Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

Cripto-1: a multifunctional modulator during embryogenesis

and oncogenesis

Luigi Strizzi1, Caterina Bianco1, Nicola Normanno2 and David Salomon*,1

1Tumor Growth Factor Section, Mammary Biology & Tumorigenesis Laboratory, Center for Cancer Research, NationalCancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; 2Division of Haematological Oncology andDepartment of Experimental Oncology, ITN-Fondazione Pascale, 80131 Naples, Italy

It is increasingly evident that genes known to performcritical roles during early embryogenesis, particularlyduring stem cell renewal, pluripotentiality and survival,are also expressed during the development of cancer. Inthis regard, oncogenesis may be considered as therecapitulation of embryogenesis in an inappropriatetemporal and spatial manner. The epidermal growthfactor-Cripto-1/FRL1/cryptic family of proteins consistsof extracellular and cell-associated proteins that havebeen identified in several vertebrate species. During earlyembryogenesis, epidermal growth factor-Cripto-1/FRL1/cryptic proteins perform an obligatory role as coreceptorsfor the transforming growth factor-beta subfamily ofproteins, which includes Nodal. Cripto-1 has also beenshown to function as a ligand through a Nodal/Alk4-independent signaling pathway that involves binding toglypican-1 and the subsequent activation through src ofphosphoinositol-3 kinase/Akt and ras/mitogen-activatedprotein kinase intracellular pathways. Expression ofCripto-1 is increased in several human cancers and itsoverexpression is associated with the development ofmammary tumors in mice. Here, we review the role ofCripto-1 during embryogenesis, cell migration, invasionand angiogenesis and how these activities may relate tocellular transformation and tumorigenesis. We also brieflydiscuss evidence suggesting that Cripto-1 may be involvedin stem cell maintenance.Oncogene (2005) 24, 5731–5741. doi:10.1038/sj.onc.1208918

Keywords: Cripto-1; embryogenesis; oncogenesis; EHT;engiogenesis; therapy

Introduction

Embryonic genes are important in regulating asym-metric cell division, pluripotentiality and/or in main-taining cellular and tissue-specific niches that arenecessary for stem cell survival (Kopper and Hajdu,2004; Ohlstein et al., 2004; Sell, 2004). Genetic muta-

tions within stem cells or alterations in signalingpathways within the stem cell niche are almost certainlycentral to the early appearance of premalignant cells.Stem cells, therefore, represent desirable targets for thedevelopment of future cancer therapies (Reya et al.,2001; Beachy et al., 2004). Growth factors that areimportant in development, oncogenesis and stem cellself-renewal include members of the Hedgehog (Hh),Wnt, Notch, transforming growth factor beta (TGFb/Activin/Nodag/BMP) and epidermal growth factor-Cripto-1/FRL1/cryptic (EGF-CFC) superfamilies(Salomon et al., 2000; Shen and Schier, 2000; Kodja-bachian, 2001; Kleber and Sommer, 2004; Nelson andNusse, 2004; Tabata and Takei, 2004).

Identification and structure of the EGF-CFC gene family

Human Cripto-1 (CR-1), also known as teratocarcino-ma-derived growth factor-1 (TDGF-1), is a member ofthe EGF-CFC protein family (Salomon et al., 2000).Orthologous genes have been identified in the mouse(Cr-1) (Dono et al., 1993), chicken (Colas and Schoen-wolf, 2000), zebrafish (Zhang et al., 1998) and Xenopus(FRL1) (Kinoshita et al., 1995). Related genes includemouse cryptic (Cfc1) and human cryptic (CFC1) (Shenet al., 1997; Bamford et al., 2000; Shen and Schier, 2000;de la Cruz et al., 2002). EGF-CFC family memberscontain an NH2-terminal signal peptide, a modifiedEGF-like region, a conserved cysteine-rich domain(CFC motif) and a short hydrophobic COOH-terminusthat contains additional sequences for glycosyl-phosphatidylinositol (GPI) cleavage and attachment(Minchiotti et al., 2000) (Figure 1). In addition, allEGF-CFC proteins contain a consensus O-linkedfucosylation site within the EGF-like motif that isnecessary for their ability to function as coreceptors forthe TGFb-related proteins, Nodal or Vg1/GDF-1(Schiffer et al., 2001; Yan et al., 2002). Most of theEGF-CFC proteins are cell-associated glycoproteinsthat contain from 171 to 202 amino acids and thatrange from 18 to 21 kDa in size. However, the nativemouse and human Cripto-1 proteins are 24, 28 and36 kDa in size and additional proteins ranging from 14to 60 kDa have also been identified and are the result ofdifferential glycosylation at N- and O-linked asparagineand serine residues (Brandt et al., 1994; Kenney et al.,

*Correspondence: DS Salomon, Tumor Growth Factor Section,Mammary Biology & Tumorigenesis Laboratory, National CancerInstitute, National Institutes of Health, Buillding 37, Room 118B,Bethesda, MD 20892, USA; E-mail: [email protected]

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1996; Seno et al., 1998; Niemeyer et al., 1999; Minchiottiet al., 2000; Schiffer et al., 2001). The mouse Cr-1protein can be released by treatment of cells withphosphatidylinositol-specific phospholipase C (PI-PLC)(Minchiotti et al., 2000). Removing the COOH-terminalstretch of residues where GPI linkage occurs generatessoluble forms of biologically active mouse and humanCripto-1 (Xu et al., 1999; Minchiotti et al., 2001; Biancoet al., 2002b, 2003; Yan et al., 2002). Full activityrequires the presence of a peptide containing only anintact EGF domain and CFC domain (Minchiotti et al.,2001; Yan et al., 2002). However, whether there aresignificant qualitative and/or quantitative differences inthe biological activities that are regulated by Cripto-1between the soluble versus cell-associated forms is notyet known since Cripto-1 can function both as acoreceptor in cis (autocrine/cell-autonomous) and asligand in trans (paracrine/cell-nonautonomous) (Yanet al., 2002).

