TY - JOUR
AU - Lorico, Aurelio
AB - Cancer stem cells, CD133, Lipid droplets, Wnt pathway We read with great interest a recent publication entitled “Lipid Droplets: A New Player in Colorectal Cancer Stem Cells Unveiled by Spectroscopic Imaging” by Tirinato et al. released in Stem Cells (2014), which highlights by means of Raman microspectroscopy high levels of lipid droplets in colorectal-cancer stem cells (CR-CSCs) by comparison to the differentiated tumor cells and normal colon epithelial cells [1]. The authors propose that a cellular organelle (i.e., lipid droplets) might be considered, in addition to single molecular markers, as a new signature of CSCs. The relation between excess lipids as measured by label-free coherent anti-Stokes Raman scattering (CARS) and aggressive tumor behaviors is not restricted to colon cancers and earlier studies support the present hypothesis [2-4]. Indeed, intracellular lipid droplets as detected by CARS could serve as a biomarker for prostate circulating tumor cells [3, 4]. Along the same line, an aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases was recently reported [5]. Here, Tirinato et al. [1] also pointed out as “a remarkable correlation” the observation that the lipid droplet content in CR-CSCs (as measured by flow cytometry using hydrophobic dyes) is elevated in cells with higher expression of CD133 (prominin-1) and Wnt/β-catenin pathway activity. Unfortunately, it is not further substantiated and no link between CD133, Wnt/β-catenin signaling pathway, and lipid droplets is provided. It is now well accepted that CD133/1 and CD133/2 epitopes may be undetected despite the presence of CD133 protein or its mRNA, and that CD133 protein may be expressed beyond stem and CSCs [6, 7]. It would have been interesting to document the respective profiles of the cancer cell lines (HCT116 and RKO) used in this study as colon cancer cells (CCC) and how they correlate with their Wnt/β-catenin activity levels. Yet the observations made by Tirinato et al. [1] in colorectal cancers are in line with part of those reported earlier by our groups in melanoma. We have indeed demonstrated a link between CD133 and Wnt/β-catenin pathway and their incidence on the amount of lipid droplets in human melanoma cells as well as their impact on their metastatic capacity [8, 9]. We propose to develop here potential scenarios (Fig. 1), which are not mutually exclusive, and may help the readers of Stem Cells to further dissect the current observation. Open in new tabDownload slide Cell biology of CD133 and potential crosstalk of molecular pathways that could link its expression to the relative amount of lipid droplets. (A, B): Distinct molecular mechanisms regulate the expression of CD133 at the PM. Therein, CD133 is concentrated in membrane protrusions such as microvilli and its specific retention involves a cholesterol-based membrane microdomain (lipid raft, red). The surface expression of CD133 protein can be modulated by two distinct mechanisms that are not mutually exclusive. First, CD133 can be internalized and transported to the early endosomal compartment (A) and afterward delivered to late endosomal multivesicular bodies, which either fuse with the plasma membrane, and hence, release internal vesicles (exosomes), or lead to the proteolytic degradation of CD133 by heterotypic fusion with lysosomes (not depicted) [10]. Second, CD133 can be released into the extracellular compartment (e.g., urine, saliva, cerebrospinal, and seminal fluids) by budding of small membrane vesicles (microvesicles or ectosomes) from membrane protrusions (B) [11, 12]. Binding of specific antibodies to CD133 (potentially mimicking unidentified ligands) can also promote its internalization and retrograde transport to the Golgi complex (not depicted) [9]. Biochemically, the release of CD133-containing membrane vesicles might involve a specific membrane microdomain [13, 14]. In all scenarios, the intracellular and extracellular trafficking of CD133 as a cholesterol-binding protein may modulate the lipid composition and organization of the plasma membrane, which in turn may influence intracellular accumulation of lipid contents. (C–F): Signaling pathways that could be influenced by CD133 and vice versa. The Src-mediated phosphorylation of CD133 could promote its interaction with the PI3K 85 kDa regulatory subunit resulting in the activation