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What makes cancer stem cell markers different?
SpringerPlus volume 2, Article number: 301 (2013)
Since the cancer stem cell concept has been widely accepted, several strategies have been proposed to attack cancer stem cells (CSC). Accordingly, stem cell markers are now preferred therapeutic targets. However, the problem of tumor specificity has not disappeared but shifted to another question: how can cancer stem cells be distinguished from normal stem cells, or more specifically, how do CSC markers differ from normal stem cell markers? A hypothesis is proposed which might help to solve this problem in at least a subgroup of stem cell markers. Glycosylation may provide the key.
The cancer stem cell hypothesis (Reya et al. 2001; Al-Hajj et al. 2003; Dalerba et al. 2007; Lobo et al. 2007) proposes that tumors - analogous to normal tissues (Blanpain and Fuchs 2006) - grow and develop from a distinct subpopulation of cells named “cancer stem cells” or “cancer-initiating cells”. Stem cells are able to manage, by asymmetric cell division, two conflicting tasks, self-renewal on the one hand, and (restricted) proliferation and differentiation on the other hand. Cancer stem cells (CSC) are thought to be transformed stem or progenitor cells with novel properties such as enhanced proliferation, enhanced mobility and limited ability for differentiation.
Cancer stem cells differ considerably from the majority of cells of the tumor mass. It is assumed that the unlimited growth capacity of the tumor as well as the capability to develop metastases rest on the CSC population. Cancer stem cells divide relatively slowly and are essentially drug-resistant, two properties which make them refractory to conventional chemotherapy. The acceptance of the CSC concept therefore demands re-evaluation and potentially re-direction of cancer therapies: instead of trying solely to reduce the tumor mass, the CSC subset should be specifically targeted. This aim implies the need to search for CSC-specific therapeutic target marker molecules. Cancer stem cells are, however, in many aspects very similar to normal stem cells. They apparently express the same markers as normal stem cells. Therapies aimed at cancer stem cells therefore have a new problem: how to target cancer stem cells and leave normal stem cells intact? Or, in other words, how can CSC markers be distinguished from markers of normal stem cells?
Stem cell markers
In recent years considerable effort has been invested in the detection and characterization of stem cell markers. The result is that there are now an overwhelming and steadily increasing number of such marker molecules. Some markers are indeed more or less specific for different types of stem cells, for example, markers that differentiate embryonic from adult stem cells or pluripotent from progenitor cells. With the exception of pluripotent embryonic stem cells all other stem cells carry, in addition, lineage-specific markers. Stem cells are also defined by the absence of certain markers. Contemplating these data, several questions arise. First, as already mentioned, almost all markers of normal stem cells are also found on cancer stem cells. Examples are shown in Table 1. This, of course, poses a problem with respect to their potential use as therapeutic targets. Ectopic (non-lineage) expression of stem cell markers on cancer cells does not resolve the therapeutic dilemma. Currently the best option for a therapeutic target would be to rely on onco-fetal stem cell markers which are not expressed on normal adult stem cells. Otherwise there is at present no clear-cut distinction available between normal and cancer stem cell markers. Even at the level of regulatory miRNA clusters, identical patterns were observed (Shimono et al. 2009). Several stem cell markers are upregulated in cancer, e.g. ABCG or Bmi-1. In other instances, mutations have been detected (Lobo et al. 2007; Guo et al. 2008). In some cases isotypes of stem cell markers are preferentially expressed on tumor cells (e.g. CD44v, Günthert et al. 1991; or ALDH1A3, Marcato et al. Marcato et al. 2011), although this issue is not finally settled (Zöller 2011). We believe that a different, more general approach should be considered.
Hypothesis: what makes CSC markers different?
Most stem cell markers described so far are proteins. A relatively small number of stem cell markers have been shown to be glycans bound to proteins or lipids (Table 2). Glycans are known to be developmentally regulated (Solter and Knowles 1978; Muramatsu 1988; Fenderson and Andrews 1992; Cao et al. 2001), and are often altered on tumor cells (Hakomori 1989; Cao et al. 1995; Dabelsteen 1996; Cao et al. 1997; Brockhausen 1999; Le Pendu et al. 2001; Cao et al. 2008). The question arises whether glycans may be able to play a role as stem cell markers in a more comprehensive sense. Interestingly, the glycosylation of stem cell markers has so far not been systematically examined.
For many years we have been interested in the Thomsen-Friedenreich antigen or, more precisely, epitope (TF; CD176), which is an onco-fetal glycan structure (Galβ1-3GalNAcα1-). Although known since the mid-twenties of the last century, it was only in 1975 that Georg F. Springer discovered that this otherwise common cryptic structure is exposed (unmasked) on tumor cells (Springer et al. 1975; Springer 1984). We and others have developed monoclonal antibodies towards TF (Clausen et al. 1988; Karsten et al. 1995; Goletz et al. 2003) and examined its expression on different types of tumor tissues (Itzkowitz et al. 1989; Langkilde et al. 1992; Cao et al. 1995; Cao et al. 1999; Cao et al. 2000; Baldus et al. 2000; Goletz et al. 2003; Cao et al. 2008) as compared to their corresponding normal tissues (Cao et al. 1996). As a result of comprehensive studies it can be stated that in adults TF is a tumor marker of exceptional specificity. Among normal tissues, TF is expressed on activated T cells (Hernandez et al. 2007).
