New Insights into Cancer Targeted Therapy: Nodal and Cripto-1 as Attractive Candidates

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.

Keywords: Cripto-1; Nodal; biomarker; drug resistance; proliferation; therapeutic targets.

Figure 1

Schematic representation of Nodal/CR-1 signaling pathway in cancer stem cells. CR-1 acts as a cofactor for Nodal to activate downstream SMADs effectors. In the absence of Nodal, CR-1 can also signal in a non-canonical pathway through Frizzled and LRP4/5 complex, activating β-catenin signaling. In addition, CR-1 interacts with Glypican-1 and GRP78, triggering PIK3/AKT activation by Src phosphorylation. In addition, the GPI-specific phospholipase D (GPI-PLD) is able to cleave CR-1, generating a biological active soluble form.

Figure 2

Timeline of the most relevant findings about Nodal and CR-1.