of PI3K/Akt pathway that would stimulate self-renewal and tumorigenicity of cancer stem cells. The activation of PI3K would lead to the conversion of PIP2 into PIP3, and Akt (green) would bind to PIP3 through its Pleckstrin Homology domain prior to its activation (C). Then, the nuclear localization of β-catenin could be modulated via Akt/GSK-3β cascade or its direct phosphorylation (P) by activated Akt [15, 16]. Thus, CD133 could indirectly be a facilitator of the canonical Wnt/β-catenin pathway (E, for more details about this pathway see [17]). Interestingly, cytoplasmic activated Akt (pink) can potentially regulate the lipid droplets by increasing the expression level of the lipid-storage protein LSD2/perilipin [18]. The latter protein may also play a role in the transport of lipid droplets along microtubules leading to their local accumulation in a polarized fashion [19]. The lipid droplets are reservoirs of COX-2 and sites of PGE2 synthesis in colon cancer cells. The overexpression of COX-2, and hence the production of PGE2, which can activate EP2 receptors that are coupled to heterotrimeric G proteins of the Gs family, could also modulate the PI3K/Akt and Wnt/β-catenin signaling pathways (D). For instance, upon GDP/GTP exchange, the α subunit of Gs could bind through axin to the β-catenin destruction complex (axin, CK1, APC, and GSK-3β), thereby promoting the release of GSK-3β and its subsequent phosphorylation by Akt, and hence, its inactivation. At the same time, free βγ subunits would stimulate the PI3K/Akt signaling route, which causes the phosphorylation of GSK-3β. Interaction of CD133 with HDAC6 also results in β-catenin stabilization leading to the activation of signaling targets. Conversely, reduced availability of CD133 would facilitate acetylation of β-catenin and its degradation, resulting in decreased cell proliferation. A possible interchange of β-catenin between the CD133-HDAC6 complex and E-cadherin during the loss of cellular polarity was proposed (F). (G): TCF-LEF-binding sites are present in the PROM1 and COX-2 gene promoters, but direct transcriptional activation of CD133 by Wnt/β catenin remains to be demonstrated. Part of these pathways is controversial or putative and therefore depicted with dashed lines. Their connection with CD133 requires further experimental demonstration. Abbreviations: APC, adenomatosis polyposis coli; CK1, casein kinase 1α; COX-2, cyclooxygenase-2; GSK-3β, glycogen synthase kinase-3β; LEF, lymphoid enhancing factor; PGE2, prostaglandin-E2; PM, plasma membrane; TCF, T-cell factor. Open in new tabDownload slide Cell biology of CD133 and potential crosstalk of molecular pathways that could link its expression to the relative amount of lipid droplets. (A, B): Distinct molecular mechanisms regulate the expression of CD133 at the PM. Therein, CD133 is concentrated in membrane protrusions such as microvilli and its specific retention involves a cholesterol-based membrane microdomain (lipid raft, red). The surface expression of CD133 protein can be modulated by two distinct mechanisms that are not mutually exclusive. First, CD133 can be internalized and transported to the early endosomal compartment (A) and afterward delivered to late endosomal multivesicular bodies, which either fuse with the plasma membrane, and hence, release internal vesicles (exosomes), or lead to the proteolytic degradation of CD133 by heterotypic fusion with lysosomes (not depicted) [10]. Second, CD133 can be released into the extracellular compartment (e.g., urine, saliva, cerebrospinal, and seminal fluids) by budding of small membrane vesicles (microvesicles or ectosomes) from membrane protrusions (B) [11, 12]. Binding of specific antibodies to CD133 (potentially mimicking unidentified ligands) can also promote its internalization and retrograde transport to the Golgi complex (not depicted) [9]. Biochemically, the release of CD133-containing membrane vesicles might involve a specific membrane microdomain [13, 14]. In all scenarios, the intracellular and extracellular trafficking of CD133 as a cholesterol-binding protein may modulate the lipid composition and organization of the plasma membrane, which in turn may influence intracellular accumulation of lipid contents. (C–F): Signaling pathways that could be influenced by CD133 and vice versa. The Src-mediated phosphorylation of CD133 could promote its interaction