TF does not exist as a separate entity, but as part of a larger carbohydrate structure (O-glycan core-1) carried by many glycoproteins primarily of the mucin-type. In the case of tumor cells, these glycans are truncated or otherwise modified, and the core-1 structure (Galβ1-3GalNAcα1-) becomes exposed. Knowing that the glycosylation machinery of tumor cells is generally disturbed (Brockhausen 1999), one might expect that TF is expressed on most if not all glycoproteins of a tumor cell. However, this is not the case. During recent years several carrier molecules have been identified, and it was found that TF is in fact expressed on a very restricted number of proteins of a given tumor type (in most cases one or very few: Matsuura et al. 1988; Zebda et al. 1994; Singh et al. 2001; Baba et al. 2007; Cao et al. 2008). An even greater surprise to us was the fact that almost all TF carrier proteins identified so far turned up as known stem cell markers (Table 3). There are very few exceptions to this statement. The most remarkable exception is oncofetal fibronectin (onfFN, Matsuura et al. 1988), which is characterized by a single O-glycosylation (either TF or Tn) at a specific sequence. OnfFN is not a CSC marker per se, but an indicator and promoter of epithelial-mesenchymal transition (EMT) of epithelial cancer cells to secondary stem cell-like cells (Ding et al. 2012). A second example are two TF carrying glycoproteins (140 and 110 kDa) found in melanoma cells strongly correlated with high metastatic activity (Zebda et al. 1994). It is not known but conceivable that these proteins are in fact stem cell markers.
These data and other more general considerations led us to propose the following hypothesis.
During the process of malignant transformation from a normal stem or progenitor cell to a cancer stem cell, stem cell glycoprotein markers undergo alterations in their glycosylation.
As a consequence, cancer stem cells carry cancer-specific glycans.
This appears to be a selective process. Accordingly, these cancer-specific glycans are CSC makers.
Changes in stem cell marker glycosylation contribute to the altered biological behavior of these cells.
In brief, we propose that cancer stem cell markers differ from their normal counterparts by the expression of tumor-specific glycans.
In order to substantiate the suggestion that CD176 (Thomsen-Friedenreich antigen) is specifically carried on CSC markers, we have recently performed a study on lung, breast and liver cancer cell lines as well as on tissue sections, in which we examined the co-expression of CD176 with the stem cell markers CD44 and CD133 (Lin et al. 2010a). In tissue sections of all three cancer types 5–30% of cells revealed co-expression of CD176/TF with CD44. Corresponding cell lines confirmed these data but showed greater variability in the number of co-expressing cells. This is not surprising since cell lines in vitro, and especially cancer cell lines, are the subject of manifold variation, selection and evolution processes. More importantly, we were able to provide direct evidence by a sandwich ELISA that CD44 is indeed the carrier molecule for CD176/TF in lung, breast and liver cancer cells (Lin et al. 2010a), confirming earlier data from colorectal carcinoma (Singh et al. 2001).
Other data support the proposed hypothesis or are at least not at odds with it.
The cancer stem cell concept implies that metastatic spread is, in principle, restricted to CSCs. In fact, metastases show in most cases a higher percentage of TF-positive cells or of TF-positive cases (Cao et al. 1995). Disseminated breast cancer cells in the bone marrow (DTC-BM, identified as cytokeratin+/MUC1+) are in almost all cases (96%) positive for CD176/TF (Schindlbeck et al. 2005). This is remarkable, since sections of primary tumors often show a mosaic of TF-positive and TF-negative cells (which is to be expected if TF is a CSC marker). In the light of our hypothesis the expression of TF on DTC might be interpreted as indicating that these cells are cancer stem cells, and thereby able to generate distant metastases. With respect to claim #4 of our hypothesis, it is interesting to note that a number of studies demonstrate the involvement of CD176/TF in metastasis formation (Beuth et al. 1988; Okuno et al. 1993; Shigeoka et al. 1999; Cao et al. 1995). Several modes of TF-mediated adhesion mechanisms leading to metastasis have been described. One is the binding of CD176/TF carrying cells to asialoglycoprotein receptors (ASGPR) in the liver (Schlepper-Schäfer and Springer 1989), which is confirmed by clinical (Cao et al. 1995) and experimental data (Shigeoka et al. 1999). Another TF-mediated mechanism, which leads to hematogenic metastatic spread, has also been described (Yu et al. 2007), and could be experimentally inhibited with TF-carrying anti-freeze glycoprotein from polar fish (Guha et al. 2013). Of course, both mechanisms do not exclude each other. Antibodies to CD176/TF have been demonstrated to prevent TF-mediated metastatic spread (Shiogeoka et al. 1999) and to induce apoptosis (Yi et al. 2011). Furthermore, the expression of TF has been found to be correlated with invasive tumor growth (Limas and Lange 1986; Zebda et al. 1994), and interestingly also in a special case of normal cells (trophoblast cells) invading the decidua (Jeschke et al. 2002). The lectin Jacalin induces T lymphocyte activation following binding to TF on Jurkat cells (an acute T cell leukemia cell line, Baba et al. 2007).
