD133 in the glioblastoma CSCs membrane is high. CD133 has fundamental properties for cancer cells, such as tumourigenesis and differentiation. Studies showed that CD133 physically interacts with HDAC6 that encourages cell motility and cancer cell metastasis (top box on the left). CD133 through recruitment of HDAC6 contribute to deacetylate β-catenin that gives rise to positive regulation of Wnt/β-catenin signalling and stabilisation. Accumulated β-catenin enters the nucleus of the cell and connects to TCF. By inhibiting the formation of the HDAC6-β-catenin-tubulin complex, HDAC6 does not bind CD133. In this condition, acetylated tubulin will be boosted, and thus the destabilisation of β-catenin. Therefore, the Wnt/β-catenin stimulatory effect is removed on the CSCs stemness and prevented from cell proliferation. As results of this strategy, angiogenesis decreases and available oxygen is increased. By reducing the level of hypoxia, ROS, NO, HIF-1α and VEGF-A will diminish, which lessen the stimulation of CSCs and angiogenesis, respectively.

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Prominin-1/CD133 interaction with the Wnt/β-catenin and PI3K-Akt signaling pathways

Wnt/β-catenin

The canonical form of Wnt pathway referred to as the Wnt/β-catenin pathway, plays a pivotal role in morphogenesis, embryogenesis and proliferation, and is principally involved in vertebrate and invertebrate development. In addition, this pathway also plays a role in maintaining and protecting neural connections. The canonical Wnt pathway is also known to play a role in tumourigenesis [28]. Recent studies have shown a role for the Wnt/β-catenin pathway in the development of glioblastomas [28,65]. However, the physiological role of this pathway is not completely understood. The Wnt/β-catenin pathway comprise a variety of different proteins including, the Frizzled receptor (FZD), axin, GSK3β, adenomatous polyposis coli (APC), dishevelled and TCF/LEF. Numerous studies have shown that a dysregulation or a mutation in each of these components results in the formation of cancerous cells [28,66]. In 2012, Mak and colleagues reported a physical interaction between CD133 and histone deacetylase 6 (HDAC6) [67]. CD133, by recruiting HDAC6, contributes to the deacetylation of β-catenin leading to activation of Wnt/β-catenin signalling and the stabilisation of β-catenin. β-Catenin can then enter the nucleus where it interacts with TCF. Thus, CD133 can accelerate cancer cell growth by activating the Wnt/β-catenin pathway [68,69] (Figure 4).

PI3K-Akt

Phosphatidylinositol 3-kinases (PI3Ks), a family of threonine kinases, are involved in the activation of kinases involved in signal transduction and therefore have effects on cell growth, proliferation, and survival. Most PI3Ks contain a p110 catalytic subunit and a p85 regulatory subunit. The p85 subunit contains two SH2 domains, which can bind directly to phosphotyrosine, which then leads to activation of the p110 subunit [70]. In CD133-positive cancer cells, Src kinase phosphorylates tyrosine-828 in the C-terminal cytoplasmic domain of CD133. Following this, the phosphotyrosine-828 residue interacts with p85 leading to the activation of the p110 catalytic subunit of PI3K. Activated PI3K converts PIP2 (phosphatidylinositol 4,5-bisphosphate) into PIP3 (phosphatidylinositol 3,4,5-trisphosphate). PIP3 then leads to the phosphorylation and activation of Akt (also known as protein kinase B) [70,71]. The level of phosphorylated-Akt in CD133-positive cancer cells is higher than in CD133 negative cancer cells, especially in glioma stem cells [70,71]. Therefore, based on the findings of Wei and his colleagues [71], we can consider CD133 to be an activator of the PI3K-Akt pathway (Figure 5).

Figure 5. Scheme illustrating the role of phosphorylation of the C terminus of CD133 in activation of the PI3K-Akt pathway.