with the PI3K 85 kDa regulatory subunit resulting in the activation of PI3K/Akt pathway that would stimulate self-renewal and tumorigenicity of cancer stem cells. The activation of PI3K would lead to the conversion of PIP2 into PIP3, and Akt (green) would bind to PIP3 through its Pleckstrin Homology domain prior to its activation (C). Then, the nuclear localization of β-catenin could be modulated via Akt/GSK-3β cascade or its direct phosphorylation (P) by activated Akt [15, 16]. Thus, CD133 could indirectly be a facilitator of the canonical Wnt/β-catenin pathway (E, for more details about this pathway see [17]). Interestingly, cytoplasmic activated Akt (pink) can potentially regulate the lipid droplets by increasing the expression level of the lipid-storage protein LSD2/perilipin [18]. The latter protein may also play a role in the transport of lipid droplets along microtubules leading to their local accumulation in a polarized fashion [19]. The lipid droplets are reservoirs of COX-2 and sites of PGE2 synthesis in colon cancer cells. The overexpression of COX-2, and hence the production of PGE2, which can activate EP2 receptors that are coupled to heterotrimeric G proteins of the Gs family, could also modulate the PI3K/Akt and Wnt/β-catenin signaling pathways (D). For instance, upon GDP/GTP exchange, the α subunit of Gs could bind through axin to the β-catenin destruction complex (axin, CK1, APC, and GSK-3β), thereby promoting the release of GSK-3β and its subsequent phosphorylation by Akt, and hence, its inactivation. At the same time, free βγ subunits would stimulate the PI3K/Akt signaling route, which causes the phosphorylation of GSK-3β. Interaction of CD133 with HDAC6 also results in β-catenin stabilization leading to the activation of signaling targets. Conversely, reduced availability of CD133 would facilitate acetylation of β-catenin and its degradation, resulting in decreased cell proliferation. A possible interchange of β-catenin between the CD133-HDAC6 complex and E-cadherin during the loss of cellular polarity was proposed (F). (G): TCF-LEF-binding sites are present in the PROM1 and COX-2 gene promoters, but direct transcriptional activation of CD133 by Wnt/β catenin remains to be demonstrated. Part of these pathways is controversial or putative and therefore depicted with dashed lines. Their connection with CD133 requires further experimental demonstration. Abbreviations: APC, adenomatosis polyposis coli; CK1, casein kinase 1α; COX-2, cyclooxygenase-2; GSK-3β, glycogen synthase kinase-3β; LEF, lymphoid enhancing factor; PGE2, prostaglandin-E2; PM, plasma membrane; TCF, T-cell factor. In a first series of experiments published in Stem Cells (2008), we demonstrated that downregulation of CD133 using short hairpin (sh) RNAs resulted in vitro a in slower cell growth, reduced motility, and decreased capacity of melanoma cells to produce spheroids under stem cell-like growth conditions [8]. In vivo, the lack of CD133 severely reduced the capacity of the cells to metastasize. Microarray analysis of CD133-downregulated cells identified a change in expression levels for 143 annotated genes among which 10 of the 76 upregulated ones coded for established or putative Wnt inhibitors (e.g., DKK1 and DACT1) indicating a link between CD133 and the canonical Wnt pathway [8]. In a second series of experiments published in Experimental Cell Research (2013), we were able to demonstrate that the suppression of CD133 prevents the nuclear localization of β-catenin and reduces Wnt pathway signaling through T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors. Nuclear localization of β-catenin was nevertheless restored upon addition of Wnt3a to CD133-knockdown cells, indicating that the Wnt/β-catenin pathway can still be activated by physiological ligands in the absence of CD133 [9]. Moreover, and readily pertinent to the observation of Tirinato et al. [1] this effect was confirmed in the human Caco-2 colon carcinoma cell-line [9]. As TCF-LEF-binding sites are found in the PROM1 promoter [20], it could in turn be a direct target of the Wnt pathway. The relation between CD133 and the Wnt/β-catenin pathway is further strengthened by several reports. It has been proposed that the interaction of CD133 with histone deacetylase 6 (HDAC6) could favor the stabilization of β-catenin leading to the activation of signaling targets [21]. Interchange