An instructive example of how TF at a specific site can lead to a re-direction of differentiation is fibronectin (FN). Malignant FN (onfFN) differs from normal FN (norFN) by a glycosylation at the threonine of the sequence VTHPGY by either TF or its precursor, Tn, leading to a conformational change of the FN molecule which completely modifies its function (Matsuura et al. 1988). OnfFN, but not norFN, is able to induce EMT in carcinoma cells. Moreover, onfFN acts synergistically in this repect with the transforming growth factor, TGFβ1 (Ding et al. 2012). Interestingly, tumor MUC1 differs from normal epithelial MUC1 in a similar conformational change induced by O-glycosylation at the threonine of the sequence PDTRP with either TF or Tn (Karsten et al. 2005).
Taken together, direct and circumstantial evidence suggest that the TF disaccharide is typically found on proteins which are (cancer) stem cell markers or which are proteins with similar functions. Moreover, TF confers direct and indirect properties enhancing the malignancy of the cancer cell. Thereby TF is a characteristic example for the type of changes which occur on glycoprotein stem cell markers during malignant transformation and which, according to our hypothesis, make the difference between normal and cancer stem cell markers.
Questions to be answered
The fact that the glycosylation of cellular glycoproteins is altered in cancer has been well known for decades (Hakomori 1989). Our hypothesis, however, does not simply extend this idea to stem cell markers but claims that this is not a random process. It appears to be selective with respect to the proteins as well as with respect to the glycans involved. This raises several questions, for instance, what is the reason for the apparent selectivity of expression of, e.g., CD176/TF (and probably certain other glycans) on stem cell marker molecules? We are at present unable to offer an explanation for this type of selectivity. However, remarkable selectivity of glycan changes has already been reported in other cases (Hernandez et al. 2007; Singh et al. 2001).
Furthermore, one may ask which other glycans from a great diversity of potential candidates (Hakomori 1989; Zhang et al. 1997) might be able to confer the property of being selectively expressed as CSC markers. Tumor specificity may be the most important qualifier. According to this, CD176/TF is a prime candidate. However, it remains open to what extent other known carbohydrate tumor markers such as, for instance, CD175 (Tn), CD175s (sialyl-Tn), CD174 (Lewis Y), CD15 (Lewis X), CD15s (sialyl-Lewis X), CA19-9 (sialyl-Lewis a), or some subtypes of A or H (blood group-related glycans) might also be carried on CSC marker proteins. So far only few data are available. Lewis Y is at present the second most likely CSC marker-specific glycan. It has been found co-expressed with CD44 in breast cancer tissues (Lin et al. 2010b). Tn expression apparently alternates with TF (Barrow et al. 2013), and has also been found on oncofetal fibronectin in exchange to TF (Matsuura et al. 1988). It may be that these different glycans indicate different stages of the malignant stem cell-progenitor-tumor end cell lineage. Lewis X is carried on CD147, a potential CSC marker (Miyauchi et al. 1990; Riethdorf et al. 2006), but also known as a normal stem cell marker (Hennen and Faissner 2012).
Our hypothesis applies so far essentially to stem cell markers which are mucin-like surface proteins, which predominantly carry O-glycans. N-glycans are also altered on cancer stem cells (Hemmoranta et al. 2007). Their suitability as CSC markers remains to be elucidated. However, strong support for our hypothesis comes from glycolipids, whose changes in malignant transformation and in EMT are well known (Hakomori 1996). Some of them are CSC markers (Table 2). For instance, both the globoside Gb3 and the ganglioside GD2 have been described as breast cancer stem cell markers (Gupta et al. 2012; Battula et al. 2012).
It should be mentioned that some stem cell markers are intracellular proteins, such as Oct-4 (Monk and Holding 2001) or nestin (Krupkova et al. 2010). Their glycosylation is different from that of surface proteins, and so are any deviations in cancer cells (Slawson and Hart 2011).
The CSC concept, although well founded, has had to adapt to complex and partially adverse processes such as the role of EMT or the influence of the microenvironment on cancer stem cells (Medema 2013). The role of glycosylation of stem cells, and especially of stem cell markers, may add a further dimension to it.
