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Peter C Gray - One of the best experts on this subject based on the ideXlab platform.

  • A Multidisciplinary Review of the Roles of Cripto in the Scientific Literature Through a Bibliometric Analysis of its Biological Roles.
    Cancers, 2020
    Co-Authors: Elisa Rodrigues Sousa, Sofia Karkampouna, Peter C Gray, Eugenio Zoni, Federico La Manna, Marta De Menna, Marianna Kruithof-de Julio
    Abstract:

    Cripto is a small glycosylphosphatidylinisitol (GPI)-anchored and secreted oncofetal protein that plays important roles in regulating normal physiological processes, including stem cell differentiation, embryonal development, and tissue growth and remodeling, as well as pathological processes such as tumor initiation and progression. Cripto functions as a co-receptor for TGF-β ligands such as Nodal, GDF1, and GDF3. Soluble and secreted forms of Cripto also exhibit growth factor-like activity and activate SRC/MAPK/PI3K/AKT pathways. Glucose-Regulated Protein 78 kDa (GRP78) binds Cripto at the cell surface and has been shown to be required for Cripto signaling via both TGF-β and SRC/MAPK/PI3K/AKT pathways. To provide a comprehensive overview of the scientific literature related to Cripto, we performed, for the first time, a bibliometric analysis of the biological roles of Cripto as reported in the scientific literature covering the last 10 years. We present different fields of knowledge in comprehensive areas of research on Cripto, ranging from basic to translational research, using a keyword-driven approach. Our ultimate aim is to aid the scientific community in conducting targeted research by identifying areas where research has been conducted so far and, perhaps more importantly, where critical knowledge is still missing.

  • Cripto promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma
    The Journal of Pathology, 2018
    Co-Authors: Sofia Karkampouna, Danny Van Der Helm, Peter C Gray, Lanpeng Chen, I Klima, Joel Grosjean, Mark C Burgmans, Arantza Farinasarasqueta, Ewa Snaarjagalska, Deborah Stroka
    Abstract:

    : Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. Cripto (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of Cripto in HCC. We investigated Cripto expression levels in three cohorts of clinical cirrhotic and HCC specimens. We addressed the role of Cripto in hepatic tumourigenesis using Cre-loxP-controlled lentiviral vectors expressing Cripto in cell line-derived xenografts. Responses to standard treatments (sorafenib, doxorubicin) were assessed directly on xenograft-derived ex vivo tumour slices. Cripto-overexpressing patient-derived xenografts were established and used for ex vivo drug response assays. The effects of sorafenib and doxorubicin treatment in combination with a Cripto pathway inhibitor were tested in ex vivo cultures of xenograft models and 3D cultures. Cripto protein was found highly expressed in human cirrhosis and hepatocellular carcinoma specimens but not in those of healthy participants. Stable overexpression of Cripto in human HepG2 cells caused epithelial-to-mesenchymal transition, increased expression of cancer stem cell markers, and enhanced cell proliferation and migration. HepG2-Cripto cells formed tumours when injected into immune-compromised mice, whereas HepG2 cells lacking stable Cripto overexpression did not. High-level Cripto expression in xenograft models was associated with resistance to sorafenib, which could be modulated using a Cripto pathway inhibitor in ex vivo tumour slices. Our data suggest that a subgroup of Cripto-expressing HCC patients may benefit from a combinatorial treatment scheme and that sorafenib resistance may be circumvented by inhibition of the Cripto pathway. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • identification of trophectoderm derived Cripto as an essential mediator of embryo implantation
    Endocrinology, 2018
    Co-Authors: Eran Gershon, Evan Booker, Ron Hadas, Michal Elbaz, Moran Muchnik, Alona Kleinjanelazary, Sharon Karasenti, Olga Genin, Yuval Cinnamon, Peter C Gray
    Abstract:

    Cripto-1 (TDGF1) is a multifunctional signaling factor that stimulates cellular effects, including proliferation, migration, survival, epithelial-to-mesenchymal transition, and angiogenesis, to regulate embryogenesis, tissue homeostasis, and tumorigenesis. Those cell behaviors are also associated with implantation of the embryo into the uterine wall, and this led us to investigate the role of embryo-derived Cripto in embryo attachment and implantation. In this study, we show that Cripto and its signaling mediator GRP78 are uniquely localized to embryo implantation sites. We knocked down Cripto expression specifically in trophoblast cells and found that this resulted in a corresponding decrease in the levels of its downstream signaling mediators, phosphorylated (phospho-)SMAD2, phospho-SRC, phospho-extracellular signal-regulated kinase, and phospho-AKT, which are also known mediators of embryo implantation. We then transplanted Cripto knockdown and control embryos into uteri of pseudopregnant female mice and found that embryos with Cripto-depleted trophoblast cells had dramatically impaired capacity to attach to the uterine wall when compared with controls. This loss of appropriate embryo attachment following Cripto knockdown in trophoblast cells was associated with abnormally enlarged implantation sites that were almost completely devoid of microvessels. A role for Cripto in embryo implantation was further supported by our demonstration that attachment of trophoblast-derived spheroids to endometrial cells in vitro was stimulated by Cripto treatment and diminished by treatment with either of two mechanistically distinct Cripto blocking agents. Collectively, our findings identify Cripto as a novel and critical embryo attachment factor and suggest that modulation of Cripto signaling may have significant therapeutic potential for the treatment of infertility and other related disorders.

  • abstract 3304 targeting Cripto in breast cancer plasticity
    Cancer Research, 2016
    Co-Authors: Peter C Gray, Evan Booker, Berhane M Hagos, Masami Furphy, Benjamin T Spike
    Abstract:

    The ability of cancer cells to adapt to various extrinsic challenges such as nutrient deprivation, hypoxia and chemotherapy may underlie their tumorigenicity as well as their ability to disseminate to distant organs. Therefore, identifying molecular mechanisms that govern such cellular plasticity may be critical to the development of anti-cancer therapies that target situationally defined tumor stem cells in metastasis, resistance, dormancy and recurrence. We considered the GPI-anchored/secreted Cripto protein to be an excellent target in this regard, as it regulates cellular plasticity during normal development including promotion of EMT, the embryonic stem cell state, and reacquisition of the stem cell state in cellular reprogramming. Cripto also regulates tissue specific stem cells including those of the mammary gland as we recently demonstrated. Due to the rarity of tissue stem cells under homeostasis, Cripto protein is generally low or undetectable in normal adult tissues but it is highly expressed in a wide variety of human tumors including breast cancers where its levels correlate with tumor aggressiveness and poor patient outcomes. Furthermore, inhibition of Cripto expression at the transcript level was recently reported to block metastasis in a mouse mammary tumor model. We have used xenograft assays to demonstrate that the requirement for Cripto function during metastasis, and to a lesser extent in primary tumor growth is conserved in human triple negative breast cancer cells. Critically, we demonstrate this through the use of a biologic/recombinant therapeutic protein specifically engineered to target Cripto. This recombinant protein, ALK4L75A-Fc, is comprised of an Fc-domain fused to a mutant extracellular domain of the natural Cripto binding partner and activin/Nodal type I signaling receptor, ALK4. The relatively modest effect of Cripto blockade on bulk primary tumors relative to metastasis and our inability to identify significant inhibitory effects of ALK4L75A-Fc on these cells in standard in vitro assays suggests that Cripto may only be critical for a subset of cancer cells and/or in specific microenvironmental contexts in the course of tumor progression. Consistent with this, we previously reported that Cripto signaling depends on its cell surface interaction with the stress inducible HSP70 family member and ER chaperone, GRP78 (glucose regulated protein, 78 kDa). Stresses including nutrient deprivation and chemotherapy strongly induce GRP78 expression and increase its levels at the cell surface and we find that nutrient deprivation in vitro elicits sensitivity of the MDA-MB-231 breast cancer cell line to inhibition of migration by ALK4L75A-Fc. Together, these results suggest that Cripto/GRP78 signaling promotes cancer cell plasticity and adaptation to microenvironmental challenge and that ALK4L75A-Fc may have therapeutic potential as an inhibitor of tumor cell plasticity. Citation Format: Peter C. Gray, Evan Booker, Berhane Hagos, Masami Furphy, Benjamin T. Spike. Targeting Cripto in breast cancer plasticity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3304.

