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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.

SUBMITTER: Arboretto P

PROVIDER: S-EPMC8345935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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New Anti-Nodal Monoclonal Antibodies Targeting the Nodal Pre-Helix Loop Involved in Cripto-1 Binding.

Project description:Nodal is a potent embryonic morphogen belonging to the TGF-β superfamily. Typically, it also binds to the ALK4/ActRIIB receptor complex in the presence of the co-receptor Cripto-1. Nodal expression is physiologically restricted to embryonic tissues and human embryonic stem cells, is absent in normal cells but re-emerges in several human cancers, including melanoma, breast, and colon cancer. Our aim was to obtain mAbs able to recognize Nodal on a major CBR (Cripto-Binding-Region) site and to block the Cripto-1-mediated signalling. To achieve this, antibodies were raised against hNodal(44-67) and mAbs generated by the hybridoma technology. We have selected one mAb, named 3D1, which strongly associates with full-length rhNodal (KD 1.4 nM) and recognizes the endogenous protein in a panel of human melanoma cell lines by western blot and FACS analyses. 3D1 inhibits the Nodal-Cripto-1 binding and blocks Smad2/3 phosphorylation. Data suggest that inhibition of the Nodal-Cripto-1 axis is a valid therapeutic approach against melanoma and 3D1 is a promising and interesting agent for blocking Nodal-Cripto mediated tumor development. These findings increase the interest for Nodal as both a diagnostic and prognostic marker and as a potential new target for therapeutic intervention.

| S-EPMC4613256 | biostudies-literature

Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.

Project description:The glycosylphosphatidylinositol (GPI)-anchored proteoglycan Cripto binds Nodal and its type I receptor Alk4 to activate Smad2,3 transcription factors, but a role during Nodal precursor processing has not been described. We show that Cripto also binds the proprotein convertases Furin and PACE4 and localizes Nodal processing at the cell surface. When coexpressed as in early embryonic cells, Cripto and uncleaved Nodal already associated during secretion, and a Cripto-interacting region in the Nodal propeptide potentiated the effect of proteolytic maturation on Nodal signalling. Disruption of the trans-Golgi network (TGN) by brefeldin A blocked secretion, but export of Cripto and Nodal to the cell surface was not inhibited, indicating that Nodal is exposed to extracellular convertases before entering the TGN/endosomal system. Density fractionation and antibody uptake experiments showed that Cripto guides the Nodal precursor in detergent-resistant membranes to endocytic microdomains marked by GFP-Flotillin. We conclude that Nodal processing and endocytosis are coupled in signal-receiving cells.

| S-EPMC2567404 | biostudies-literature

Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids.

Project description:Cancer is a complex multifactorial disease that results from alterations in many physiological and biochemical functions. Over the last few decades, it has become clear that cancer cells can acquire multidrug resistance to conventional anticancer drugs, resulting in tumor relapse. Thus, there is a continuous need to discover new and effective anticancer drugs. Natural products from plants have served as a primary source of cancer drugs and continue to provide new plant-derived anticancer drugs. The present review describes plant-based alkaloids, which have been reported as active or potentially active in cancer treatment within the past 4 years (2017-2020), both in preclinical research and/or in clinical trials. In addition, recent insights into the possible molecular mechanism of action of alkaloid prodrugs naturally present in plants are also highlighted.

| S-EPMC8716855 | biostudies-literature

Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling.