If confirmed, this hypothesis has several consequences. First, stem cell markers which are found on normal as well as on tumor stem cells should be systematically analyzed for their glycan patterns in both circumstances. In particular, CSC markers should be examined for their potential expression of CD176/TF, CD175/Tn, and CD174/Lewis Y. Second, these tumor-related glycans could become very important or even crucial therapeutic targets. Third, targeting CD176/TF might also help to overcome the therapeutic problem of EMT, i.e. the generation of secondary cancer stem cells, because CD176/TF is expressed on oncofetal fibronectin, which plays a key role in this process (Matsuura et al. 1988).
In this connection the remarkably successful treatments of breast cancer patients by Georg F. Springer with a TF-carrying vaccine (Springer et al. 1994; Springer 1997) should be remembered. They may now be seen in a new light.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003, 100: 3983-3988.
Annaloro C, Onida F, Saporiti G, Lambertenghi Deliliers G: Cancer stem cells in hematological disorders: current and possible new therapeutic approaches. Curr Pharm Biotechnol 2011, 12: 217-225.
Augello A, Kurth TB, De Bari C: Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. Eur Cells Mat 2010, 20: 121-133.
Baba M, Ma BY, Nonaka M, Matsuishi Y, Hirano M, Nakamura N, Kawasaki N, Kawasaki N, Kawasaki T: Glycosylation-dependent interaction of Jacalin with CD45 induces T lymphocyte activation and Th1/Th2 cytokine secretion. J Leukoc Biol 2007, 81: 1002-1011.
Badcock G, Pigott C, Goepel J, Andrews PW: The human embryonal carcinoma marker antigen TRA-1-60 is a sialylated keratin sulfate proteoglycan. Cancer Res 1999, 59: 4715-4719.
Baldus SE, Zirbes TK, Hanisch FG, Kunze D, Shafizadeh ST, Nolden S, Mönig SP, Schneider PM, Karsten U, Thiele J, Hölscher AH, Dienes HP: Thomsen-Friedenreich (TF) antigen presents as a prognostic factor in colorectal carcinoma: a clinico-pathological study including 264 patients. Cancer 2000, 88: 1536-1543.
Barrow H, Tam B, Duckworth CA, Rhodes JM, Yu L-G: Suppression of core-1 Gal-transferase is associated with reduction of TF and reciprocal increase of Tn, sialyl-Tn and core-3 glycans in human colon cancer cells. PLoS One 2013, 8: e59792. 10.1371/journal.pone.0059792
Basso G, Timeus F: Cytofluorimetric analysis of CD34 cells. Bone Marrow Transplant Suppl 1998, 5: S17-S20.
Battula VL, Shi Y, Evans KW, Wang R-Y, Spaeth EL, Jacamo RO, Guerra R, Sahin AA, Marini FC, Hortobagyi G, Mani SA, Andreeff M: Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis. J Clin Invest 2012, 122: 2066-2078.
Beuth J, Ko HL, Schirrmacher V, Uhlenbruck G, Pulverer G: Inhibition of liver tumor cell colonization in two animal tumor models by lectin blocking with D-galactose or arabinogalactan. Clin Exp Metastasis 1988, 6: 115-120.
Blanpain C, Fuchs E: Epidermal stem cells of the skin. Annu Rev Cell Dev 2006, 22: 339-373.
Brockhausen I: Pathways of O-glycan biosynthesis in cancer cells. Biochim Biophys Acta 1999, 1473: 67-95.
Bunting KD: ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells 2002, 20: 11-20.
Cao Y, Karsten U, Liebrich W, Haensch W, Springer GF, Schlag PM: Expression of Thomsen-Friedenreich-related antigens in primary and metastatic colorectal carcinomas: a reevaluation. Cancer 1995, 76: 1700-1708.
Cao Y, Stosiek P, Springer GF, Karsten U: Thomsen-Friedenreich-related carbohydrate antigens in normal adult human tissues: a systematic and comparative study. Histochem Cell Biol 1996, 106: 197-207.
Cao Y, Blohm D, Ghadimi BM, Stosiek P, Xing P-X, Karsten U: Mucins (MUC1 and MUC3) of gastrointestinal and breast epithelia reveal different and heterogeneous tumor-associated aberrations in glycosylation. J Histochem Cytochem 1997, 45: 1547-1557.
Cao Y, Karsten U, Otto G, Bannasch P: Expression of MUC1, Thomsen-Friedenreich antigen, Tn, sialosyl-Tn, and α2,6-linked sialic acid in hepatocellular carcinomas and preneoplastic hepatocellular lesions. Virchows Arch 1999, 434: 503-509.
Cao Y, Karsten U, Zerban H, Bannasch P: Expression of MUC1, Thomsen-Friedenreich-related antigens, and cytokeratin 19 in human renal cell carcinomas and tubular clear cell lesions. Virchows Arch 2000, 436: 119-126.
