The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition

Abstract

Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that can function either in cis (autocrine) or in trans (paracrine). The cell membrane cis form is found in lipid rafts and endosomes while the trans acting form lacking the GPI anchor is soluble. As a member of the epidermal growth factor (EGF)/Cripto-1-FRL-1-Cryptic (CFC) family, CR-1 functions as an obligatory co-receptor for the transforming growth factor-β (TGF-β) family members, Nodal and growth and differentiation factors 1 and 3 (GDF1/3) by activating Alk4/Alk7 signaling pathways that involve Smads 2, 3 and 4. In addition, CR-1 can activate non-Smad-dependent signaling elements such as PI3K, Akt and MAPK. Both of these pathways depend upon the 78 kDa glucose regulated protein (GRP78). Finally, CR-1 can facilitate signaling through the canonical Wnt/β-catenin and Notch/Cbf-1 pathways by functioning as a chaperone protein for LRP5/6 and Notch, respectively. CR-1 is essential for early embryonic development and maintains embryonic stem cell pluripotentiality. CR-1 performs an essential role in the etiology and progression of several types of human tumors where it is expressed in a population of cancer stem cells (CSCs) and facilitates epithelial-mesenchymal transition (EMT). In this context, CR-1 can significantly enhance tumor cell migration, invasion and angiogenesis. Collectively, these facts suggest that CR-1 may be an attractive target in the diagnosis, prognosis and therapy of several types of human cancer.

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.