Function of Cripto-1 during embryonic development

Genetic studies in zebrafish and mice have defined anessential role for Nodal that functions through Cripto-1in the formation of the primitive streak, patterning ofthe Anterior/Posterior axis (A/P) and specification ofmesoderm and endoderm (mesoendoderm) during gas-trulation, whereas later in embryogenersis Nodal func-tions through cryptic in the establishment of Left/Right(L/R) asymmetry of developing organs (Ding et al.,1998; Yan et al., 1999; Schier and Shen, 2000; Hamadaet al., 2002; Schier, 2003). Cr-1-null mice (Cr-1�/�) die atday 7.5 due to their inability to gastrulate and formappropriate germ layers (Liguori et al., 1996; Ding et al.,1998). Nodal, which functions through Cripto-1, co-operates with wnt3 in the mouse in initiating thespecification of mesoderm and endoderm formationand in regulating the development of dorsal and anteriormesoderm and head structures (Harland and Gerhart,1997; Beddington and Robertson, 1999; Liu et al., 1999;Thisse et al., 2000; Kodjabachian, 2001; Robb and Tam,2004). In contrast, Cripto-1 in conjunction with Fgf8and brachyury are important for initiating and main-taining the migration of mesodermal cells through theprimitive streak (Conlon and Smith, 1999; Ciruna andRossant, 2001; Griffin and Kimelman, 2003; Warga andKane, 2003). Mutations in zebrafish of the Cripto-1ortholog, one-eyed pinhead (oep) result in cyclopia, an

absence of head and trunk mesoderm, loss of prechordalplate and ventral neuroectoderm, impairment of gas-trulation movements, loss of A/P axis positioning andleft/right laterality defects (Zhang et al., 1998; Gritsmanet al., 1999). One-eyed pinhead, like mouse Cr-1, isabsolutely required for the migration of mesendodermcells through the primitive streak (Warga and Kane,2003). Mutations of oep effectively block the ability ofepiblast cells to migrate and induce a more cohesiveinteraction between these cells. This effect is indepen-dent of the two zebrafish Nodal-related genes, squint(Sqt) and Cyclops (Cyc), suggesting that these pheno-types are unique to oep.

Mouse Cr-1 is expressed in the precardiac mesodermand performs an essential role during the early stages ofcardiac lineage specification and differentiation (Donoet al., 1993). Homozygous knockout of the Cr-1 gene(Cr-1�/�) in pluripotential embryonic stem (ES) cellsimpairs their ability to spontaneously differentiate invitro into cardiomyocytes (Parisi et al., 2003) withoutaffecting the ability of ES cells to differentiate into othercell types (Xu et al., 1998). In fact, Cr-1�/� ES cellsactually show extensive neural differentiation in vitroand in vivo suggesting that neuroectodermal differentia-tion is the preferred default pathway that occurs in theabsence of Cr-1 expression (Parish et al., 2005; Sonntaget al., 2005). Chimeric embryos that were generatedbetween wild-type and Cr-1�/� ES cells in vitro werenormal indicating that Cr-1 produced by the wild-typehost cells could rescue the mutant phenotype in aparacrine manner (Xu et al., 1998). Germline disruptionof Cr-1 in Cr-1�/� embryos results in the formation ofembryos that possess a head without a trunk demon-strating that there is a severe deficiency in embryonicmesoderm and endoderm without a loss of anteriorneuroectoderm formation (Xu et al., 1999).

Intracellular signal transduction pathways that mediateCripto-1 activity

Cripto-1 is involved in the activation of several differentsignaling pathways during embryonic development andcellular transformation (Bianco et al., 2004). The majorsignaling pathways activated by Cripto-1 are a Nodal/ALK4/ALK7/Smad-2 signaling pathway and a Glypican-1/c-Src/MAPK/AKT signaling pathway.