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Prominin-1/CD133 as a marker of bioenergetics in cancer cells hypoxia

One noteworthy feature of cancer cells is the presence of mitochondrial dysfunction and hypoxia. Mitochondria are referred to as the ‘powerhouses’ of the cell because they are responsible for generating the vast majority of cellular ATP. Mitochondria also play a role in the metabolism of lipids, carbohydrates, amino acids and in apoptosis (also referred to as programmed cell death) [72]. As cancer cells spread they require energy to grow. In order to obtain energy, cancer cells significantly upregulate angiogenesis. This large increase in angiogenesis results in the formation of vessels with incompletely formed endothelial linings. This defect in vessel structure leads to leakage of the tumour vessels surrounding the tumours, and thus exacerbates tumour hypoxia [73–76]. Under these conditions, cancer cells cannot produce sufficient energy (ATP) through mitochondrial oxidative phosphorylation (OXPhos), and therefore use anaerobic metabolism (glycolysis) as an alternative route [73,77,78]. Griguer et al. have shown that both a hypoxic microenvironment and mitochondrial dysfunction upregulate the expression of CD133 in glioblastoma cells and pancreatic cancer cells [74,79,80]. In addition, hypoxia results in increased expression of hypoxia inducible factor 1α (HIF-1α). HIFα then dimerises with HIFβ and the HIFα-HIFβ dimer interacts with hypoxia regulatory elements (HREs) and activates p300, which enhance the expression of transcription factors involved in growth and angiogenesis [73,81,82].

Previous studies have shown that under conditions of lack of oxygen or hypoxia, the expression of CD133 increases dramatically (hypoxia-induced CD133) [83]. However, in this review article, we looked at the indirect role of CD133 on hypoxia (CD133-induced hypoxia). In other words, we have shown the reciprocal influence of CD133 and hypoxia. The blood vessels of the tumour are different from the anatomical and functional properties of the normal vessels and are divided into six categories accordingly. (1) Mother vessels (MV), (2) glomeruloid microvascular proliferation (GMP), (3) vascular malformations (VM), (4) feeder arteries (FA), (5) draining veins (DV) and (6) capillaries. All of these vessels have several features in common, such as large size, hyperpermeable and pericyte-poor sinusoids [84]. Although they are large in number and size, their blood flow is low. The cause of this phenomenon can be explained by the physical principles of pressure and blood flow. There are two kinds of blood flow in the vessels (Laminar and Turbulent or eddy flow). In normal blood vessels, the blood flow is laminar, and in the tumour, vessels are probably turbulent [85].

When the blood flow rate is too high, or it passes over a rough surface, the flow may become turbulent (tumour vessels). The tendency for turbulent current has a direct proportion to the velocity of the blood flow (V), the diameter of the blood vessels (d), density (ρ) and it was inversely proportional to the viscosity of the blood (η). By Reynolds number (Re=(V×d×ρ)/(η)) [85,86], by increasing the diameter of tumour vessels, the tendency for turbulent flow increases and blood remains longer in the vessels, but as the tumour vessels are leaky, blood goes through intercellular space and hypoxia is intensified. This loss of oxygen causes defective angiogenesis in the tumour, and its cells grow.

In this article, we present a new model (CD133-induced hypoxia) for the growth of CSCs, significantly glioblastoma multiform. According to this model, the expression of CD133 in CSCs is initially increased. This protein then activates the Wnt/β-catenin pathway and increases in tumour cells. Because of the increase in cells and oxygen consumption, hypoxia develops. Hypoxia through the production of growth factors (VEGF) and especially VEGF-A, causes angiogenesis in the tumour vessels. Therefore, new vessels are formed with a larger diameter (Re number rises). However, because of the turbulent flow and the inherent leakage of these vessels, by increasing the angiogenesis, the amount of hypoxia increases, and this cycle, which has been triggered by the activation of the CD133, has expanded with hypoxia and angiogenesis in the CSCs (Figure 6).