  • Cripto grp78 modulation of the tgf β pathway in development and oncogenesis
    FEBS Letters, 2012
    Co-Authors: Peter C Gray, Wylie Vale
    Abstract:

    Cripto is a small, GPI-anchored signaling protein that regulates cellular survival, proliferation, differentiation and migration during normal developmental processes and tumorigenesis. Cripto functions as an obligatory co-receptor for the TGF-β ligands Nodal, GDF1 and GDF3 but attenuates signaling of others such as activin-A, activin-B and TGF-β1. Soluble, secreted forms of Cripto also activate Src, ras/raf/MAPK and PI3K/Akt pathways via a mechanism that remains largely obscure. This review describes the biological roles and signaling mechanisms of Cripto, highlighting our identification of the 78 kDa glucose regulated protein (GRP78) as a cell surface receptor/co-factor required for Cripto signaling via both TGF-β and Src/MAPK/PI3K pathways. We discuss emerging evidence indicating that Cripto/GRP78 signaling regulates normal somatic stem cells and their tumorigenic counterparts.

Jonathan A Kelber - One of the best experts on this subject based on the ideXlab platform.

  • Mechanism, function and modulation of oncogenic Cripto signaling
    2020
    Co-Authors: Jonathan A Kelber
    Abstract:

    Cripto is a multifunctional protein with key roles during embryonic development and tumorigenesis. Cripto's oncogenic functions have been linked to its regulation of TGF-[beta] ligand signaling via the Smad2/3 pathway and its growth factor activity via the MAPK/PI3K pathways. Notably, Cripto is required for signaling by certain TGF- [beta] superfamily members such as Nodal, but also antagonizes others such as activin and TGF-[beta]. The opposing effects of Cripto on Nodal and activin signaling seem contradictory, however, since these closely related ligands utilize the same receptors. Chapter one addresses this apparent paradox by demonstrating that Cripto forms analogous receptor complexes with Nodal and activin and functions as a non-competitive activin antagonist. The results show that activin-A and Nodal elicit similar maximal signaling responses in the presence of Cripto that are substantially lower than that of activin-A in the absence of Cripto. In addition, biochemical data reveal complexes containing activin-A, Cripto and both receptor types and show that the assembly of such complexes is competitively inhibited by Nodal. Furthermore, both Nodal and activin-A share the same binding residues on ActRII. Finally, data presented here demonstrate that the ALK4 ECD has distinct and separable binding sites for activin-A and Cripto. Importantly, ALK4 ECD mutants with disrupted activin-A binding can bind and block Cripto effects on both activin-A and Nodal signaling. We recently demonstrated that Cripto forms a cell surface complex with glucose-regulated protein-78 (GRP78). Chapter two provides evidence that shRNA knockdown or immunoneutralization of GRP78 inhibits the ability of Cripto to function as a Nodal co-receptor, an antagonist of activin and TGF-[beta] signaling and an activator of MAPK/PI3K pathways. Disrupting the Cripto/GRP78 complex also prevents Cripto from increasing cellular proliferation, downregulating E- Cadherin, decreasing cell adhesion and promoting mitogenic activin-A and Nodal signaling. The results indicate that GRP78 is a critical mediator of Cripto signaling in human tumor, mammary epithelial and embryonic stem cells and suggest that the Cripto/GRP78 complex plays key roles during normal developmental processes and tumorigenesis. Collectively, the work presented in this dissertation represents seminal advances in understanding the mechanism and function of Cripto-mediated signaling

  • Cripto and its signaling partner grp78 drive the metastatic phenotype in human osteotropic prostate cancer
    Oncogene, 2017
    Co-Authors: Sofia Karkampouna, Lanpeng Chen, Eugenio Zoni, Zoraide Granchi, Esther I Verhoef, F La Manna, Jonathan A Kelber
    Abstract:

    Cripto (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of Cripto correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. Cripto and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced Cripto and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, Cripto or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. Cripto knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for Cripto and GRP78 in PCa metastasis and suggest that targeting Cripto/GRP78 signaling may have significant therapeutic potential.