Signal sequence EGF-like domain CFC-domain GPI siteNH2 COOH

1 169 188

O-linked(Ser 40)

N-linked(Asn 79)

O-linked(Ser 161)

O-fucose(Thr 88)

Figure 1 Schematic diagram illustrating the different domains composing the Cripto-1 glycoprotein

Cripto-1: a modulator during embryogenesis and oncogenesisL Strizzi et al

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Nodal/ALK4/ALK7/Smad-2 signaling pathway

During embryogenesis, EGF-CFC proteins function ascell-surface coreceptors for Nodal through activation ofthe serine threonine kinase type I (ALK4) and type II(ActRIIB) receptor complex in Xenopus (Schier, 2003).Biochemical evidence has demonstrated a direct inter-action between mouse Cr-1 and ALK4 in Xenopusoocytes and this interaction is necessary for Nodal tobind to the ALK4/ActRIIB receptor complex and tostimulate Smad-2 phosphorylation and activation (Yeoand Whitman, 2001; Bianco et al., 2002a). Cripto-1 canalso directly interact with serine threonine kinasereceptor ALK7 enhancing the ability of ALK7 torespond to Nodal (Reissmann et al., 2001). However,Nodal can directly bind ALK7 in the absence of Cripto-1, although Cripto-1 significantly enhances its signalingactivity (Reissmann et al., 2001). Site-directed mutagen-esis experiments have shown that Cripto-1 interacts withNodal through the EGF-like domain, while the CFCdomain mediates binding of Cripto-1 to ALK4 (Yeoand Whitman, 2001). In addition to functioning as acoreceptor for Nodal, Cr-1 has been shown to mediatesignaling of other TGFb ligands, such as Activin andXenopus Vg1 and its ortholog in mouse GDF1 (Chenget al., 2003). Similar to Nodal, Vg1 and GDF1 can bindto ALK4/ActRIIB receptor complex only in thepresence of EGF-CFC coreceptors. In contrast, bindingof CR-1 to Activin can inhibit Activin signaling inmammalian cells (Adkins et al., 2003; Gray et al., 2003).In this regard, Adkins et al. have demonstrated that CR-1 interacts with Activin B through the CFC domain,sequestering Activin B from a functional ALK4/ActRIIB receptor complex and blocking its ability tofunction as an inhibitor of cell growth in cancer cells.Therefore, antagonism of Activin signaling by CR-1may represent an additional mechanism used by CR-1to promote tumorigenesis. In addition to being EGF-CFC-dependent, Nodal signaling is regulated by severalantagonists that function at different levels. Tomoregu-lin-1, Lefty A and B and Antivin can antagonize Nodalsignaling through EGF-CFC coreceptors. In this regard,the transmembrane protein Tomoregulin-1 inhibitsNodal signaling in Xenopus embryos through interac-tion with the CFC domain of CR-1 (Harms and Chang,2003). Furthermore, Tomoregulin-1, through its EGF-like domain, can specifically bind with low affinity to thetyrosine kinase receptor erbB-4 (Uchida et al., 1999).Since CR-1 can indirectly increase the tyrosine phos-phorylation of erbB-4 in several mouse and humanmammary epithelial cells, interaction between CR-1 andTomoregulin-1 might explain erbB-4 trans-phosphory-lation by CR-1 in mammalian cells (Bianco et al., 1999).The Lefty/Antivin subfamily has also been shown toantagonize Nodal and Vg1/GDF1 signalings through adirect interaction with EGF-CFC coreceptors (Chenand Shen, 2004). Similarly, Xantivin, a Lefty-relatedprotein in Xenopus, interacts directly with XenopusFRL-1 and CR-1, leading to inhibition of Nodalsignaling (Tanegashima et al., 2004). Although EGF-CFC proteins play an essential role in mediating Nodal

signaling, CR-1 and Nodal may have distinct functionalroles independently of one another. For example,zebrafish oep regulates cell motility independently ofZebrafish Nodal-related proteins Cyc and Sqt, whereasNodal can inhibit BMP signaling by binding directly toBMP independently of CR-1 (Yeo and Whitman, 2001;Warga and Kane, 2003).

Glypican-1/c-Src/MAPK/AKT signaling pathway

Our lab has previously demonstrated that CR-1 canactivate the ras/raf/MAPK and PI3-K/AKT/GSK-3bsignaling pathways (De Santis et al., 1997; Kannanet al., 1997; Ebert et al., 1999; Bianco et al., 2004).Interestingly, activation of these signaling pathways canbe achieved with a soluble GPI-truncated CR-1 recom-binant protein (Kannan et al., 1997; Bianco et al.,2002b). Since soluble CR-1 has been found to besecreted in the conditioned medium of several humancarcinoma cell lines, it is possible that a functionalsoluble isoform of CR-1 is naturally cleaved from thecell membrane (Brandt et al., 1994; Minchiotti et al.,2000; Normanno et al., 2004). Activation of these twointracellular pathways is independent of Nodal andALK4, since CR-1 can stimulate MAPK and AKTphosphorylation in EpH4 mouse mammary epithelialcells and MC3T3-C1 osteoblast cells that lack ALK4and Nodal expression, respectively (Bianco et al.,2002a). Furthermore, activation of these two intracel-lular pathways occurs through a direct binding of CR-1to Glypican-1, a membrane-associated heparan sulfateproteoglycan (HSPG) that functions as a coreceptor forseveral different growth factors (i.e. Wnts, FGF, HB-EGF) (Bianco et al., 2003). Binding of CR-1 toGlypican-1 activates the cytoplasmic tyrosine kinase c-Src, triggering the MAPK and AKT signaling pathways(Bianco et al., 2003). Since MAPK and AKT signalingpathways have been involved in regulating cell pro-liferation and survival, CR-1 might be involved in thepathogenesis of human cancer through the inappropri-ate activation of these two signaling pathways indepen-dently of Nodal and ALK4. CR-1 has also been shownto function during development through an FGFR-1signaling pathway. In Xenopus oocytes and in yeast,Xenopus FRL1 can indirectly increase the phosphoryla-tion of Xenopus FGFR-1 (Kinoshita et al., 1995).However, no direct binding between FGFR-1 andFRL1 could be detected. Finally, several findingssuggest a potential interaction of the CR-1 signalingpathway with the wnt/b-catenin/Lef-1 signaling path-way. In fact, Cr-1 has been identified by microarrayanalysis as a primary target gene in the wnt/b-cateninsignaling pathway during embryonic development(Morkel et al., 2003). More recently, FRL1 and mouseCr-1 have been found to function as coreceptors forwnt-11 by binding directly to Wnt-11, providing a linkbetween the EGF-CFC proteins and wnt familymembers (Tao et al., 2005). Interestingly, in Xenopus,glypican-4 physically interacts with Wnt-11 suggestingthat both glypican-4 and FRL1 are involved inregulating Wnt signaling (Ohkawara et al., 2003).