Figure 6. Physiopathological hypothesis concerning the relationship between hypoxia, ROS, NO and CSCs. PI3Ks: phosphatidylinositol 3-kinases; ROS: reactive oxygen species; mTOR: mechanistic target of rapamycin; HIF-1α: hypoxia-inducible factor 1α; iNOS: inducible NOS; VEGF: vascular endothelial growth factor; SDF-1: stromal cell-derived factor 1; Ang-2: angiopoietin-2; MMPs: matrix metalloproteinase; CSCs: cancer stem cells; eNOS: endothelial NOS; SGc: soluble guanylyl cyclase; cGMP: cyclic guanosine monophosphate; cGK-1: cGMP-dependent protein kinase 1.

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Reactive oxygen species

O²^– (superoxide), H₂O₂ (hydrogen peroxide) and HO^. (hydroxyl free radical) are different types of ROS. ROS are essential at both low and medium levels for various cellular functions such as proliferation, differentiation and survival [87,88]. Under physiological conditions in mammalian cells, ROS levels are maintained at a low level because of their high chemical reactivity. Maintaining this intracellular balance is achieved by the action of scavenger antioxidative enzyme systems [87]. Elevation of ROS levels under physiological conditions helps remove potentially pathogenic molecules from the cell, but an excessive amount of ROS production can lead to cell death. The amount of ROS in cancer cells is well known to be higher than in normal cells. This relative increase in ROS levels in cancer cells and CSCs can cause death as a result of DNA damage. In contrast, ROS levels are low in CSCs [89]. Recent studies in CD133⁺ glioblastoma and prostate CSCs have shown that activity of the antioxidant scavenger system in CSCs is higher than in non-CSCs, which keeps ROS levels in CSCs low [90]. In response to hypoxia, the production of ROS is elevated leading to increased levels of HIF-1α. HIF-1α helps increase the growth of cancer cells by increasing the expression of VEGF [91] (Figure 6).

Nitric oxide: from a messenger molecule to complicated physiological processes

NO and NO metabolites play crucial roles in cellular processes such as proliferation, apoptosis, necrosis, angiogenesis and DNA damage [80,92]. NO has a wide variety of roles, from being a small signalling molecule to being involved in angiogenesis in the tumour. In addition, it plays a variety of other roles such as in the cardiovascular system, development of the nervous system, vascular permeability, smooth muscle relaxation, cytostatic or cytolysis, promotion of an inhibitory effect on tumourigenesis, regulation of blood flow and sensitisation of tumour cells to radiation [92,93]. NO is a highly reactive free radical that is synthesised from l-arginine, NADPH and oxygen by NO synthase (NOS). NOS has three isoforms: endothelial NOS (eNOS or NOS3), inducible NOS (iNOS or NOS2) and neuronal NOS (nNOS or NOS1). Evidence has shown that NO, predominantly synthesised by eNOS, through recruiting perivascular cells, plays a vital role in the maturation and remodelling of blood vessels [93] (Figure 6).

Nitric oxide in tumor progression or regression

The role of NO in cancer cells is totally dependent on its concentration. At low concentrations, it has pro-tumour effects (increases in proliferation, angiogenesis, metastasis and decreased apoptosis), whereas at high concentrations, NO has anti-tumour effects (increased DNA damage, nitrosative stress and apoptosis) [94,95]. Numerous studies have shown that eNOS, iNOS and nNOS are expressed in cancer cells and that they all play a role in the aetiology of cancer. One of the key steps that occurs in the development of cancer cells is neoplastic transformation [96]. This is thought to occur through the action of NO produced by iNOS. The increased levels of NO lead to DNA damage and to an increase in p53 that result in the death of the transformed cells. Alternatively, at low levels of NO, DNA-dependent protein kinase (DNA-PK) upregulates NO production, resulting in the integration of genome. Therefore, low concentrations of NO retain blood vessel integrity, whereas high concentrations of NO might increase vascular permeability through VEGF mediated by eNOS [96]. Studies have also shown that under hypoxic condition, iNOS is induced through HIF-1α [97]. Furthermore, Gilbertson et al. have shown that CD133+ CSCs in glioblastoma secrete VEGF [98]. Endothelial cells can act in the reverse direction, emitting NO that activates Notch signalling with the glioblastoma score indicating clinched alongside glioma. Eyler et al. have shown that production of NO in glioblastoma arises as a result of the action of NO synthase-2 (Figure 6).

