1. Introduction
Human Cripto-1 is a member of the Epidermal Growth Factor-Cripto-FRL-1-cryptic (EGF-CFC) family of peptides (Bianco et al., 2010; de Castro et al., 2010). During early vertebrate development, Cripto-1 functions as a co-receptor for transforming growth factor β (TGF-β) ligands, such as Nodal and growth and differentiation factor-1 and -3 (GDF-1 and GDF-3), through an heteromeric complex composed of Activin type II and type I (ALK4) serine threonine kinase receptors in the plasma membrane. Genetic studies in zebrafish and mice have demonstrated that Cripto-1/Nodal signaling is essential for the formation of the primitive streak, patterning of the anterior/posterior (A/P) axis, specification of mesoderm and endoderm and establishment of left/right (L/R)asymmetry(Bianco et al., 2010; de Castro et al., 2010). In adult tissues, Cripto-1 is expressed at low levels in all stages of mammary gland development and its expression increases during pregnancy and lactation. Overexpression of Cripto-1 in mouse mammary epithelial cells leads to their transformation
2. The EGF-CFC family
Human Cripto-1 is a member of the EGF-CFC family of peptides identified only in vertebrates, and plays an important role in embryonic development and in tumor progression. The EGF-CFC family includes monkey Cripto-1, mouse Cripto-1 (Cr-1=cfc2), chicken Cripto-1, zebrafish one-eyed pinhead (
Cripto-1 contains several glycosylation sites and the residue Threonin 88 within the EGF-like domain modulates Cripto-1 ability to activate a Nodal-dependent signaling pathway. Cripto-1 can be cleaved from the cell membrane and can be releasedin the supernatant of cells by activity of the enzyme GPI-phospholipase D(GPI-PLD). EGF: epidermal growth factor, CFC: Cripto-FRL-1-Cryptic, GPI: glycosylphosphatidylinositol, Ser: Serine, Asn: Asparagine, Thr: Threonine.
GPI anchoring determines membrane localization of Cripto-1 within lipid rafts microdomains and is required for the paracrine activity of Cripto-1 as a Nodal co-receptor (Bianco et al., 2008; Watanabe et al., 2007b). Removal of the GPI anchor by GPI-PLD generates a soluble form of Cripto-1, which can therefore function both as a cell membrane anchored protein or as a soluble protein (Watanabe et al., 2007a; Watanabe et al., 2007b). In fact, soluble forms of Cripto-1 are biologically active in a number of different
3. Cripto-1 during embryonic development
In the embryonic development EGF-CFC proteins function as co-receptors for the TGF- ligands Nodal, GDF-1 and GDF-3 (Bianco et al., 2010; de Castro et al., 2010 as cited in Yeo et al. 2001; Andersson at al. 2007). Genetic studies in zebrafish and mice have defined an essential role for Nodal that functions through
Cripto-1 is a co-receptor for Nodal, GDF-1 and GDF-3, allowing them to interact with ALK4 (ActRIB). The Cripto-1/Nodal/ALK4/ActRII receptor complex triggers activation and phosphorylation of Smad-2 and Smad-3. Phosphorylated Smad-2 and Smad-3 form a complex with Smad-4 and they translocate into the nucleus. In the nucleus, Smad-2/-3/-4 complex interacts with CREB binding protein (CBP)/p300 and activates transcription of specific target genes. The heat shock protein GRP78 can also enhance Cripto-1/Nodal-dependent signaling pathway, as discussed later in the text. GDF-1/-3: growth and differentiation factor-1/3, GRP78: glucose-regulated protein 78.