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Biological effects of Cripto-1

Regulation of milk protein expression

It has been shown that CR-1 can modulate milk proteinexpression in HC-11 mouse mammary epithelial cells.HC-11 mouse mammary epithelial cells express the milkprotein b-casein at confluency after exposure to thelactogenic hormones dexamethasone, insulin and pro-lactin (DIP) (De Santis et al., 1997). Like other EGF-related peptides, pretreatment of HC-11 cells with CR-1during logarithmic growth induces an optimal responseto DIP with respect to the induction of the milk proteinb-casein (De Santis et al., 1997). In contrast, thesimultaneous treatment of HC-11 cells with CR-1 inthe presence of DIP inhibits b-casein expression. Inaddition, HC-11 cells that overexpress Cr-1 protein alsoexhibit low levels of b-casein expression following DIPtreatment (De Santis et al., 1997). This inhibitory effectof CR-1 on b-casein expression in response to DIP is notunique to this mouse mammary epithelial cell line, sincea similar inhibitory effect on b-casein expression in thepresence of DIP is observed in CID-9 overexpressingQJ;Cr-1 (Niemeyer et al., 1998). In addition, CR-1modulates expression of other milk proteins in responseto lactogenic hormones in primary mouse mammaryexplant cultures established from midpregnant mice(De Santis et al., 1997). In this regard, concurrenttreatment with DIP plus CR-1 significantly impairsDIP-induced expression of b-casein and whey acidicprotein (WAP) in mammary explant cultures. Theability of CR-1 to block lactogenic hormone-inducedexpression of b-casein is mediated through a ras-dependent, PI3-K-dependent pathway (De Santiset al., 1997). This inhibitory effect of CR-1 on milkprotein expression may be biologically significant sinceendogenous Cr-1 expression is upregulated in mousemammary epithelial cells during pregnancy and lacta-tion and soluble CR-1 protein is secreted in human milk(Bianco et al., 2001).

Regulation of angiogenesis

We have recently demonstrated that human CR-1, inaddition to regulating cell proliferation, survival andtransformation, plays an essential role also in themultistep process of tumor angiogenesis (Bianco et al.,2005). In fact, CR-1 has a strong angiogenic activity invitro in cultured human umbilical endothelial cells(HUVECs). CR-1 enhances proliferation of HUVECsin a dose-dependent manner, stimulates their migrationand invasion and induces formation of vascular-likestructures on Matrigel. In addition, the chemotacticactivity of CR-1 in HUVEC is mediated by c-Src andPI3-K/AKT signaling pathways. The angiogenic activityof CR-1 in endothelial cells is not dependent on theautocrine production of VEGF, since a specific VEG-FRI inhibitor does not block CR-1 angiogenic activityin vitro in HUVECs. In vivo, recombinant CR-1 proteininduces microvessel formation in silicone cylinders filledwith Matrigel and microvessel formation is strongly

inhibited with a blocking anti-CR-1 monoclonal anti-body (A8.G3.5), suggesting that CR-1 directly mod-ulates angiogenesis. Finally, overexpression of CR-1 inMCF-7 human breast cancer cells enhances tumorneovascularization in a xenograft model.