Project description:The signaling pathway for Nodal, a ligand of the TGF? superfamily, plays a central role in regulating the differentiation and/or maintenance of stem cell types that can be derived from the peri-implantation mouse embryo. Extra-embryonic endoderm stem (XEN) cells resemble the primitive endoderm of the blastocyst, which normally gives rise to the parietal and the visceral endoderm in vivo, but XEN cells do not contribute efficiently to the visceral endoderm in chimeric embryos. We have found that XEN cells treated with Nodal or Cripto (Tdgf1), an EGF-CFC co-receptor for Nodal, display upregulation of markers for visceral endoderm as well as anterior visceral endoderm (AVE), and can contribute to visceral endoderm and AVE in chimeric embryos. In culture, XEN cells do not express Cripto, but do express the related EGF-CFC co-receptor Cryptic (Cfc1), and require Cryptic for Nodal signaling. Notably, the response to Nodal is inhibited by the Alk4/Alk5/Alk7 inhibitor SB431542, but the response to Cripto is unaffected, suggesting that the activity of Cripto is at least partially independent of type I receptor kinase activity. Gene set enrichment analysis of genome-wide expression signatures generated from XEN cells under these treatment conditions confirmed the differing responses of Nodal- and Cripto-treated XEN cells to SB431542. Our findings define distinct pathways for Nodal and Cripto in the differentiation of visceral endoderm and AVE from XEN cells and provide new insights into the specification of these cell types in vivo.

| S-EPMC3160087 | biostudies-literature

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Project description:This brief report summarizes Dr. Pao's talk at the 54th Annual Meeting of the Thomas L. Petty Aspen Lung Conference, in Aspen, Colorado, on June 11, 2011. In this talk, Dr. Pao discussed three main topics: (1) DETECT (DNA Evaluation of Tumors for Enhanced Cancer Treatment), (2) MyCancerGenome.org (web-based decision support), and (3) DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment).

| S-EPMC3359104 | biostudies-literature

New perspectives on targeted therapy in ovarian cancer.

Project description:Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose) inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer.

| S-EPMC4324539 | biostudies-literature

Protein kinase C: an attractive target for cancer therapy.

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| S-EPMC3756376 | biostudies-literature

A GPI processing phospholipase A2, PGAP6, modulates Nodal signaling in embryos by shedding CRIPTO.

Project description:Glycosylphosphatidylinositol-anchored proteins (GPI-APs) can be shed from the cell membrane by GPI cleavage. In this study, we report a novel GPI-processing enzyme, termed post-glycosylphosphatidylinositol attachment to proteins 6 (PGAP6), which is a GPI-specific phospholipase A2 mainly localized at the cell surface. CRIPTO, a GPI-AP, which plays critical roles in early embryonic development by acting as a Nodal coreceptor, is a highly sensitive substrate of PGAP6, whereas CRYPTIC, a close homologue of CRIPTO, is not sensitive. CRIPTO processed by PGAP6 was released as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D. CRIPTO shed by PGAP6 was active as a coreceptor in Nodal signaling, whereas cell-associated CRIPTO activity was reduced when PGAP6 was expressed. Homozygous Pgap6 knockout mice showed defects in early embryonic development, particularly in the formation of the anterior-posterior axis, which are common features with Cripto knockout embryos. These results suggest PGAP6 plays a critical role in Nodal signaling modulation through CRIPTO shedding.

| S-EPMC5147002 | biostudies-literature

Cripto promotes A-P axis specification independently of its stimulatory effect on Nodal autoinduction.

Project description:The EGF-CFC gene cripto governs anterior-posterior (A-P) axis specification in the vertebrate embryo. Existing models suggest that Cripto facilitates binding of Nodal to an ActRII-activin-like kinase (ALK) 4 receptor complex. Cripto also has a crucial function in cellular transformation that is independent of Nodal and ALK4. However, how ALK4-independent Cripto pathways function in vivo has remained unclear. We have generated cripto mutants carrying the amino acid substitution F78A, which blocks the Nodal-ALK4-Smad2 signaling both in embryonic stem cells and cell-based assays. In cripto(F78A/F78A) mouse embryos, Nodal fails to expand its own expression domain and that of cripto, indicating that F78 is essential in vivo to stimulate Smad-dependent Nodal autoinduction. In sharp contrast to cripto-null mutants, cripto(F78A/F78A) embryos establish an A-P axis and initiate gastrulation movements. Our findings provide in vivo evidence that Cripto is required in the Nodal-Smad2 pathway to activate an autoinductive feedback loop, whereas it can promote A-P axis formation and initiate gastrulation movements independently of its stimulatory effect on the canonical Nodal-ALK4-Smad2 signaling pathway.

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