Abstract
The transforming growth factor beta (TGF-β) signaling is fundamental for correct embryonic development. However, alterations of this pathway have been correlated with oncogenesis, tumor progression and sustaining of cancer stem cells (CSCs). Cripto-1 (CR-1) and Nodal are two embryonic proteins involved in TGF-β signaling. Their expression is almost undetectable in terminally differentiated cells, but they are often re-expressed in tumor cells, especially in CSCs. Moreover, cancer cells that show high levels of CR-1 and/or Nodal display more aggressive phenotypes in vitro, while in vivo their expression correlates with a worse prognosis in several human cancers. The ability to target CSCs still represents an unmet medical need for the complete eradication of certain types of tumors. Given the prognostic role and the selective expression of CR-1 and Nodal on cancer cells, they represent archetypes for targeted therapy. The aim of this review is to clarify the role of CR-1 and Nodal in cancer stem populations and to summarize the current therapeutic strategy to target CSCs using monoclonal antibodies (mAbs) or other molecular tools to interfere with these two proteins.
Highlights
Nodal in cancer stem populations and to summarize the current therapeutic strategy to target cancer stem cells (CSCs) using monoclonal antibodies or other molecular tools to interfere with these two proteins
Nodal ligands bind to cell-surface serine/threonine kinase receptors known as transforming growth factor β (TGF-β) type I, known as Activin receptorlike kinase4/7 (ALK4/7), and type II receptors (ActRIIA/ActRIIB) [6]
The type II receptor phosphorylates and activates the type I receptor which in turn phosphorylates and activates the type II [8]. This activation mediates the exposure of docking site for SMAD Anchor for Receptor Activation (SARA) in the endosomal compartment which recruits receptor-regulated SMAD proteins (R-SMADs) [9]
Summary
The transforming growth factor β (TGF-β) signaling family plays a pivotal role in early vertebrate development, in inflammation and in host immunity [1]. Nodal proteins show a different affinity to TGF-β receptors; it was demonstrated that the presence of binding proteins that act as partners enhances the signal cascade, improving the interactions between Nodal and its receptors. CR-1 can bind Activin in the presence of ActRII/ActRIIB, creating a complex that inhibits Activin-ALK4 interaction and blocking downstream signaling This antagonistic behavior provides proof that CR-1 is involved in the regulation of TGF-β signal transduction and in cellular growth [26]. The activation of these two signaling cascades is sustained by CR-1 interaction with its binding partner Glypican-1 [28] This interaction may occur within plasma membrane lipid raft microdomains that play a key role in the activation of PI3K signaling by facilitating the interaction of tyrosine-protein kinase Src with specific PI3K isoforms [30]. The GPI-specific phospholipase D (GPI-PLD) is able to cleave CR-1, generating a biological active soluble form
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