Regulation of cellular migration and invasion by Cripto-1

Overexpression of Cr-1 in the mouse EpH4 mammaryepithelial cells caused not only an increase in cellproliferation and anchorage-independent growth in softagar but formation of duct-like structures when grownin collagen type I matrix and increased chemotaxis andmigration when these cells were cultured on plastic or onporous filters coated with extracellular matrix proteins(Wechselberger et al., 2001). The effects of Cr-1 in EpH4cells was the first study which suggested that Cr-1 mayplay a role in inducing epithelial to mesenchymaltransition (EMT) of mammary epithelial cells. Similarly,human MCF-7 breast cancer cells, which overexpressCR-1 in addition to acquiring higher proliferationrates in serum-free medium, increased colony formationin soft agar and increased resistance to anoikisalso showed increased invasion through matrix-coatedmembranes as demonstrated by Boyden chamberinvasion assay (Normanno et al., 2004). Furtherevidence of the role that CR-1 might play in theinduction of EMT comes from a recent study where theexpression of markers that characteristically defineEMT was investigated in mammary gland hyperplasiasand tumors from MMTV-CR-1 transgenic mice andin HC-11/Cr-1 cells (Strizzi et al., 2004). DuringEMT, intercellular contacts between epithelial cells arelost due to decreased E-cadherin expression anddisruption of the adherens junction complex as cellsbecome less adhesive and potentially more motile(Boyer et al., 2000; Thiery, 2002). E-cadherin expressionwas significantly decreased in tissue extracts from themammary tumor lesions that express the CR-1 trans-gene and in extracts from HC-11/Cr-1 cells. Further-more, the zinc-finger repressor transcription factorsnail, which is known to downregulate or interferewith the normal expression of E-cadherin (Savagner,2001), was detected, by RT–PCR and Westernblot analysis, at significantly higher levels in MMTV-CR-1 mammary tumor lesions and HC-11/Cr-1 cells ascompared to control nontumorigenic mammary tissueand HC-11 wild-type cells, respectively (Strizzi et al.,2004). Expression of the mesenchyme cell cytoskeletoncomponent, vimentin, is also increased in epithelial cellsand tumors during EMT (Casaroli-Marano et al., 1999;Dandachi et al., 2001; Ackland et al., 2003). Over-expression of CR-1 in human cervical carcinomacells was associated with the increased expression ofvimentin in these cells as they exhibited increasedmigration and invasion through matrix-coated mem-branes suggesting that CR-1-induced vimentin expres-sion may contribute to a more aggressive phenotypeof cervical carcinoma (Ebert et al., 2000). Expressionfor vimentin was also increased in extracts frommammary gland hyperplasias and tumors from


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MMTV-CR-1 transgenic mice and from HC-11/Cr-1cells. In addition, mammary tumors from the MMTV-CR-1 transgenic mice and HC-11/Cr-1 cells showedincreased expression of active c-Src, focal adhesionkinase (FAK) and AKT (Strizzi et al., 2004). Thesesignaling molecules can be activated during EMT andmay play a role in increasing tumor cell migration andinvasion (Thiery and Chopin, 1999). Interestingly,mammary tumors from the MMTV-CR-1 transgenicmice and HC-11/Cr-1 cells were found to express theinactive form of glycogen synthease kinase 3 beta (GSK-3b) as well as the active form of b-catenin. During wntsignaling, GSK-3b is inactivated by phosphorylationcausing accumulation of nonphosphorylated b-cateninwhich translocates to the nucleus in a complex with Tcf/Lef-1 and functions as a transcription factor activatinggenes involved in increased cell survival, proliferationand migration such as, c-myc, cyclin-D1, snail and slug(Polakis, 2000). These data suggest that Cripto-1 mayplay a role in the regulation of cellular migration andinvasion possibly through crosstalk with the Wntsignaling pathway (Figure 2).

Role of Cripto-1 in transformation and cancer

In vitro transformation of cells by Cripto-1

The first in vitro study suggesting a potential role forCripto-1 during cell transformation involved transfec-tion of human CR-1 into NIH3T3 cells which inducedmorphological changes and colony formation of thesecells when grown in monolayer (Ciccodicola et al.,1989). When full-length CR-1 DNA was transfected intoimmortalized mouse NOG-8 mammary epithelial cells,those cells that expressed CR-1 were able to formcolonies in soft agar and exhibited anchorage-indepen-dent growth in soft agar as compared to the neo-transfected NOG-8 cells (Ciardiello et al., 1991).Similarly, overexpression of CR-1 cDNA in normalrat fibroblasts was shown to induce growth of these cellsin soft agar (Brandt et al., 1994) and exogenousrecombinant CR-1 protein was shown to stimulate cellproliferation of differentiated and undifferentiatedembryonal carcinoma cells (Su et al., 1993; Baldassarreet al., 1997). Further support for transforming potentialof Cripto-1 stems from studies showing increasedexpression of CR-1 in cells transformed by differentoncogenes. For instance, overexpression of Cr-1 mRNAwas detected in tumorigenic and metastatic Ha-ras-transformed rat CREF embryo fibroblasts (Su et al.,1993). Interestingly, in these cells, reversion of thetransformed phenotype of the Ha-ras-transformed cellsby overexpression of a Krev-1 ras suppressor generesulted in a loss of expression of Cr-1. This suggeststhat Cr-1 may play a role in ras-induced CREF celltransformation. Cripto-1 was also found to be over-expressed in K-ras-transformed FRLT-5 rat thyroidepithelial cells which show TSH-independent growthcapability (Mincione et al., 1998). Also v-ras/Smad-7-transformed keratinocytes develop skin tumors thatoverexpress Cr-1 (Liu et al., 2003), suggesting thatSmad-7-induced tumor formation may require upregu-lation of Cr-1 and other EGF-related peptides.