  • abstract 3035 Cripto grp78 signaling promotes the stem cell phenotype in normal and neoplastic mammary epithelial cells
    Cancer Research, 2014
    Co-Authors: Benjamin T Spike, Jonathan A Kelber, Evan Booker, Madhuri Kalathur, Julia Lipianskaya, Rose Rodewald, Justin La, Marielle He, Tracy Wright, Richard L Klemke
    Abstract:

    Microenvironmental factors are critical regulators of stem cell and tumor cell behavior. However, few stem cell factors have been identified and targeted in breast and other cancers. Using a highly enriched stem cell pool isolated from fetal mammary rudiments and single cell analyses, we have identified the onco-fetal protein Cripto as a potent soluble factor that regulates the mammary stem cell state. Cripto is a GPI-anchored/secreted signaling protein and a known regulator of PI3K/AKT and TGF-beta pathways. Here, we develop a novel Cripto antagonist, ALK4L75A-Fc, which selectively blocks the growth factor-like effects of soluble Cripto. We show that this antagonist promotes the differentiation of mammary stem cells cultured ex vivo while Cripto treatment maintains the stem cell phenotype and yields colonies with enhanced mammary gland reconstitution capacity. We previously discovered that Cripto signaling requires binding to cell surface Glucose Response Protein 78kDa (GRP78). GRP78 is an HSP70 family member that is induced by stresses including hypoxia and glucose deprivation and it is highly expressed in tumors where these conditions prevail. We show here that cell surface GRP78 marks fetal mouse mammary stem cells and a population of bipotent adult mammary epithelial cells that are selectively responsive to soluble Cripto in vitro. GRP78high mammary epithelial cells also harbor substantially higher stem cell activity upon transplantation than GRP78low cells. Consistently, we further show that deletion of GRP78 from adult mammary epithelial cells ex vivo blocks mammary gland reconstitution. Finally, we find that Cripto antagonism with ALK4L75A-Fc inhibits the proliferation of triple negative breast cancer cell lines in vitro and that this antagonist can also inhibit tumor growth in vivo. Since Cripto and GRP78 are both induced by hypoxia and other stressful conditions found in tumors, our data raise the possibility that Cripto/GRP78 signaling may exacerbate breast and other cancers by increasing the number of stem cell-like tumor cells in tumor microenvironments where these conditions predominate. Citation Format: Benjamin T. Spike, Jonathan A. Kelber, Evan Booker, Madhuri Kalathur, Rose Rodewald, Julia Lipianskaya, Justin La, Marielle He, Tracy Wright, Richard Klemke, Geoffrey Wahl, Peter C. Gray. Cripto/GRP78 signaling promotes the stem cell phenotype in normal and neoplastic mammary epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3035. doi:10.1158/1538-7445.AM2014-3035

  • Cripto grp78 signaling maintains fetal and adult mammary stem cells ex vivo
    Stem cell reports, 2014
    Co-Authors: Benjamin T Spike, Jonathan A Kelber, Evan Booker, Madhuri Kalathur, Julia Lipianskaya, Rose Rodewald, Justin La, Marielle He, Tracy Wright, Richard L Klemke
    Abstract:

    Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify Cripto and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a Cripto antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, Cripto treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks Cripto-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the Cripto/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers.

  • Cripto/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo.
    Stem cell reports, 2014
    Co-Authors: Benjamin T Spike, Jonathan A Kelber, Evan Booker, Madhuri Kalathur, Julia Lipianskaya, Rose Rodewald, Justin La, Marielle He, Tracy Wright, Richard L Klemke
    Abstract:

    Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify Cripto and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a Cripto antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, Cripto treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks Cripto-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the Cripto/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers.

Wylie Vale - One of the best experts on this subject based on the ideXlab platform.