With the exception of the developing heart, little if any expression of Cripto-1 can be detected in the embryo after day 8 (Bianco et al., 2010; de Castro et al., 2010 as cited in Dono et al., 1993; Minchiotti et al., 2000). Disruption of Cripto-1 in Cripto-1 -/- embryos is embryonically lethal and results in the formation of embryos that possess a head without a trunk, demonstrating that there is a severe deficiency in embryonic mesoderm and endoderm without a loss of anterior neuroectoderm formation (de Castro et al., 2010 as cited in Ding et al. 1998). Initiation of the primitive heart tube in Cripto-1 -/- mice is severely inhibited due to failure in the development of functional beating cardiomyocytes, as demonstrated by the absence of expression of terminal myocardial differentiation genes (de Castro et al., 2010 as cited in Xu et al., 1998). Cripto-1 -/- embryonic bodies (EB) derived from Cripto-1-/-embryonic stem (ES) cells fail to form beating cardiomyocytes, while they differentiate into neuronal cells. Addition of a Cripto-1 recombinant protein to Cripto-1 -/-EBs during early time points (0–2 days) of differentiationis able to rescue cardiomyocyte differentiation. However, addition of Cripto-1 recombinant protein during later stages of differentiation fails to rescue cardiamyocyte differentiation, suggesting that Cripto-1 ability to promote cardiac differentiation of EB is restricted to an early window of this differentiation program (Minchiotti, 2005, as cited in Parisi et al., 2003).Interestingly, a microarray study revealed that Cripto-1 -/- ES cells had a reduced mRNA expression of the G protein coupled receptor APJ (also known as angiotensin type I-like receptor) and its ligand Apelin, as compared to control wild type ES cells. Gain of function experiments showed that APJ redirects the neural fate of Cripto-1 -/- ES cells and restores the cardiogenic program. Furthermore,comparison of Cripto-1,APJ and Apelinexpression profile in mouse embryo by
3.1. Cripto-1 in embryonic stem cells
Stem cells have the capacity to divide for an undetermined period of time and a potential to develop into many different cell types throughout early life and growth. Stem cells are distinguished from other cell types by two important characteristics. First, they possess the capability to differentiate into mature cells of any particular tissue (pluripotency). Second, they can undergo through numerous cell cycle divisions while maintaining their undifferentiated state (self-renewal). ES cells can be isolated from a 3- to 5-day-old embryo, called blastocyst, and have the potential to give rise to all specialized tissues and organs of a mature organism. Adult stem cells are found in various adult tissues, and function as a reservoirfor cells that are lost during injuryor disease (Bendall et al., 2008). Mouse embryonic stem cells (mES) or human embryonic stem cells (hES) have been very useful in the field of stem cell research. Comparison of gene expression profiles across species has shown that mouse and human ES cells share common highly conserved signaling pathways that regulate self-renewaland pluripotency, including the Cripto-1/Nodal signaling pathway. For example,in addition to Cripto-1, genes such as Oct-4, Lefty, Nodal, Sox-2, Utf-1 (undifferentiated embryonic cell transcription factor-1) andTert (telomerase reverse transcriptase) are highly enriched in both mouse and human ES cells (Wei et al., 2005). Additionally, Cripto-1 has been identified as a pluripotency marker also in primate ES cells together with Oct-4, Nanog, Sox-2, Tert, LeftyA, and Rex-1 (Chang et al., 2010). In 2007 a comparative study of a large and diverse set of hES cell lines assessed the expression pattern of commonly used stem cell markers. All the hES cells analyzed exhibited similar expression profile for several stem cell markers, including the glycolipid stage specific embryonic antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, and the developmentally regulated genes including Nanog,Oct-4,Dnmt3b,Gabrb3, GDF-3 and Cripto-1(Adewumi et al., 2007; Bianco et al., 2010; de Castro et al., 2010). Finally, Cripto-1 has been reported as a direct target gene of stem cell transcription factors (Bianco et al., 2010; de Castro et al., 2010; Hough et al., 2009). For instance, using the ChIP paired-end ditags method, Loh and collaborators mapped the binding sites of the transcription factors Oct-4 and Nanog in the mouse ES cell genome. Cripto-1 promoter was found to include Oct-4 and Nanog binding sites, suggesting that key modulators of stem cell self-renewal and pluripotentiality directly regulate Cripto-1 expression in ES cells(Bianco et al., 2010; de Castro et al., 2010; Loh et al., 2006).
3.1.1. Cross-talk of Cripto-1 with stem cell signature pathways
Several signaling pathways regulate in a coordinate fashion early embryonic development and stem cell proliferation, maintenance and differentiation. Some of these signaling cascades have been shown to cross-talk with Cripto-1 signaling, suggesting a pivotal role played by Cripto-1 in stem cell self-renewal and maintenance. Among these signaling pathways are genes in the Wnt/-cateninsignaling pathway, TGF- family members, the Notch pathway, and hypoxia inducible factor-1 alpha (HIF-1) (Bianco et al., 2010; de Castro et al., 2010). A schematic diagram of the cross-talk of Cripto-1/Nodal signaling with other stem cell signature signaling pathways is shown in figure 3.