In concert with Cripto-1 cellular transforming poten-tial, it appears that Cripto-1 levels may affect celldifferentiation. Mouse CID-9 mammary epithelial cellsare derived from mammary glands of 14.5-day pregnantmice and normally express Cr-1 (Niemeyer et al., 1998).When these cells are treated with lactogenic hormonesand prolactin and are cultured on extracellular matrixsubstrates, they form differentiated polarized epithelialstructures called mammospheres and express the milkprotein b-casein and Cr-1. This suggests that hormonesreleased during pregnancy may be involved in theregulation of Cr-1 expression. When CID-9 cells over-express Cr-1, they show significantly higher proliferationrates, increased colony formation in soft agar and cellsurvival, but no longer form mammospheres and showreduced expression of b-casein. Conversely, if undiffer-entiated human or mouse teratocarcinoma cells areinduced to differentiate by treatment with retinoicacid, expression of Cripto-1 is significantly reduced(Ciccodicola et al., 1989). These data suggest thatincreased CR-1 levels may negatively affect cell

Apical

Basolateral

Lipid Raft

Glypican-1Wnt3

Cripto-1

Src

LRP5/6 Glypican-4

Cripto-1

Trans-Golgi

Frz Frz

Wnt5A

Dsh

GSK-3β

β-CateninApcAxin

βTrCP

Dsh

JNKROCK

Rho Rac

Jun

MAPK

MEKPI-3K

Akt

Lef-1/Tcf

Figure 2 Cripto-1 is a target gene in a canonical Wnt3/b-catenin/Lef-1 (Tcf) signaling pathway and also a coreceptor for Wnt andglypican-1. Wnt3 binds to a frizzled (Frz) receptor and coreceptorsLRP5/6 and Cripto-1. Activation of Dishevelled (Dsh) results inthe inactivation of the b-catenin degradation complex (GSK-3b/Axin/Apc), which promotes ubiquination and proteosomal degra-dation of b-catenin. b-Catenin accumulates and can bind to theDNA-binding proteins of the transcription factor family Lef-1/Tcfafter translocation to the nucleus. Cripto-1 and glypican-4 can alsofunction as coreceptors for Wnts such as Wnt5A with Frz toactivate the planar cell polarity pathway (PCP). This pathway isalso regulated through Dsh which can stimulate RhoA/ROCK andRac/JNK to activate the transcription factor c-Jun and compo-nents of the cytoskeleton and cell motility. Finally, Cripto-1 canbind to glypican-1 in lipid rafts and activate c-src which can thenenhance the ras/MAPK and/or PI-3 kinase/Akt pathways. PI3K/Akt signaling molecules are also known to be capable ofinactivating GSK-3b causing similar cellular modifications thatoccur during Wnt signaling


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differentiation. However, the effects of Cripto-1 ob-served in vitro may depend on the type of cells used andtheir responsiveness to variations in growth conditions,reflecting the fact that the mammary gland epitheliumcyclically goes through phases of proliferation andinvolution depending on the variable levels of growthfactors and hormones present in the environment inwhich they grow. For instance, normal HC-11 cellscultured in low serum and treated with CR-1 show anincrease in apoptosis through activation of caspase-3protease and downregulation of expression of theantiapoptotic protein Bcl-xl (De Santis et al., 2000).

Cripto-1 is upregulated in transgenic mouse mammarytumors

Transgenic mice overexpressing either neu (erbB-2),TGF-a, int-3, polyoma middle T (PyMT) or simianvirus 40 large T antigens have been shown to developmammary gland tumors (Jhappan et al., 1990, 1992;Guy et al., 1992; Maroulakou et al., 1994; Muller et al.,1998). All of these tumors were found to expresssignificant levels of Cr-1 mRNA and protein asdetermined by RT–PCR, Western blot analysis andimmunohistochemistry (Kenney et al., 1996). In addi-tion to expression in mammary gland tumors oftransgenic mice, Cr-1 was also consistently expressedin hyperplastic lesions in mammary glands of PyMT,neu and TGF-a mouse transgenic models suggesting arole for Cr-1 in deregulation of mammary epithelialproliferation (Niemeyer et al., 1999). The insertionof Elvax pellets containing the EGF-like motif ofCR-1 protein into the mammary gland of ovariecto-mized virgin mice produced a dramatic increase inDNA synthesis in mammary epithelial cells imme-diately adjacent to the pellets (Kenney et al., 1997). Inaddition, increased ductal branching and hyperplasiawas observed when FVB/N or C57B1/6 mousemammary epithelial cells, containing retroviral-drivenoverexpression of Cr-1 cDNA, were subsequentlytransplanted into cleared mammary fat pad of syngenicovariectomized virgin mice (Kenney et al., 1997).Although mammary carcinomas were not observed toarise from the transplanted hyperplasias, the hyperpla-sias could be serially transplanted, suggesting thepresence of a Cr-1-induced immortalized population ofmammary epithelial cells. Similarly, when NOG-8 orCID-9 Cripto-1-transformed cells were subsequentlytransplanted in vivo, these cells were unable to formtumors (Ciardiello et al., 1991; Niemeyer et al., 1998).This suggests that other genetic alterations must takeplace in addition to Cripto-1 overexpression for tumorsto develop.