Prominin-1/CD133 as an inhibitor in cancer cells

Apoptosis

Apoptosis, or type 1 programmed cell death, is an irreversible process that can be initiated by either the intrinsic or extrinsic pathway. In general, the processes that occur during cellular apoptosis are cell wrinkling, chromosome thickening, nucleation and DNA fragmentation, the formation of apoptotic bodies and phagocytosis. In apoptosis, proteolytic enzymes (caspases) form small vesicles in the membrane (apoptotic bodies). As a result, phosphatidylserine is transferred from the inner leaflet to the outer leaflet of the cell membrane and this event acts as a signal to allow the cell to be detected by phagocytic macrophages [99].

Intrinsic pathway of apoptosis (mitochondrial cell death)

The intrinsic pathway of apoptosis is also referred to as mitochondrial cell death. In this process, mitochondrial damage leads to an increase in the activity of caspases. This, in turn, leads to increased mitochondrial calcium levels in the mitochondrial matrix. As a result, a large hole is formed in the mitochondrion, which is referred to as the mitochondrial permeability transition pore (MPTP). This hole allows the release of cytochrome C into the cytoplasm that initiates the formation of the apoptosome (cytochrome C + apoptotic protease-activating factor (APAF-1)), which in the presence of ATP leads to the sequential activation of caspase 9 and caspase 3 resulting in apoptosis [100].

Extrinsic pathway of apoptosis (death signal pathway)

In this pathway, a death receptor located on the plasma membrane is activated by a death-inducing ligand. Following death ligand-induced trimerisation of the death receptor, a death signal is transmitted into the cell. The trimeric receptor complex interacts with Fas-associated death domain (FADD), which recruits Fas, an adapter for recruiting and activating caspase 8. Active caspase 8 then activates caspases 3 and 7 [101].

Apoptosis and CD133

CD133-positive cells, by upregulating the expression of the FLICE-like inhibitory protein (FLIP), inhibit TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Furthermore, resistance to staurosporine (a natural product with anti-cancer activity that inhibits protein kinase by preventing ATP binding)-induced apoptosis in CD133 positive cells is much higher than in CD133-negative cells [102]. The p53 protein plays a key role in stress-induced apoptosis, where it can trigger apoptosis in cancer cells and prevent their growth. The expression of p53 has an inverse relationship with CD133 expression [102,103]. In 2015, Park et al. reported that under conditions of stress, p53 suppresses the activity of the CD133 promotor by binding to the p53-binding site in the promoter.

Autophagy and CD133

Autophagy (or autophagocytosis) is the natural, regulated, homoeostatic mechanism by which the cell can degrade cellular components. These components are first encased in a membrane (the autophagosome), which is then fused with the lysosome to allow the targeted components to be degraded by the lysosomal enzymes. In this way, damaged cellular components are recycled to be used for the production of energy and/or the synthesis of new cellular components [104]. Although it may seem like autophagy is a destructive process, it is a natural mechanism used for cell defence. When insufficient nutrients are available to the cell (starvation) or if the cell needs to destroy foreign agents such as bacteria and viruses, autophagy is necessary to eliminate cellular waste and reduce cell consumption [104,105]. Through this process, the cell destroys the waste materials that it produces, as well as aged of damaged components, and uses the raw materials produced to synthesise new components and materials [104,106].