of β-catenin between CD133-HDAC6 complex and E-cadherin is not excluded (Fig. 1) [22]. Besides the connection of CD133 and Wnt/β-catenin pathway, we uncovered for the first time using CARS imaging and oil red O staining that the relative amount of lipid droplets in metastatic melanoma cells is directly correlated to the expression of CD133, and hence the Wnt/β-catenin pathway activity, as their amount decreased upon downregulation of CD133 using shRNAs [9]. As discussed by Tirinato et al. [1], the role of lipid droplets other than lipid storage starts to be unveiled, particularly their impact on inflammatory responses in cancer through the synthesis of inflammatory mediators (eicosanoids) [23]. Chronic inflammation could promote carcinogenesis at many stages. Similarly, CD133 expression, like Wnt/β-catenin pathway activity, has been linked to inflammatory processes. For instance, its expression is enhanced in cells located in intercalated ducts within inflammatory regions of salivary glands, exocrine pancreas, and prostate cancers [24-26]. Moreover, treatment of colon cancer or neuroblastoma cells with the nonsteroidal anti-inflammatory drug celecoxib or indomethacin—two cyclooxygenase-2 (COX-2) inhibitors—was shown to decrease the amount of CD133+ tumor cells [27, 28], and an increased amount of eicosanoid-forming enzyme COX-2 was detected in medulloblastoma and glioblastoma-derived CD133+ cells by comparison to negative ones [29]. Whether the dual expression of CD133/Wnt pathway and lipid droplets is causal in these contexts or merely an indicator of inflammation and carcinogenesis is still an open question. At first glance, no direct link between CD133 and lipid droplets can be drawn. CD133 is a pentaspan membrane glycoprotein selectively associated with plasma membrane protrusions (microvillus and primary cilium), while lipid droplets are cytoplasmic organelles originating from endoplasmic reticulum (Fig. 1). Whether CD133 regulates the proper lipid composition of lipid droplets through its intracellular trafficking [9, 10] as reported for the cholesterol and fatty acid-binding caveolins or, inversely, requires a certain balance of lipid droplets to support its activity remains to be determined. CD133 might act in concert with surrounding lipids and proteins as an organizer and regulator of the dynamics of plasma membrane, as illustrated by its involvement in endocytosis in Caco-2 cells [30], its release into the extracellular milieu in association with membrane vesicles derived from metastatic melanoma cells [9], or the altered photoreceptor cell architecture in CD133-null mouse line [31]. Comparative lipidome determination in a given cell type derived from CD133-null versus wild-type mice might be very informative in this context. The ligand and the physiological function of this glycoprotein are nevertheless still unknown. The direct binding of CD133 to membrane cholesterol [32], its incorporation in cholesterol-based lipid rafts, and its interaction with phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), whose activity leads to the conversion of docking phospholipids such as phosphatidylinositol(4,5)-bisphosphate (PIP2) into phosphatidylinositol(3,4,5)-triphosphate (PIP3) [33], could directly regulate the level and/or fluidity of certain lipids in the plasma membrane of cancer cells, which in turn may influence the cytoplasmic lipid content (Fig. 1A–1C) [34]. The activation of various signal transduction pathways (e.g., PI3K-activated protein kinase B [Akt]) through Src-mediated phosphorylation of CD133 or CD133+ lipid rafts may then indirectly control the general cellular metabolism and/or the content of lipid droplets (Fig. 1C–1F) [30, 33, 35]. One cannot exclude that some interplay between PI3K/Akt activation and Wnt/β-catenin pathway may occur, and specifically the Akt-mediated phosphorylation and inactivation of glycogen synthase kinase-3β, an essential component of β-catenin destruction complex [36]. Moreover, Akt could directly phosphorylate β-catenin leading to enhanced transcriptional activity and promotion of tumor development and invasiveness [15, 37, 38]. Interestingly, cytoplasmic phosphorylated Akt was proposed to regulate the accumulation of large lipid droplets via a mechanism that, in part, involves LSD2/perilipin, a protein regulator of lipid storage in drosophila nurse cells [18]. The expression of