In vivo tumorigenesis induced by Cripto-1

The first in vivo study that showed CR-1-dependenthyperplasia and tumor growth in mouse mammaryglands used the mouse mammary tumor virus (MMTV)to drive CR-1 overexpression (Wechselberger et al.,2005). Virgin MMTV-CR-1 transgenic mice exhibited

enhanced ductal branching and dilatation, intraductalhyperplasia and hyperplastic alveolar nodules. Mam-mary glands from 12- to 20-month-old multiparousMMTV-CR-1 mice showed multifocal hyperplasias andapproximately 33% of these mice subsequently devel-oped papillary adenocarcinomas (Figure 3). The longlatency period suggests that additional genetic altera-tions are required to facilitate mammary tumor forma-tion in conjunction with CR-1. The WAP promoter canbe used to drive high levels of transgene expression in asignificantly greater number of mammary epithelialcells, predominantly during pregnancy and lactation(Kordon et al., 1995). This allows assessment of anysignificant effect on mammary gland development orformation of premalignant or malignant lesions in thepregnant and lactating mammary gland of multiparousmice. Mice expressing the human CR-1 transgene underthe regulation of the WAP promoter in FVB/N micehave been recently developed (Sun et al., 2005,submitted). Higher levels of phosphorylated AKT andMAPK were detected in mammary glands of multi-parous WAP-CR-1 mice as compared to multiparousFVB/N mice, suggesting increased cell proliferation andsurvival of the transgenic mammary gland. In addition,over half of the WAP-CR-1 multiparous female micedeveloped multifocal mammary tumors of mixedhistological subtypes. These tumors were histologicallydistinct from the mammary tumors that developed inthe MMTV-CR-1 transgenic mouse. The mammarytumors from the WAP-CR-1 mice contained foci ofepithelial hyperplasia mixed with glandular, papillaryand solid carcinomas. Areas of adenosquamous andmyoepithelial differentiation were also identified withinthese tumors (Figure 4). These tumors were similar tothe mixed histotype of mammary tumors that arise in

Figure 3 A histological section (20� ) of a mammary tumor fromthe MMTV-CR-1 transgenic mice shows the papillary morphologyof this adenocarcinoma. The same figure also shows evidence ofhigh-grade proliferation by immunohistochemical staining of thetumor cell nuclei with the cell proliferation marker PCNA


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MMTV-Wnt1 mice or mammary tumors that develop inmice expressing stabilized mutant forms of b-cateninwith either the MMTV or WAP promoters (Miyoshiet al., 2002a, b; Rosner et al., 2002; Li et al., 2003;Teuliere et al., 2005). In fact, increased expression ofdephosphorylated b-catenin in WAP-CR-1 mammarytumors suggests that a canonical Wnt signaling pathwaymay be activated in these tumors. In addition, asdescribed for Wnt pathway mammary tumors (Miyoshiet al., 2002a), evidence of epidermal transdifferentiation,as determined by positive immunostaining for theepidermal cell cytokeratins CK-1 and CK-6 and forhair and nail cytokeratin, AE-13 (Weiss et al., 1984;Fuchs and Byrne, 1994) was also found in the mammarytumors from the WAP-CR-1 transgenic mice. Theseresults demonstrate that overexpression of CR-1 duringpregnancy and lactation can lead to the development ofmammary tumors in multiparous mice and that CR-1may be a significant mediator of some of the oncologicaleffects of an activated canonical Wnt signaling pathwayin the mammary gland.

Expression of Cripto-1 in human carcinomas andpremalignant lesions

Expression of CR-1 mRNA and/or immunoreactiveprotein has been demonstrated to occur with highfrequency in colorectal, breast, ovarian and gastriccancers in different studies that have examined arelevant number of tumor specimens (Kuniyasu et al.,1991; Saeki et al., 1992, 1994a, b; Qi et al., 1994;Stromberg et al., 1994; Normanno et al., 1995; Panicoet al., 1996; Niikura et al., 1997; De Angelis et al., 1999;

D’Antonio et al., 2002). Expression of CR-1 in normaltissues has been examined in some of these studies. CR-1protein is usually expressed with low frequency and atlow levels in normal mucosae, whereas an increase inCR-1 expression has been observed in the normalmucosa adjacent to either colon or breast carcinoma(Saeki et al., 1992; Panico et al., 1996). Furthermore,CR-1 expression is significantly increased in premalig-nant lesions, such as colon adenomas, intestinalmetaplasia of the gastric mucosa and ductal carcinomain situ (DCIS) of the breast. In this respect, thefrequency of CR-1 expression in the adenomas wasfound to correlate directly with the degree of dysplasia,and with the size and the histological subtype of colonadenomas (Saeki et al., 1994b). CR-1 expression wasalso detected in 62% of normal colon mucosa specimensfrom individuals that belong to families with a highincidence of colorectal carcinomas, whereas only 20% ofcolon mucosa from low-risk patient specimens waspositive for CR-1 (De Angelis et al., 1999). In anadditional study, expression of CR-1 immunoreactivityin normal rectal mucosa adjacent to carcinoma wasassociated with an increase in the incidence of bowelwall penetration, lymph node involvement and arecurrence rate of 100% (Gagliardi et al., 1994).Therefore, the gradual increase in CR-1 expression thatoccurs in the multistage process that evolves fromnormal mucosa to premalignant lesions, and frompremalignant lesions to carcinoma, suggests that CR-1may be involved in the early events of carcinogenesis indifferent tissues. Although no significant correlationshave been found between CR-1 expression and patientprognosis in human carcinomas, several findings suggestthat CR-1 has an important role in tumor progression.For example, a statistically significant higher expressionof CR-1 was found in extra-ovarian specimens ascompared with ovarian primary tumors, in a subset ofpatients for which both type of tissues were available(D’Antonio et al., 2002). This observation suggests thatoverexpression of CR-1 might be associated with anincreased ability to form metastasis. This hypothesis isin agreement with recent in vitro findings discussedabove that have demonstrated that expression of CR-1is associated with increased motility and invasiveness oftumor cells (Wechselberger et al., 2001; Bianco et al.,2003; Normanno et al., 2004; Strizzi et al., 2004).Interestingly, CR-1 is frequently coexpressed with otherEGF-related peptides, such as TGF-b, amphiregulinand heregulin in human breast and mouse epidermalcarcinomas, implying that different growth factorsmight cooperate in supporting the autonomous prolif-eration of cancer cells (Saeki et al., 1992; Qi et al., 1994;Normanno et al., 1995; Panico et al., 1996; De Angeliset al., 1999; D’Antonio et al., 2002; Liu et al., 2003).Finally, expression of CR-1 has been reported in othercarcinoma types, including lung carcinoma (Fontaniniet al., 1998), nonseminomatous testicular tumors(Baldassarre et al., 1997), pancreatic ductal adenocarci-noma (Friess et al., 1994; Tsutsumi et al., 1994), basalcell carcinoma (Welss et al., 2003) and bladdercarcinoma (Byrne et al., 1998).

