Targeting the embryonic gene Cripto-1 in cancer and beyond

Bianco, Caterina; Salomon, David

doi:10.1517/13543776.2010.530659

Cited by 33 publications

(18 citation statements)

References 70 publications

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“…Cripto functions as an obligatory coreceptor for Nodal, GDF1, and GDF3 but antagonizes activin A and TGF-␤ (33,34,43,(45)(46)(47). The expression of Cripto has been described to be silent in the postnatal situation, except in a few aberrant cases, such as epithelial cancers or melanomas (48). Therefore, the expression of Cripto in myogenic cells is intriguing.…”

Section: Discussionmentioning

confidence: 99%

Cell‐type specific regulation of myostatin signaling

et al. 2011

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The transforming growth factor (TGF)-β family member myostatin is an important regulator of myoblast, adipocyte, and fibroblast growth and differentiation, but the signaling mechanisms remain to be established. We therefore determined the contribution of myostatin type I receptors activin receptor-like kinase-4 (ALK4) and -5 (ALK5) and different coreceptors in C2C12 myoblasts, C3H10T1/2 mesenchymal stem cells, and 3T3-L1 fibroblasts, as well as in primary myoblast and fibroblasts. We performed siRNA-mediated knockdown of each receptor and measured signaling activity using Smad3-dependent luciferase and Smad2 phosphorylation assays with nontargeting siRNA as control. We find that myostatin utilizes ALK4 in myoblasts, whereas it has a preference for ALK5 in nonmyogenic cells. Notably, our results show that coreceptor Cripto is expressed in myoblasts but not in the nonmyogenic cells and that it regulates myostatin activity. More specifically, myostatin requires Cripto in myoblasts, whereas Cripto represses activin activity and TGF-β signaling is Cripto independent. Cripto-mediated myostatin signaling is dependent on both epidermal growth factor (EGF)-like and Cripto-FRL1-cryptic (CFC) domains, whereas activin signaling is solely conferred by the CFC domain. Furthermore, Cripto down-regulation enhances myoblast differentiation, showing its importance in myostatin signaling. Together, our results identify a molecular mechanism that explains the cell-type specific aspects of signaling by myostatin and other TGF-β family members.

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Section: Discussionmentioning

confidence: 99%

Cell‐type specific regulation of myostatin signaling

et al. 2011

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“…Previous reports established that CRIPTO1 is expressed in various tumors, but not in normal tissues (29). We assessed CRIPTO1 expression in 21 resected snap-frozen NSCLC tumor samples by Western blot.…”

Section: Cripto1 Is Expressed In Nsclc Tumors But Not In Cell Linesmentioning

confidence: 95%

“…CRIPTO1 was originally isolated from human undifferentiated NTERA-2 embryonic carcinoma cells and is not expressed in most adult tissues (27,28). High levels of CRIPTO1 expression have been reported in a variety of human carcinomas (29) and associated with poor prognosis in gastric (30), colorectal (31), and breast cancer (32) patients. In vivo studies showed that ectopic CRIPTO1 expression induced epithelial-to-mesenchymal transition (EMT), and MMTV-CRIPTO1 transgenic mice developed hyperplasias and tumors in the mammary gland (33).…”

Section: Introductionmentioning

confidence: 99%

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

Park¹,

Raffeld²,

Moon³

et al. 2014

J. Clin. Invest.

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“…demonstrated that the block of Cripto signaling with an anti-CFC domain antibody determined a strong inhibition of tumor cell growth in vivo [ 34 ]. Ever since, different approaches based on the use of oligonucleotides, vaccines or antibodies have been successfully applied to target Cripto by inhibiting its activity and/or expression in tumors and in neurodegenerative diseases [ 35 ]. Cripto inhibition by different approaches always resulted in inhibition of cancer cell proliferation in vitro and of tumor growth in vivo [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variants Modulating CRIPTO Serum Levels Identified by Genome-Wide Association Study in Cilento Isolates

et al. 2015

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Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5’UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.

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Targeting the embryonic gene Cripto-1 in cancer and beyond

Cited by 33 publications

References 70 publications

Cell‐type specific regulation of myostatin signaling

Cell‐type specific regulation of myostatin signaling

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

Genetic Variants Modulating CRIPTO Serum Levels Identified by Genome-Wide Association Study in Cilento Isolates

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