Cripto-1 signaling is a downstream target of Oct-4, Nanog, Wnt/β-catenin, Notch and Hypoxia/HIF-1α pathways. Cripto-1 also mediates signaling of TGF-β family members and enhances Notch signaling by facilitation of Notch receptor maturation. TGF-: transforming growth factor-,HIF-1: hypoxia inducible factor-1, GDF-1/-3: growth and differentiation factor-1/-3, BMP-4: bone morphogenetic protein-4, ES cells: embryonic stem cells, mES cells: mouse embryonic stem cells.
Activation of the canonical Wnt
4. Cripto-1 in cancer
Similarities between embryonic development and cellular transformation during oncogenesis have led to the identification of common signaling pathways, suggesting that reactivation of developmental signaling pathways might drive cell transformation and tumor progression in adult tissues (Bianco et al., 2010). Cripto-1 is a typical example of an embryonic gene that is re-expressed in human tumors, promoting cellular proliferation, migration, and tumor angiogenesis (Figure 4).
Cripto-1 is highly expressed in undifferentiated embryonic stem cells and germ cells. Cripto-1 is important for mesoendoderm differentiation of ES cells and its expression is lost upon differentiation of ES cells toward the three germ cell layers. In the adult, Cripto-1 is re-expressed by tumor cells. Green color: no Cripto-1 expression, red color: Cripto-1 expression. ICM: Inner cell mass, ES: embryonic stem cells.
4.1. Cripto-1 oncogenic activities in vitro and in vivo
The first evidence of Cripto-1 oncogenic activity derives from studies demonstrating that Cripto-1 overexpression can induce
4.1.1. Intracellular signaling pathways activated by Cripto-1 during oncogenic transformation
While Cripto-1 functions mostly in a Nodal-dependent manner during embryogenesis, several studies have demonstrated that Cripto-1 induces cellular proliferation, motility, survival and EMT in a Nodal-independent fashion. Following binding to the GPI-linked heparan sulphate proteoglycan Glypican-1, Cripto-1 induces activation and phosphorylation of the cytoplasmic tyrosine kinase c-Src, which in turn activates mitogen-activated protein kinase (MAPK)/Phosphatydil inositol 3’ kinase (PI3K)/Akt signaling pathways (Figure 5) (Bianco et al., 2005b).
Cripto-1 upon binding to Glypican-1 activates MAPK and Akt signaling pathways during tumor progression, enhancing cell proliferation and survival. MAPK and PI3K/Akt pathways can also inhibit GSK-3β leading to activation and stabilization of β-catenin. GRP78 can also enhance Cripto-1 activation of the MAPK/Akt signaling pathways. GRP78: glucose-regulated protein 78, MAPK: mitogen-activated protein kinase, PI3K: phosphatydil inositol 3’ kinase, GSK3 : glycogen synthase kinase 3, TCF/LEF: T-cell factor/lymphoid enhancer factor, RSK: Ribosomal s6 kinase, STAT: signal transducers and activators of transcription.