Some studies have shown that the strong tumourigenicity of CD133-positive cells is related to the initiation of autophagy by CD133. In addition, it has also been shown that under conditions of glucose deprivation, CD133 increases the uptake of glucose and promotes the formation of the autophagosome [107,108]. Li et al. have speculated that CD133-mediated autophagy occurs as a result of phagophore formation. CD133 by initiating autophagy and interfering with energy metabolism is beneficial for the survival of CSCs. In 2013, Galavotti et al. reported that high levels of damage-regulated autophagy modulator-1 (DRAM-1) are associated with shorter survival in glioblastoma patients. In glioblastoma CSCs, the expression of DRAM-1 is accompanied by the expression of c-MET (tyrosine-protein kinase Met) and activation of MAPKs (mitogen-activated kinases). DRAM1 by localising p62 to the autophagosome can mediate autophagy and regulates the invasion of glioblastoma CSCs [109,110].

Treatment-resistance and prominin-1/CD133

In general terms, apoptosis and autophagy have reciprocal inhibitory effects on each other. Studies have indicated that chemotherapy and irradiation of CD133-positive cells can promote autophagy in CSCs and prevent apoptosis [111–113]. In CD133-positive cells, the expression of ABCG5 (an ATP-binding cassette transporter) is high [114]. In addition, the expression of FLIP, a caspase-8 inhibitor, is higher in CD133-positive cells than it is in CD133 negative cells. As a result resistance to both chemotherapy and apoptosis is observed in these cells [114–117] . In CSCs, the expression and activation of CD133 are high [118]. CD133 activates the PI3K pathway, and as a result, Akt is also enabled. Activation of Akt leads to increases in the activity of anti-apoptosis factors (BCL-2, BCL-XL, MCL-1) and decreases in the operation of pro-apoptosis factors (Bid, Bax, Bim) [71]. Thus, apoptosis is prevented, and cell proliferation can occur. Moreover, CD133 upregulates the expression of the FLIP protein. This protein inhibits autophagy and activates the ERK, JNK, ERK and Wnt pathways.

In contrast, FLIP inhibits FADD, and as a result, active caspase 8 is not produced [115]. Caspases are inactive cysteine proteins in the cytoplasm that turn into an active form by losing their aspartate. They are divided into two groups of initiating caspases (2, 8, 9, 10) and functional caspases (3, 6, 7). Functional caspases are proteolytic that have cytosolic and nuclear targets [119]. Including their cytosolic targets gelsolin, which, if cleavage by caspases, causes the breakdown of actin filaments and ultimately cell destruction. Their nuclear targets are inhibitor of caspase-activated DNase (ICAD), which connects typically to caspase-activated DNase (CAD) and disables it. Functional caspases with the release of CAD into the nucleus, destroy DNA [120]. Besides, caspase 8 converts Bid to truncated Bid (tBid) and then, proteins tBid, p53, Noxa, Puma and Bax together form the pore-forming proteins complex in the mitochondrial outer membrane. With the release of cytochrome C and apoptosome formation, activated-caspase 9 is produced and pro-caspase 3, 6, 7 converted to activated-caspase 3, 6, 7 [121]. When caspase 8 is not created, this disrupts the intrinsic apoptosis pathway. The result of these events is an increase in cancer cell invasion. Park et al. studies showed that we could consider the interaction of CD133-p53 as a new strategy to target CSCs. Their results demonstrated that P53 is one of the leading obstacles in the formation of CSCs and suppressing of CD133 by p53 leads to a reduction in the expression of stemness genes (SOX2, c-MYC, NANOG and OCT4) [103,122]. (Figure 7)

Figure 7. Potential mechanism of CD133 in cancer stem cells. TRAIL: TNF-related apoptosis-inducing ligand; FADD: Fas-associated protein with death domain; PI3Ks: phosphatidylinositol 3-kinases; Akt (protein kinase B), ERK pathway: extracellular-signal-regulated kinase; JNK pathway: c-Jun N-terminal kinase; Wnt pathway: Wingless.