perilipins was shown to correlate with lipid droplets accumulation in different human carcinomas [39]. In addition to its implication in lipid-storage, LSD2/perilipin could also regulate the transport of lipid droplets, and consequently their subcellular localization [19]. It remains to be determined whether perilipins are involved in the polarized distribution of the lipid droplets observed in cancer cells, notably in M109 lung carcinoma cell line and melanoma cells [2, 9]. Yet irrespectively of the mechanism regulating their motion such concentration of lipid droplets could alter the membrane composition of surrounding cellular compartments (e.g., plasma membrane and endosomes) by sequestering and/or rerouting their components, or interfering with the membrane fusion machinery [40, 41], therefore indirectly influencing the membrane fluidity, which is an important characteristic during the migration and invasion of cancer cells (reviewed in [42]). It would thus be interesting to perform dual evaluation of CD133 expression (or Wnt/β-catenin pathway activity) and perilipins and/or PI3K/Akt-dependent transcriptional factors that regulated lipogenic enzymes in CSCs versus differentiated tumor cells and normal counterpart. With regard to COX-2, its bioactive product, prostaglandin-E2 (PGE2), could activate components of the canonical Wnt system [43, 44], which in turn can regulate COX-2 transcription (Fig. 1G) [45, 46]. It may be more than a coincidence that COX-2 and PGE2 synthesis was shown to colocalize with lipid droplets in colon cancer cells (Fig. 1) [47]. In conclusion, the data presented by Tirinato et al. [1] nicely extend part of our initial observations made in metastatic melanoma cells to the colon-derived CSCs, and support our hypothesis that intracellular lipid level could potentially serve as a marker of prominin-1 (CD133) expression level, changes of membrane fluidity, and metastatic potential of cancer cells [9]. Besides further dissecting this surprising relationship between lipid droplets and expression of CD133 and activation of the Wnt/β-catenin signaling pathway, it would be of interest to investigate whether it could be extrapolated to CD133+ stem/progenitor cells under normal physiological condition and/or regeneration. Acknowledgments This work was supported by U.S. NIH R01CA133797 (G.R.), Deutsche Forschungsgemeinschaft through SFB655 and TRR83 (D.C.) and Sächsisches Staatsministerium für Wissenschaft und Kunst (D.C. and C.A.F). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Author Contributions G.R., C.A.F., and T.T.L.: conception and design and manuscript writing; D.C. and A.L.: conception and design, manuscript writing, and final approval of manuscript. Disclosure of Potential Conflicts of Interest The authors indicate no potential conflicts of interest. References 1 Tirinato L , Liberale C, Di Franco S et al. Lipid droplets: A new player in colorectal cancer stem cells unveiled by spectroscopic imaging . Stem Cells 2015 ; 33 : 35 – 44 Google Scholar Crossref Search ADS PubMed WorldCat 2 Le TT , Huff TB, Cheng JX. Coherent anti-Stokes Raman scattering imaging of lipids in cancer metastasis . BMC Cancer 2009 ; 9 : 42 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Mitra R , Chao O, Urasaki Y et al. Detection of lipid-rich prostate circulating tumour cells with coherent anti-Stokes Raman scattering microscopy . BMC Cancer 2012 ; 12 : 540 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Mitra R , Goodman OB, Le TT. Enhanced detection of metastatic prostate cancer cells in human plasma with lipid bodies staining . BMC Cancer 2014 ; 14 : 91 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Yue S , Li J, Lee SY et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness . Cell Metab 2014 ; 19 : 393 – 406 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Corbeil D , Röper K, Hellwig A et al. The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions . J Biol Chem 2000 ; 275 : 5512 – 5520 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Florek M , Haase M, Marzesco AM et al. Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer . Cell Tissue Res 2005 ; 319 : 15 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Rappa G , Fodstad O, Lorico A. The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma . Stem Cells 2008 ; 26 : 3008 – 3017 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Rappa G , Mercapide J, Anzanello F et al. Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells . Exp Cell Res 2013 ; 319 : 810 – 819 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Bauer N , Wilsch-Bräuninger M, Karbanová J et al. Haematopoietic stem cell differentiation promotes the release of prominin-1/CD133-containing membrane vesicles—A role of the endocytic-exocytic pathway . EMBO Mol Med 2011 ; 3 : 398 – 409 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Marzesco AM , Janich P, Wilsch-Bräuninger M et al. Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells . J Cell Sci 2005 ; 118 : 2849 – 2858 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Marzesco AM. Prominin-1-containing membrane vesicles: Origins, formation, and utility . Adv Exp Med Biol 2013 ; 777 : 41 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Marzesco AM , Wilsch-Bräuninger M, Dubreuil V et al. Release of extracellular membrane vesicles from microvilli of epithelial cells is enhanced by depleting membrane cholesterol . FEBS Lett 2009 ; 583 : 897 – 902 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Rappa G , Mercapide J, Anzanello F et al. Biochemical and biological characterization of exosomes containing prominin-1/CD133 . Mol Cancer 2013 ; 12 : 62 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Fang D , Hawke D, Zheng Y et al. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity . J Biol Chem 2007 ; 282 : 11221 – 11229 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Korkaya H , Paulson A, Charafe-Jauffret E et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling . PLoS Biol 2009 ; 7 : e1000121 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Clevers H , Nusse R. Wnt/beta-catenin signaling and disease . Cell 2012 ; 149 : 1192 – 1205 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Vereshchagina N , Wilson C. Cytoplasmic activated protein kinase Akt regulates lipid-droplet accumulation in Drosophila nurse cells . Development 2006 ; 133 : 4731 – 4735 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Welte MA , Cermelli S, Griner J et al. Regulation of lipid-droplet transport by the perilipin homolog LSD2 . Curr Biol 2005 ; 15 : 1266 – 1275 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Katoh Y , Katoh M. Comparative genomics on PROM1 gene encoding stem cell marker CD133 . Int J Mol Med 2007 ; 19 : 967 – 970 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 21 Mak AB , Nixon AM, Kittanakom S et al. Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation . Cell Rep 2012 ; 2 : 951 – 963 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Gay DL , Yang CC, Plikus MV et al. CD133 expression correlates with membrane beta-catenin and e-cadherin loss from human hair follicle placodes during morphogenesis . J Invest Dermatol 2015 ; 135 : 45 – 55 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Bozza PT , Viola JP. Lipid droplets in inflammation and cancer . Prostaglandins Leukot Essent Fatty Acids 2010 ; 82 : 243 – 250 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Immervoll H , Hoem D, Sakariassen PO et al. Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas . BMC Cancer 2008 ; 8 : 48 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Missol-Kolka E , Karbanová J, Janich P et al. Prominin-1 (CD133) is not restricted to stem cells located in the basal compartment of murine and human prostate . Prostate 2011 ; 71 : 254 – 267 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Karbanová J , Laco J, Marzseco AM et al. Human PROMININ-1 (CD133) is detected in both neoplastic and non-neoplastic salivary gland diseases and released into saliva in a ubiquitinated form . PLoS One 2014 ; 9 : e98927 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Lonnroth C , Andersson M, Nordgren S, Lundholm K. Downregulation of Prominin 1/CD133 expression in colorectal cancer by NSAIDs following short-term preoperative treatment . Int J Oncol 2012 ; 41 : 15 – 23 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 28 Ma HI , Chiou SH, Hueng DY et al. Celecoxib and radioresistant glioblastoma-derived CD133+ cells: Improvement in radiotherapeutic effects. Laboratory investigation . J Neurosurg 2011 ; 114 : 651 – 662 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Chen KH , Hsu CC, Song WS et al. Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells . Childs Nerv Syst 2010 ; 26 : 1605 – 1612 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Bourseau-Guilmain E , Griveau A, Benoit JP et al. The importance of the stem cell marker prominin-1/CD133 in the uptake of transferrin and in iron metabolism in human colon cancer Caco-2 cells . PloS One 2011 ; 6 : e25515 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Zacchigna S , Oh H, Wilsch-Bräuninger M et al. Loss of the cholesterol-binding protein prominin-1/CD133 causes disk dysmorphogenesis and photoreceptor degeneration . J Neurosci 2009 ; 29 : 2297 – 2308 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Röper K , Corbeil D, Huttner WB. Retention of prominin in microvilli reveals distinct cholesterol-based lipid micro-domains in the apical plasma membrane . Nat Cell Biol 2000 ; 2 : 582 – 592 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Wei Y , Jiang Y, Zou F et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells . Proc Natl Acad Sci USA 2013 ; 110 : 6829 – 6834 . Google Scholar Crossref Search ADS PubMed WorldCat 34 Fargeas CA , Karbanová J, Jászai J et al. CD133 and membrane microdomains: Old facets for future hypotheses . World J Gastroenterol 2011 ; 17 : 4149 – 4152 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Boivin D , Labbe D, Fontaine N et al. The stem cell marker CD133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by Src and Fyn tyrosine kinases . Biochemistry 2009 ; 48 : 3998 – 4007 . Google Scholar Crossref Search ADS PubMed WorldCat 36 McCubrey JA , Steelman LS, Bertrand FE et al. Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: Opportunities for therapeutic intervention . Leukemia 2014 ; 28 : 15 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Tian Q , Feetham MC, Tao WA et al. Proteomic analysis identifies that 14-3-3zeta interacts with beta-catenin and facilitates its activation by Akt . Proc Natl Acad Sci USA 2004 ; 101 : 15370 – 15375 . Google Scholar Crossref Search ADS PubMed WorldCat 38 Lee G , Goretsky T, Managlia E et al. Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis . Gastroenterology 2010 ; 139 : 869 – 881 , 881. Google Scholar Crossref Search ADS PubMed WorldCat 39 Straub BK , Herpel E, Singer S et al. Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis . Mod Pathol 2010 ; 23 : 480 – 492 . Google Scholar Crossref Search ADS PubMed WorldCat 40 Welte MA. Proteins under new management: Lipid droplets deliver . Trends Cell Biol 2007 ; 17 : 363 – 369 . Google Scholar Crossref Search ADS PubMed WorldCat 41 Söllner TH. Lipid droplets highjack SNAREs . Nat Cell Biol 2007 ; 9 : 1219 – 1220 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Baenke F , Peck B, Miess H et al. Hooked on fat: The role of lipid synthesis in cancer metabolism and tumour development . Dis Models Mech 2013 ; 6 : 1353 – 1363 . Google Scholar Crossref Search ADS WorldCat 43 Castellone MD , Teramoto H, Williams BO et al. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis . Science 2005 ; 310 : 1504 – 1510 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Buchanan FG , DuBois RN. Connecting COX-2 and Wnt in cancer . Cancer Cell 2006 ; 9 : 6 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 45 Araki Y , Okamura S, Hussain SP et al. Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways . Cancer Res 2003 ; 6 : 728 – 734 . Google Scholar OpenURL Placeholder Text WorldCat 46 Nunez F , Bravo S, Cruzat F et al. Wnt/beta-catenin signaling enhances cyclooxygenase-2 (COX2) transcriptional activity in gastric cancer cells . PLoS One 2011 ; 6 : e18562 . Google Scholar Crossref Search ADS PubMed WorldCat 47 Accioly MT , Pacheco P, Maya-Monteiro CM et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells . Cancer Res 2008 ; 68 : 1732 – 1740 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes available online without subscription through the open access option. The copyright line for this article was changed on 30 June after original online publication. © 2015 AlphaMed Press This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Letter to the Editor: An Intriguing Relationship Between Lipid Droplets, Cholesterol-Binding Protein CD133 and Wnt/β-Catenin Signaling Pathway in Carcinogenesis
JF - Stem Cells
DO - 10.1002/stem.1953
DA - 2015-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/letter-to-the-editor-an-intriguing-relationship-between-lipid-droplets-slU3emGyIX
SP - 1366
EP - 1370
VL - 33
IS - 4
DP - DeepDyve
ER -