Cao Y, Merling A, Karsten U, Schwartz-Albiez R: The fucosylated histo-blood group antigens H type 2 (blood group O, CD173) and Lewis Y (CD174) are expressed on CD34+ hematopoietic progenitors but absent on mature lymphocytes. Glycobiology 2001, 11: 677-683.
Cao Y, Merling A, Karsten U, Goletz S, Punzel M, Kraft R, Butschak G, Schwartz-Albiez R: Expression of CD175 (Tn), CD175s (sialosyl-Tn) and CD176 (Thomsen-Friedenreich antigen) on malignant human hematopoietic cells. Int J Cancer 2008, 123: 89-99.
Carpenter MK, Rosler E, Rao MS: Characterization and differentiation of human embryonic stem cells. Cloning Stem Cells 2003, 5: 79-88.
Chang W-W, Lee CH, Lee P, Lin J, Hsu C-W, Hung J-T, Lin J-J, Yu J-C, Shao L, Yu J, Wong C-H, Yu AL: Expression of globo H and SSEA3 in breast cancer stem cells and the involvement of fucosyl transferases 1 and 2 in globo H synthesis. Proc Natl Acad Sci USA 2008, 105: 11667-11672.
Clausen H, Stroud M, Parker J, Springer G, Hakomori S-I: Monoclonal antibodies directed to the blood group A associated structure, glactosyl-A: specificity and relation to the Thomsen-Friedenreich antigen. Mol Immunol 1988, 25: 199-204.
Cloosen S, Gratama JW, van Leeuwen EBM, Senden-Gijsbers BLMG, Oving EBH, von Mensdorff-Pouilly S, Tarp MA, Mandel U, Clausen H, Germeraad WTV, Bos GMJ: Cancer specific Mucin-1 glycoforms are expressed on multiple myeloma. Brit J Haematol 2006, 135: 513-516.
Dabelsteen E: Cell surface carbohydrates as prognostic markers in human carcinomas. J Pathol 1996, 179: 358-369.
Dalerba P, Cho RW, Clarke MF: Cancer stem cells: models and concepts. Annu Rev Med 2007, 58: 267-284.
Dell’Albani P: Stem cell markers in gliomas. Neurochem Res 2008, 33: 2407-2415.
Ding Y, Gelfenbeyn K, Freire-de-Lima L, Handa K, Hakomori S-I: Induction of epithelial-esenchymal transition with O-glycosylated oncofetal fibronectin. FEBS Lett 2012, 585: 1813-1820.
Engelmann K, Shen H, Finn OJ: MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res 2008, 68: 2419-2426.
Fatrai S, Schepers H, Tadema H, Vellenga E, Daenen SMGJ, Schuringa JJ: Mucin 1 expression is enriched in the human stem cell fraction of cord blood and is upregulated in majority of the AML cases. Exp Hematol 2008, 36: 1254-1265.
Fenderson BA, Andrews PW: Carbohydrate antigens of embryonal carcinoma cells: changes upon differentiation. APMIS 1992, 100(Suppl 27):109-118.
Furness SGB, McNagny K: Beyond mere markers: functions for CD34 family of sialomucins in hematopoiesis. Immunol Res 2006, 34: 13-32.
Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW, Perlingeiro RCR: SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 2007, 109: 1743-1751.
Gibson MA, Leavesley DI, Ashman LK: Microfibril-associated glycoprotein-2 specifically interacts with a range of bovine and human cell types via αvβ3 integrin. J Biol Chem 1999, 274: 13060-13065.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer C, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007, 1: 555-567.
Goletz S, Cao Y, Danielczyk A, Ravn P, Schöber U, Karsten U: Thomsen-Friedenreich antigen: the “hidden”tumour antigen. Adv Exp Med Biol 2003, 535: 147-162.
Guha P, Kaptan E, Bandyopadhyaya G, Kaczanowska S, Davila E, Thompson K, Martin SS, Kalvakolanu DV, Vasta GR, Ahmed H: Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis. Proc Natl Acad Sci USA 2013, 110: 5052-5057.
Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P: A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 1991, 65: 13-24.
Guo W, Lasky JL, Chang C-J, Mosessian S, Lewis X, Xiao Y, Yeh JE, Chen JY, Iruela-Arispe ML, Varella-Garcia M, Wu H: Multi-genetic events collaboratively contribute to Pten-null leukemia stem-cell formation. Nature 2008, 453: 529-533.
Gupta V, Bhinge KN, Hosain SB, Xiong K, Gu X, Shi R, Ho M-Y, Khoo K-H, Li S-C, Li Y-T, Ambudkar SV, Jazwinski SM, Liu Y-Y: Ceramide glycosylation by glucosylceramide synthase selectively maintains the properties of breast cancer stem cells. J Biol Chem 2012, 287: 37195-37205.
Hakomori S-I: Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res 1989, 52: 257-331.
Hakomori S: Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res 1996, 56: 5309-5318.