  • Cripto grp78 modulation of the tgf β pathway in development and oncogenesis
    FEBS Letters, 2012
    Co-Authors: Peter C Gray, Wylie Vale
    Abstract:

    Cripto is a small, GPI-anchored signaling protein that regulates cellular survival, proliferation, differentiation and migration during normal developmental processes and tumorigenesis. Cripto functions as an obligatory co-receptor for the TGF-β ligands Nodal, GDF1 and GDF3 but attenuates signaling of others such as activin-A, activin-B and TGF-β1. Soluble, secreted forms of Cripto also activate Src, ras/raf/MAPK and PI3K/Akt pathways via a mechanism that remains largely obscure. This review describes the biological roles and signaling mechanisms of Cripto, highlighting our identification of the 78 kDa glucose regulated protein (GRP78) as a cell surface receptor/co-factor required for Cripto signaling via both TGF-β and Src/MAPK/PI3K pathways. We discuss emerging evidence indicating that Cripto/GRP78 signaling regulates normal somatic stem cells and their tumorigenic counterparts.

  • abstract 3493 soluble alk4 extracellular domain antagonizes the cancer stem cell phenotype caused by nodal and Cripto signaling in mammary epithelia
    Cancer Research, 2012
    Co-Authors: Benjamin T Spike, Jonathan A Kelber, Wylie Vale, Evan Booker, Madhuri Kalathur, Julia Lipianskaya, Richard L Klemke, Geoffrey M Wahl, Peter C Gray
    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL We recently determined that a fraction of cells in a highly enriched fetal mammary stem cell pool expresses the oncofetal protein Cripto and its receptor/co-factor GRP78 on their surfaces. Cripto is a GPI-anchored protein important for embryonic stem cell self-renewal and developmental plasticity. It is also selectively overexpressed in multiple human tumors including ∼80% of human breast tumors. Cripto overexpression increases cellular proliferation, invasion and migration in vitro and promotes mammary tumor growth in mice. Cripto functions as an obligatory co-receptor for Smad2/3 activation by the TGF-β superfamily member Nodal but attenuates activin-A and TGF-β1 signaling and the cytostatic effects of these ligands on human mammary epithelial cells. Cripto can be secreted from cells and soluble forms activate Src, ras/raf/MAPK and PI3K/Akt pathways. We recently identified the HSP70 family member GRP78 as a cell surface receptor/co-factor that is required for Cripto signaling via TGF-β and Src/MAPK/PI3K pathways. Here, we developed a soluble and highly specific Cripto antagonist based on the extracellular domain of the Activin/Nodal Type I serine/threonine kinase receptor ALK4 (sALK4-ECD). We tested the ability of this antagonist to block Cripto signaling via TGF-β and Src/MAPK/PI3K pathways in oncogenic and stem cell phenotypes in mammary epithelial cells and breast cancer cell lines. The sALK4-ECD protein dose-dependently and specifically inhibited 125I-Cripto binding to 293T cells transfected with full length ALK4. In addition, sALK4-L75A-Fc blocked 125I-Cripto binding to native human mammary epithelial MCF10A cells. sALK4-ECD inhibited Cripto-dependent Nodal signaling in 293T cells and inhibited Nodal-induced Smad2 phosphorylation in native NCCIT cells. sALK4-ECD also blocked Cripto-induced PI3K activation, cell proliferation and migration in MCF10A cells. Cripto and Nodal signaling had profound effects on MCF10A growth in suspension and mammosphere reseeding capacity that were also inhibited by sALK4-ECD. We evaluated Nodal/Cripto signaling in cancer cell lines and primary fetal mammary stem cells and tested the efficacy of sALK-ECD mediated suppression of Nodal and Cripto effects in vitro and in vivo. These studies were designed to test if Cripto represents a functional cell surface marker of normal stem cells and/or the cells that initiate or perpetuate breast cancers. Our results point to distinct roles for Cripto and Nodal/Cripto signaling in promoting the oncogenic phenotype via activation of Smad2/3 and PI3K pathways, and support a role for Cripto antagonism such as that afforded by sALK4-ECD as a potential therapeutic strategy for the treatment of human disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3493. doi:1538-7445.AM2012-3493

  • Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis
    FEBS Letters, 2012
    Co-Authors: Peter C Gray, Wylie Vale
    Abstract:

