Role of Cripto-1 in stem cell maintenance and malignant progression

Abstract

Cripto-1 is critical for early embryonic development and, together with its ligand Nodal, has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes, Cripto-1 performs important roles in the formation and progression of several types of human tumors, stimulating cell proliferation, migration, epithelial to mesenchymal transition, and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways, suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells, which may re-express embryonic genes, Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore, the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer, leading to the elimination of undifferentiated stem-like tumor initiating cells.

Figure 1

Schematic diagram of human Cripto-1 protein (amino acids 1-188). Cripto-1 is a GPI-anchored membrane protein that can be cleaved by GPI-PLD and released into the supernatant of the cells as a soluble protein. GPI-PLD: glycosylphosphatidylinositol phospholipase D.

Figure 2

Cross talk of the Nodal/Cripto-1 signaling pathway with Wnt, hypoxia, Notch, Oct-4, and Nanog signaling pathways. Activated Smad-2/Smad-3/Smad-4 complex can bind to specific TGF-β binding elements within the Cripto-1 promoter and regulate Cripto-1 gene expression. Wnt signaling pathway: Cripto-1 is a downstream target gene of the Wnt/β-catenin canonical pathway. Non-canonical Wnt11 can also bind to Cripto-1 and, in a complex with Frizzled 7 (Fzd7) and Glypican-4, induces β-catenin activation. Hypoxia: Hypoxia through HIF-1α directly regulates Cripto-1 expression in ES cells through binding to specific HREs within the Cripto-1 promoter. ES cells specific transcription factors: Oct-4 and Nanog directly regulate Cripto-1 expression in ES cells by binding to the Cripto-1 promoter. Notch signaling pathway: Cripto-1 directly interacts with Notch in ER/Golgi membranes and enhances cleavage of the Notch extracellular domain, potentiating the Notch ligand-activated signal. Nodal–independent Cripto-1 signaling pathway: Cripto-1, independently of Nodal, binds to Glypican-1 and induces activation of c-Src/MAPK/AKT, leading to cell motility and EMT. TBE: TCF/LEF binding elements; HRE: hypoxia binding elements; SBE: Smad binding elements; CBP: CREB binding protein; TCF/LEF: T-cell factor/lymphoid enhancer factor. EMT indicates epithelial to mesenchymal transition; Notch ICD, Notch intracellular domain; ER, endoplasmic reticulum; GDF, Growth and Differentiation Factor; LRP, low-density lipoprotein receptor-related protein; and MAPK, mitogen activated protein kinase.