Havens AM, Jung Y, Sun YX, Wang J, Shah RB, Bühring HJ, Pienta KJ, Taichman RS: The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis. BMC Cancer 2006, 6: 195.
Hemmoranta H, Satomaa T, Blomqvist M, Heiskanen A, Aitio O, Saarinen J, Natunen J, Partanen J, Laine J, Jaatinen T: N-glycan structures and associated gene expression reflect the characteristic N-glycosylation pattern of human hematopoietic stem and progenitor cells. Exp Hematol 2007, 35: 1279-1292.
Henderson JK, Draper JS, Baillie HS, Fishel S, Thomson JA, Moore H, Andrews PW: Preimplantation human embryos and embryonic stem cells show comparable expression of stage-specific embryonic antigens. Stem Cells 2002, 20: 329-337.
Hennen E, Faissner A: Lewis X: a neural stem cell specific glycan? Int J Biochem Cell Biol 2012, 44: 830-833.
Hernandez JD, Klein J, Van Dyken SJ, Marth JD, Baum LG: T-cell activation results in microheterogeneous changes in glycosylation of CD45. Int Immunol 2007, 19: 847-856.
Huang Y-C, Yang Z-M, Chen X-H, Tan M-Y, Wang J, Li X-Q, Xie H-Q, Deng L: Isolation of mesenchymal stem cells from human placental decidua basalis and resistance to hypoxia and serum deprivation. Stem Cell Rev 2009, 5: 247-255.
Itzkowitz SH, Yuan M, Montgomery CK, Kjeldsen T, Takahashi HK, Bigbee WL, Kim YS: Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. Cancer Res 1989, 49: 197-204.
Jeschke U, Richter DU, Hammer A, Briese V, Friese K, Karsten U: Expression of the Thomsen-Friedenreich antigen and of its putative carrier protein mucin 1 in the human placenta and in trophoblast cells in vitro . Histochem Cell Biol 2002, 117: 219-226.
Kang M-K, Kang S-K: Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Developm 2007, 16: 837-847.
Kannagi R, Cochran NA, Ishigami F, Hakomori S-I, Andrews PW, Knowles BB, Solter D: Stage-specific embryonic antigens (SSEA-3 and −4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells. EMBO J 1983, 2: 2355-2361.
Karsten U, Butschak G, Cao Y, Goletz S, Hanisch F-G: A new monoclonal antibody (A78-G/A7) to the Thomsen-Friedenreich pan-tumor antigen. Hybridoma 1995, 14: 37-44.
Karsten U, von Mensdorff-Pouilly S, Goletz S: What makes MUC1 a tumor antigen? Tumor Biol 2005, 26: 217-220.
Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoeke M, Zeilstra J, Pals ST, Mehmet H, Stassi G, Medema JP: The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res 2010, 70: 719-729.
Krause DS, Fackler MJ, Civin CI, May WS: CD34: structure, biology, and clinical utility. Blood 1996, 87: 1-13.
Krupkova O, Loja T, Zambo I, Veselska R: Nestin expression in human tumors and tumor cell lines. Neoplasma 2010, 57: 291-298.
LaBarge MA, Petersen OW, Bissell MJ: Of microenvironments and mammary stem cells. Stem Cell Rev 2007, 3: 137-146.
Langkilde NC, Wolf H, Clausen H, Orntoft TF: Human urinary bladder carcinoma glycoconjugates expressing T-(Galβ(1–3)GalNAcα1-O-R) and T-like antigens: a comparative study using peanut agglutinin and poly- and monoclonal antibodies. Cancer Res 1992, 52: 5030-5036.
Le Pendu J, Marionneau S, Cailleau-Thomas A, Rocher J, Le Moullac-Vaidye B, Clement M: ABH and Lewis histo-blood group antigens in cancer. APMIS 2001, 109: 9-31.
Limas C, Lange P: T-antigen in normal and neoplastic urothelium. Cancer 1986, 58: 1236-1245.
Lin W-M, Karsten U, Goletz S, Cheng R-C, Cao Y: Expression of CD176 (Thomsen-Friedenreich antigen) on lung, breast and liver cancer-initiating cells. Int J Exp Pathol 2010, 92: 97-105.
Lin W-M, Karsten U, Goletz S, Cheng R-C, Cao Y: Expression of CD173 (H2) and CD174 (Lewis Y) with CD44 suggests that fucosylated histo-blood group antigens are markers of breast cancer-initiating cells. Virchows Arch 2010, 456: 403-409.
Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu D, Black KL, Yu JS: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 2006, 5: 67. 10.1186/1476-4598-5-67
Lloyd KO, Burchell J, Kudryashov V, Yin BWT, Taylor-Papadimitriou J: Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines. J Biol Chem 1996, 271: 33325-33334.
Lobo NA, Shimono Y, Qian D, Clarke MF: The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007, 23: 675-699.
Lukacs RU, Memarzadeh S, Wu H, Witte ON: Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell 2010, 7: 682-693.
Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, Helyer L, Pan L, Leidal A, Gujar S, Giacomantonio CA, Lee PWK: Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells 2011, 29: 32-45.
Masuzawa Y, Miyauchi T, Hamanoue M, Ando S, Yoshida J, Takao S, Shimazu H, Adachi M, Muramatsu T: A novel core protein as well as polymorphic epithelial mucin carry peanut agglutinin binding sites in human gastric carcinoma cells: sequence analysis and examination of gene expression. J Biochem 1992, 112: 609-615.
Matsuura H, Takio K, Titani K, Greene T, Levery SB, Salina MEK, Hakomori S: The oncofetal structure of human fibronectin defined by monoclonal antibody FDC-6: unique structural requirement for the antigenic specificity provided be a glycosylhexapeptide. J Biol Chem 1988, 263: 3314-3322.
Medema JP: Cancer stem cells: the challenges ahead. Nature Cell Biol 2013, 15: 338-344.
Miyauchi T, Kanekura T, Yamaoka A, Ozawa M, Miyazawa S, Muramatsu T: Basigin, a new, broadly distributed member of the immunoglobulin superfamily, has strong homology with both the immunoglobulin V domain and the β-chain of major histocompatibility complex class II antigen. J Biochem 1990, 107: 316-323.
Mizrak D, Brittan M, Alison MR: CD133: molecule of the moment. J Pathol 2008, 214: 3-9.
Monk M, Holding C: Human embryonic genes re-expressed in cancer cells. Oncogene 2001, 20: 8085-8091.
Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C, Gritti A, Piccini A, Porro D, Santinami M, Invernici G, Parati E, Alessandri G, LaPorta CAM: Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer 2007, 43: 935-946.
Muramatsu T: Alterations of cell-surface carbohydrates during differentiation and development. Biochimie 1988, 70: 1587-1596.
O’Brien CA, Pollett A, Gallinger S, Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445: 106-110.
Okuno K, Shirayama Y, Ohnishi H, Yamamoto K, Ozaki M, Hirohata T, Nakajima I, Yasutomi M: A successful liver metastasis model in mice with neuraminidase treated colon 26. Surg Today 1993, 23: 795-799.
Ponnusamy MP, Batra SK: Ovarian cancer: emerging concept on cancer stem cells. J Ovarian Res 2008., 1: 10.1186/1757-2215-1-4
Pontier SM, Muller WJ: Integrins in mammary-stem-cell biology and breast-cancer progression – a role in cancer stem cells? J Cell Sci 2009, 122: 207-214.
Poppema S, Lai R, Visser L, Yan XJ: CD45 (leucocyte common antigen) expression in T and B lymphocyte subsets. Leuk Lymphoma 1996, 20: 217-222.
Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 2001, 414: 105-111.
Ricci-Vitani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445: 111-115.
Riethdorf S, Reimers N, Assmann V, Kornfeld J-W, Terracciano L, Sauter G, Pantel K: High incidence of EMMPRIN expression in human tumors. Int J Cancer 2006, 119: 1800-1810.
Salcido CD, Larochelle A, Taylor BJ, Dunbar CE, Varticovski L: Molecular characterization of side population cells with cancer stem cell-like characteristics in small-cell lung cancer. Brit J Cancer 2010, 102: 1636-1644.
Sangiorgi E, Capecchi MR: Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet 2008, 40: 915-920.
Schäfer R, Schnaidt M, Klaffschenkel RA, Siegel G, Schüle M, Rädlein MA, Hermanutz-Klein U, Ayturan M, Buadze M, Gassner C, Danielyan L, Kluba T, Northoff H, Flegel WA: Expression of blood group genes by mesenchymal stem cells. Brit J Haematol 2011, 153: 520-528.
Schindlbeck C, Jeschke U, Schulze S, Karsten U, Janni W, Rack B, Sommer H, Friese K: Characterisation of disseminated tumor cells in the bone marrow of breast cancer patients by the Thomsen-Friedenreich tumor antigen. Histochem Cell Biol 2005, 123: 631-637.
Schlepper-Schäfer J, Springer GF: Carcinoma autoantigens T and Tn and their cleavage products interact with Gal/GalNAc-specific receptors on rat Kupffer cells and hepatocytes. Biochim Biophys Acta 1989, 1013: 266-272.
Shigeoka H, Karsten U, Okuno K, Yasutomi M: Inhibition of liver metastases from neuraminidase-treated Colon 26 cells by an anti-Thomsen-Friedenreich-specific monoclonal antibody. Tumor Biol 1999, 20: 139-146.
Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Dien M, Liu H, Panula SP, Chiao E, Dirbas FM, Somlo G, Pera RAR, Lao K, Clarke MF: Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009, 138: 592-603.
