ReviewThe multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition
Introduction
Tumors may be considered as caricatures of the process of normal embryonic development whereby oncogeny recapitulates ontogeny in an inappropriate spatiotemporal context [1], [2]. Specifically, the subversion and corruption of embryonic signaling pathways such as Wntβ-catenin, Notch/Cbf-1, Hedgehog/Gli and Nodal/CR-1 may be instrumental as drivers in the initiation and/or progression of multiple types of cancer especially if these pathways are operative in CSCs (the cells thought to propagate the tumor) or transit amplifying (TA) progenitor populations [2], [3]. The loss of appropriate genetic or epigenetic regulatory mechanisms that might occur in normal adult somatic tissue stem cells (SCs), TA cells or the surrounding niche cell populations is a likely contributor to the alteration in expression and/or aberrant activation of these embryonic signaling pathways observed in tumors. The consequences of these alterations may then lead to a disruption in the cell-cell communication between different tissue compartments (epithelial and stromal) and a loss in normal tissue architecture as mediated by the processes of EMT and mesenchymal-epithelial transition (MET).
The normal tissue microenvironment also has a significant influence on the suppression, initiation, and progression of tumor cells. For example, the embryonic microenvironment or the adult stem cell niche can reprogram tumor cells to acquire a more normal cellular lineage restriction and to differentiate [4], [5]. Reciprocally, the tumor microenvironment that consists of myeloid suppressor cells, mesenchymal stem cells which are derived from the bone marrow or surrounding cancer-associated fibroblasts (CAFs) can directly or indirectly through secreted factors reprogram SCs and induced-pluripotent stem cells (iPSCs) to acquire properties of CSCs or tumor initiating cells (TICs) [6], [7]. Identification of these factors that are expressed in cancer cells or by the surrounding niche compartment may provide unique drug targets for cancer therapy.
In this review, we discuss the novel biological properties of the embryonic gene CR-1 and the molecular signaling pathways that are regulated by CR-1 which may contribute to its pro-tumorigenic role in various types of cancer. The expression of CR-1 in potential CSCs or TICs suggests that CR-1 coupled with its capacity to facilitate EMT could prove to be an efficacious therapeutic target for the clinical management of malignant disease.
Section snippets
Structure and mechanisms regulating expression of Cripto-1
Cripto-1/TDGF-1 is the original member of the epidermal growth factor (EGF)-Cripto-1-FRL-1-Cryptic (CFC) family of vertebrate signaling molecules. It was initially isolated from human (CR-1) NTERA-2 and mouse (Cr-1) F9 undifferentiated teratocarcinoma cells [8]. Structurally, Cripto-1 is a cell membrane-associated protein containing signal sequences for extracellular secretion, a modified EGF-like domain, a conserved cysteine-rich domain (CFC-motif) and a short hydrophobic carboxy-terminus,
Role of Cripto-1 in embryogenesis and stem cell maintenance
During embryonic development in the mouse, Cr-1 is initially detected prior to gastrulation, in the inner cell mass and in extraembryonic trophoblast cells in the 4-day blastocyst. The highest Cr-1 expression is detected in epiblast cells undergoing EMT that are migrating and that give rise to the mesoderm and endoderm. Cr-1 and Cryptic signaling are involved in regulating the formation of the primitive streak, patterning of the anterior/posterior axis, specification of mesoderm and endoderm
Cripto-1 interacting partners in cellular signaling
Cripto-1 has multiple binding partners and can modulate a variety of intracellular signaling pathways implicated in embryogenesis and oncogenic transformation (Fig. 1). During embryogenesis, Cripto-1 functions primarily as a coreceptor for the TGF-β family ligands Nodal and growth and differentiation factors (GDFs) 1 and 3, leading to the activation of type I (Alk4/Alk7) serine-threonine kinase receptors and the Activin type II receptor complex, which triggers both the phosphorylation and
Cripto-1: EMT and cancer stem cells
Broadly defined, CSCs are subsets of cells in various tumors that exhibit enhanced tumorigenicity in experimental settings and which are able to reestablish the cellular heterogeneity of the original tumor [61], [62]. CSCs, also known as tumor initiating cells, share several characteristics that have been associated with normal tissue SCs [63]. CSCs were first described in tumors of hematopoietic origin [61], [62] and have now been identified in several types of solid tumors, including cancers
Cripto-1 in transformation, migration, invasion and angiogenesis
Reactivation of certain signaling pathways that are crucial during embryonic development might induce cellular transformation and tumor progression in adult tissues [95]. CR-1 is a typical example of an embryonic gene that is re-expressed during tumorigenesis, functioning as an oncogene and driving cellular proliferation, migration, and invasion, as well as stimulating tumor angiogenesis in vitro and in vivo [30], [96]. CR-1 was first demonstrated to induce cellular transformation in vitro in
Expression of Cripto-1 in human carcinomas and premalignant lesions
As previously discussed in this review, CR-1 is not significantly expressed at significant levels in adult somatic tissues, with the possible exception of the tissue SC compartment, and its re-expression can be observed during oncogenic transformation. In addition to functioning as an oncogene in vitro and in vivo, CR-1 overexpression is detected at the mRNA and protein levels in a wide variety of solid human tumors of non-neuronal origin, including those of the reproductive and
Cripto-1 as a therapeutic target in human cancer
Due to its intimate involvement in processes such as oncogenesis and EMT and minimal expression in adult tissues, CR-1 may be considered as an attractive target for therapeutic intervention. In particular, the association of CR-1 with CSCs is intriguing as this population of cells is intrinsically resistant to standard chemotherapy and radiotherapy [105]. Current strategies that can effectively target and neutralize the potential oncogenic effects of CR-1 include the use of antisense (AS)
Conclusion and perspectives
The abnormal spatial and temporal reexpression of embryonic signaling genes at different stages of tumor development in a variety of human cancers is now a well-recognized fact. In particular, the subversion of these key regulatory genes in CSCs or transit amplifying progenitor cells in human cancers may be extremely deleterious for restricting tumor progression and for preventing the re-emergence of secondary cancer following the use of primary chemo- and/or radiotherapy. Therefore, the
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