Figure 4 A representative H&E-stained histological section (20� )of a mammary tumor from the WAP-CR-1 transgenic mice showsaspects of the different lesion types identifiable within the sametumor. Green arrow¼ductal hyperplasia; red arrow¼ tumor cellswith mesenchyme-like morphology; yellow arrow¼ squamousmetaplasia; black arrow¼ epithelial tumor cells in solid or cord-like arrangement


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Cripto-1 and Wnt in stem cell renewal and maintenance

Recently, mouse Cr-1 and human CR-1 have beenidentified as direct target genes in a canonical Wnt/b-catenin/Tcf signaling pathway (Morkel et al., 2003). Cr-1 expression was found to be downregulated in eitherb-catenin�/� or Wnt3�/� mutant mouse embryos,whereas a constitutively active form of b-catenin wasable to upregulate Cr-1 expression during early embryo-genesis. Likewise in Apc�/� Min mice, Cr-1 expressionwas elevated in intestinal adenomas that develop inthese postnatal mice. Reciprocally, in human coloncarcinoma cells that express high levels of CR-1,induction of a dominant-negative Tcf4 abolished CR-1expression. Therefore, in contrast to transient activationof Wnts and Cripto-1 which is obligatory for thepromotion of stem cell self-renewal, pluripotency andfixation of stem cell identity in ES cells and in stemcells from normal adult tissues of the haematopoieticsystem, skin, central nervous system, pancreas,intestine and breast (Beachy et al., 2004; Besser, 2004;Kanatsu-Shinohara et al., 2004; Kleber and Sommer,2004; Nelson and Nusse, 2004; Sato et al., 2004; Zhanget al., 2004; James et al., 2005; Wei et al., 2005),continuous activation of these genes is associated withthe initiation and/or progression of cancer in mouse andhuman tissues such as in the hematopoietic system, skin,colon, stomach, liver, ovary and breast (Polakis, 2000;Salomon et al., 2000). In addition to being a direct targetgene in a canonical Wnt signaling pathway, in Xenopus,the Cripto-1 ortholog, FRL1 functions as a coreceptorthrough the EGF-like domain and the juxtamembrane

region for Wnt11 in conjunction with the frizzledreceptor Xfz7 and glypican-4 to activate a canonicalWnt pathway that is dependent upon b-catenin and thatis necessary for dorsal axis specification during earlyembryogenesis (Tao et al., 2005). Finally, Wnt8c andb-catenin, which are expressed in Hensens node andwhich regulate L/R axis formation in the chick, are ableto directly induce Nodal expression (Rodriguez-Estebanet al., 2001).

In addition to maintaining stem cell identity, othersignificant biological activities that are shared by Wntsand Cripto-1 are their ability to stimulate cell motility,invasion and EMT, as previously discussed in thisreview (Wechselberger et al., 2001; Bianco et al., 2003;Kemler et al., 2004; Strizzi et al., 2004; Endo et al., 2005;Yook et al., 2005). Loss of cell–cell adhesion due to areduction in E-cadherin expression, possibly throughWnt/Cripto-1 crosstalk, may also affect the integrity ofthe stem cell niche since cell adhesion between support-ing niche cells and stem cells is required for stem cellsurvival and asymmetric cell division (Matsui andOkamura, 2005; Yamashita et al., 2005). Reciprocally,a loss of cell–cell adhesion due to a repression ofE-cadherin expression may also be important for themovement of differentiated intestinal and skin epithelialcells from the niche as occurs in the intestinal crypts andin the bulge region of the papillae of the hair follicles. Inaddition, in the intestinal epithelium, expression ofguidance proteins such as, the Wnt target gene EphB3, isalso necessary for directing migration of the Paneth cellsout of and down from the crypts (Batlle et al., 2002;Escaffit et al., 2005).

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Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

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