Singh R, Campbell BJ, Yu L-G, Fernig DG, Milton JD, Goodlad RA, FitzGerald AJ, Rhodes JM: Cell surface-expressed Thomsen-Friedenreich antigen in colon cancer is predominantly carried on high molecular weight splice variants of CD44. Glycobiology 2001, 11: 587-592.
Slawson C, Hart GW: O-GlcNAc signaling: implications for cancer cell biology. Nat Rev Cancer 2011, 11: 678-684.
Solter D, Knowles BB: Monoclonal antibody defining a stage-specific mouse embryonic antigen (SSEA-1). Proc Natl Acad Sci USA 1978, 75: 5565-5569.
Son MJ, Woolard K, Nam D-H, Lee J, Fine HA: SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 2009, 4: 440-452.
Springer GF: T and Tn, general carcinoma autoantigens. Science 1984, 224: 1198-1206.
Springer GF: Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy. J Mol Med 1997, 75: 594-602.
Springer GF, Desai PR, Banatwala I: Blood group MN antigens and precursors in normal and malignant human breast glandular tissue. J Natl Cancer Inst 1975, 54: 335-339.
Springer GF, Desai PR, Tegtmeyer H, Carlstedt SC, Scanlon EF: T/Tn antigen vaccine is effective and safe in preventing recurrence of advanced human breast carcinoma. Cancer Biotherapy 1994, 9: 7-15.
Srour EF, Brandt JE, Briddell RA, Leemhuis T, van Besien K, Hoffman R: Human CD34+ HLA-DR- bone marrow cells contain progenitor cells capable of self-renewal, multilineage differentiation, and long-term in vitro hematopoiesis. Blood Cells 1991, 17: 287-295.
Taddei I, Deugnier M-A, Faraldo MM, Petit V, Bouvard D, Medina D, Fässler R, Thiery JP, Glikhova MA: β1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells. Nature Cell Biol 2008, 10: 716-722.
Takaishi S, Okumura T, Tu S, Wang SSW, Shibata W, Vigneshwaran R, Gordon SAK, Shimada Y, Wang TC: Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009, 27: 1006-1020.
Tang C, Lee AS, Volkmer J-P, Sahoo D, Nag D, Mosley AR, Inlay MA, Ardehali R, Chavez SL, Pera RR, Behr B, Wu JC, Weissman IL, Drukker M: An antibody against SSEA-5 glycan on human pluripotent stem cells enables removal of teratoma-forming cells. Nature Biotechnol 2011, 29: 829-834.
Tardio JC: CD34-reactive tumors of the skin. An updated review of an ever-growing list of lesions. J Cutan Pathol 2009, 36: 1079-1092.
Watt SM, Chan JY-H: CD164 – a novel sialomucin on CD34+ cells. Leuk Lymphoma 2000, 37: 1-25.
Wearne KA, Winter HC, Goldstein IJ: Temporal changes in the carbohydrates expressed on BG01 human embryonic stem cells during differentiation as embryoid bodies. Glycoconj J 2008, 25: 121-136.
Wenk J, Andrews PW, Casper J, Hata J-I, Pera MF, von Keitz A, Damjanov I, Fenderson BA: Glycolipids of germ cell tumors: extended globo-series glycolipids are a hallmark of human embryonal carcinoma cells. Int J Cancer 1994, 58: 108-115.
Yanagisawa M, Yoshimura S, Yu RK: Expression of GD2 and GD3 gangliosides in human embryonic neural stem cells. ASN NEURO 2011., 3: art:e00054 10.1042/AN20110006
Yi B, Zhang M, Schwartz-Albiez R, Cao Y: Mechanisms of the apoptosis induced by CD176 antibody in human leukemic cells. Int J Oncol 2011, 38: 1565-1573.
Yu L-G, Andrews N, Zhao Q, McKean D, Williams JF, Connor LJ, Gerasimenko OV, Hilkens J, Hirabayashi J, Kasai K, Rhodes JM: Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem 2007, 282: 773-781.
Zebda N, Bailly M, Brown S, Doré JF, Berthier-Vergnes O: Expression of PNA-binding sites on specific glycoproteins by human melanoma cells is associated with a high metastatic potential. J Cell Biochem 1994, 54: 161-173.
Zhang S, Zhang HS, Cordon-Cardo C, Reuter VE, Singhal AK, Lloyd KO, Livingston PO: Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group-related antigens. Int J Cancer 1997, 73: 50-56.
Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP: Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 2008, 68: 4311-4320.
Zöller M: CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 2011, 11: 254-267.
Dedicated to the memory of Georg F. Springer (1924–1998).
U.K. is consultant, S.G. is CEO and founder of Glycotope GmbH.
Both authors contributed equally to the manuscript. Both authors read and approved the final manuscript.
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Karsten, U., Goletz, S. What makes cancer stem cell markers different?. SpringerPlus 2, 301 (2013) doi:10.1186/2193-1801-2-301
- Stem cells
- Cancer stem cells
- Thomsen-Friedenreich antigen
- Therapeutic targets