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Targeting cancer stem cells by prominin-1/CD133

Since the identification of CSCs in 1998 and up to the present day, these cells have been of special interest due to their ability to self-renew and to initiate tumour growth. Within the last two decades, studies have shown that CSCs exist in many solid tumours [123]. One of the most well-known stem cell biomarkers is CD133. CD133 has been identified in numerous CSCs derived from tumours in several tissues including the liver, lung, prostate, colon, pancreas and glioblastomas. Although the physiological roles of this protein are not entirely understood, its role in the spread of the tumour has been reported [123]. In addition, because of the association of CD133 with the Wnt and Notch signalling pathways, it can cause cell proliferation. In addition, CD133 inhibits apoptosis and upregulates FLIP leading to chemo-resistance [124]. Considering the multifaceted roles of CD133, it appears to be a good candidate for targeting cancer cells [125,126]. As discussed above, we speculate that a CD133-targeted therapy might be an efficient strategy to ablate tumours.

Conclusion and future perspectives

Today, chemotherapy drugs alone are considered to be ineffective in destroying cancer cells, and this inability is associated with several factors such as non-specific drug effects and the presence of CSCs. Studies have shown not only the role of these CSCs in the growth and recovery of tumours but also their role in resistance to chemotherapeutic drugs and radiation therapy. Therefore, the detection and targeting of CSCs could be considered as a therapeutic strategy in the future. However, the CSC-targeting therapy field is relatively new. Although much progress has been made in the field of CSCs, most studies have been performed in vitro and have not yet reached the clinical stage. The first step in the development of a therapy aimed at CSCs is to identify and isolate them and, secondly, to target them. CD133 or prominin-1 appears to be a good candidate for targeting, due to its high expression in CSCs and its important biological roles. The effects of CD133 and its expression could be modulated by numerous therapeutic methods including targeting the surface marker, targeting the tumour microenvironment, targeting the ABC cassette transporter and nanocarrier-mediated delivery of a targeting agent.

Acknowledgements

The authors acknowledge Ms. Fatemeh Tarshizi Moghaddam for her help in the graphic illustrations. Furthermore, they would like to thank Editage (www.editage.com) for English language editing. All illustrations were generated using CorelDRAW graphics suite X7.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors would like to express sincere gratitude to Universiti Putra Malaysia for the research grant UPM/700–2/1/GBP/2017/9551200.

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Journal of Drug Targeting

CD133: beyond a cancer stem cell biomarker

Review Article

CD133: beyond a cancer stem cell biomarker

AbstractFormulae display:?Mathematical formulae have been encoded as MathML and are displayed in this HTML version using MathJax in order to improve their display. Uncheck the box to turn MathJax off. This feature requires Javascript. Click on a formula to zoom.

The rise of prominin-1/CD133

Prominin-1/CD133 structure

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Prominin-1/CD133 and neuroepithelial cell differentiation

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Prominin-1/CD133 in normal and cancer cells

Published online:

Published online:

Prominin-1/CD133 interaction with the Wnt/β-catenin and PI3K-Akt signaling pathways

Wnt/β-catenin

PI3K-Akt

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Prominin-1/CD133 as a marker of bioenergetics in cancer cells hypoxia

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Reactive oxygen species

Nitric oxide: from a messenger molecule to complicated physiological processes

Nitric oxide in tumor progression or regression

Prominin-1/CD133 as an inhibitor in cancer cells

Apoptosis

Intrinsic pathway of apoptosis (mitochondrial cell death)

Extrinsic pathway of apoptosis (death signal pathway)

Apoptosis and CD133

Autophagy and CD133

Treatment-resistance and prominin-1/CD133

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Targeting cancer stem cells by prominin-1/CD133

Conclusion and future perspectives

Acknowledgements

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Funding

References

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Abstract
Formulae display:?Mathematical formulae have been encoded as MathML and are displayed in this HTML version using MathJax in order to improve their display. Uncheck the box to turn MathJax off. This feature requires Javascript. Click on a formula to zoom.