Activation of the MAPK and PI3K/Akt signaling pathways by Cripto-1 is independent of Nodal and ALK4, since Cripto-1 can enhance phosphorylation of MAPK and Akt in cells lacking ALK4 and/or Nodal expression (Bianco et al., 2002). Furthermore, the tyrosine kinase c-Src is required by Cripto-1 to induce
5. Cripto-1 and Cancer Stem Cells
Cancer stem cells (CSCs), also known as tumor initiating cells, share characteristics associated with embryonic stem cells, specifically the ability to give rise to all cell types within a particular tumor tissue. CSCs were first identified in the hematopoietic system and later they have also been reported in solid cancers, including cancers of the breast, lung, prostate, colon, brain, head and neck, and pancreas (Bianco et al., 2010; de Castro et al., 2010). CSCs represent a distinct population of cancer cells with innate chemo- and radio-resistance and therefore are responsible of tumor relapse (Bianco et al., 2010; de Castro et al., 2010 as cited in Huntly and Gilliland 2010). Moreover, CSCs are capable to self-renew and regenerate the original phenotype of the tumor when implanted into immunodeficient mice (Visvader & Lindeman, 2008). Similarities between embryonic development and cell transformation during oncogenesis have led to the identification of common contributing pathways, suggesting that reactivation of developmental signaling pathways might drive cell transformation and tumor progression in adult tissues (Bianco et al., 2010). Cripto-1 is a typical example of a common gene shared by embryonic cells and cancer cells contributing to early embryogenesis and cancer progression. More importantly, Cripto-1 is enriched in a subpopulation of cancer cells with stem-like characteristics. For instance, Watanabe and collaborators (2010) described a heterogeneous Cripto-1 expression pattern in human embryonal carcinoma (EC) with segregation of these cells into two distinct populations portraying high and low Cripto-1 expression. EC cells are pluripotent stem cells derived from germ cell teratocarcinomas and they represent the malignant counterparts of human ES cells. Interestingly, these two subpopulations showed different gene expression profiles and different
5.1. Cancer stem cells and EMT
During embryogenesis, tumor progression and metastasis, epithelial cells undergo dramatic morphological changes, acquiring mesenchymal properties in a process known as EMT. In the embryo, Cripto-1 is detected at high levels in epiblast cells undergoing EMT, which migrate through the primitive streak, eventually giving rise to the mesoderm and endoderm (Bianco et al., 2005b; Strizzi et al., 2005).In the tumor, the expression of EMT regulators at the tumor periphery is critical for tumor cells to acquire a mesenchymal phenotype that allow them to locally invade and escape from the primary tumor site, leading to the establishment of metastatic lesions(Micalizzi et al., 2010a). Cripto-1 is involved in tumor epithelial cells plasticity and may be an important EMT regulator together with Snail, Slug, Twist, and Six1 (Micalizzi et al., 2010b). It has been shown that mammary gland hyperplasias and tumors derived from MMTV-Cripto-1 transgenic mice express molecular markers and signaling molecules characteristics of EMT, suggesting that Cripto-1 might play an important role in facilitating migration and invasion of tumor cells (Strizzi et al., 2004). These findings might be significant since emerging evidence has suggested a link between stem cellsand EMT (Hollier et al., 2009). In fact, EMT induction in immortalized human mammary epithelial cells resulted in the expression of stem cell markers and increased ability to form mammospheres
6. Cripto-1 as target for cancer therapy
High expression of Cripto-1 in human carcinomas and its enrichment in a stem-like cancer cell subpopulation strongly support Cripto-1 as a promising candidate for therapeutic intervention in cancer. Two different therapeutic approaches have been successfully used to impair Cripto-1 activity in cancer cells, including anti-Cripto-1 antisense (AS) oligonucleotides and neutralizing monoclonal antibodies (Adkins et al., 2003; Hu et al., 2007; Normanno et al., 1996; Normanno et al., 2004b). For instance, a significant growth inhibition
6.1. Cripto-1 as a target for therapy in neurodegenerative and muscle degenerative diseases
Recent findings have demonstrated that Cripto-1 is a key player in the signaling pathway controlling neural induction in ES cells. Parisi and collaborators showed that Cripto-1 negatively regulated neuronal differentiation of ES cells (Parisi et al., 2003). Furthermore, disruption of Cripto-1 expression in mouse ES cells enhances neurogenesis and midbrain dopaminergic differentiation
7. Conclusions
Critical signaling pathways are involved in modulating embryonic stem cell fate and behavior, maintaining a delicate balance between survival and self-renewal signals. Among these ES cell “signature” pathways, Cripto-1 is a critical gene that is used by ES cells. For instance, Cripto-1 is either a downstream target of ES transcription factors and/or signaling pathways or can modulate other ES cell signaling cascades (Fig. 3). Further, deregulation of stem cell self-renewal is probably a requirement for the initiation and formation of CSCsand therefore embryonic stem cell signature genes are also involved in cancer formation. Cripto-1 is indeed an embryonic gene that is re-expressed in an aberrant spatial and temporal manner in a variety of human tumors. Recent evidence has clearly demonstrated that Cripto-1 is expressed by a subset of cancer cells with stem-like characteristics (Watanabe et al., 2010). CSCs are considered to be a major obstacle in the complete eradication of tumors due their innate resistance to conventional therapy and therefore identification of surface markers that might discriminateCSCs from the bulk population of tumor cells is under active investigation. Therefore, Cripto-1 targeting in human tumors might have a major breakthrough in cancer therapy. Several approaches have been used to target Cripto-1 in cancer cells
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