    Cripto is a small, GPI-anchored signaling protein that regulates cellular survival, proliferation, differentiation and migration during normal developmental processes and tumorigenesis. Cripto functions as an obligatory co-receptor for the TGF-β ligands Nodal, GDF1 and GDF3 but attenuates signaling of others such as activin-A, activin-B and TGF-β1. Soluble, secreted forms of Cripto also activate Src, ras/raf/MAPK and PI3K/Akt pathways via a mechanism that remains largely obscure. This review describes the biological roles and signaling mechanisms of Cripto, highlighting our identification of the 78 kDa glucose regulated protein (GRP78) as a cell surface receptor/co-factor required for Cripto signaling via both TGF-β and Src/MAPK/PI3K pathways. We discuss emerging evidence indicating that Cripto/GRP78 signaling regulates normal somatic stem cells and their tumorigenic counterparts.

  • abstract 4006 soluble alk4 extracellular domain antagonizes oncogenic Cripto signaling and inhibits tumor growth
    Cancer Research, 2010
    Co-Authors: Benjamin T Spike, Jonathan A Kelber, Wylie Vale, Richard L Klemke, Geoffrey M Wahl, Evan C Booker, Peter C Gray
    Abstract:

    Cripto is a small GPI-anchored glycoprotein that plays key roles during normal development and in tumorigenesis. Cripto is expressed at aberrantly high levels in human tumors and blocking its oncogenic effects on activin/Nodal/TGF-beta, Erk/MAPK and PI3K/Akt pathways represents a promising therapeutic strategy. Cripto functions as a Nodal co-receptor and binds directly to the extracellular domain (ECD) of the activin/Nodal type I receptor ALK4. We have shown that a kinase-deleted ALK4 mutant deficient in activin binding (ALK4-L75A) retains Cripto binding and can block Cripto effects on activin and Nodal signaling. We hypothesized that soluble ALK4-L75A ECD proteins would similarly bind Cripto and disrupt oncogenic Cripto function. To test this, we generated two soluble constructs incorporating the ALK4-L75A ECD, one with a C-terminal His tag (sALK4-L75A-His) and the other consisting of an ALK4-L75A ECD-Fc fusion with an N-terminal FLAG tag (sALK4-L75A-Fc). We expressed the sALK4-L75A-His and sALK4-L75A-Fc proteins in 293T cells and then purified them from conditioned media using Ni-NTA agarose and Protein-A agarose, respectively. The sALK4-L75A-Fc protein dose-dependently inhibited 125I-Cripto binding to 293T cells transfected with full length ALK4. In addition, sALK4-L75A-Fc blocked 125I-Cripto binding to untransfected human mammary epithelial MCF10A cells. In accordance with these binding data, sALK4-L75A-His inhibited Cripto-dependent Nodal signaling in 293T cells and sALK4-L75A-Fc inhibited Nodal-induced Smad2 phosphorylation in human NCCIT cells. sALK4-L75A-His also blocked Cripto-induced PI3K signaling while sALK4-L75A-Fc inhibited Cripto-induced MCF10A cell proliferation. Importantly, we have shown that sALK4-L75A-Fc can also inhibit the growth of tumor xenografts derived from NCCIT cells at doses where no toxicity was observed. Thus, we provide the first evidence that soluble forms of ALK4 inhibit oncogenic Cripto signaling. The efficacy of a soluble ALK4 receptor as an antitumor agent points to the utility of Cripto antagonists in the treatment of human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4006.

  • blockade of Cripto binding to cell surface grp78 inhibits oncogenic Cripto signaling via mapk pi3k and smad2 3 pathways
    Oncogene, 2009
    Co-Authors: Jonathan A Kelber, Wylie Vale, A D Panopoulos, G Shani, E C Booker, J C Belmonte, Peter C Gray
    Abstract:

    Cripto is a developmental oncoprotein that signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Smad2/3 pathways. However, the molecular basis for Cripto coupling to these pathways during embryogenesis and tumorigenesis is not fully understood. In this regard, we recently demonstrated that Cripto forms a cell surface complex with the HSP70 family member glucose-regulated protein-78 (GRP78). Here, we provide novel functional evidence demonstrating that cell surface GRP78 is a necessary mediator of Cripto signaling in human tumor, mammary epithelial and embryonic stem cells. We show that targeted disruption of the cell surface Cripto/GRP78 complex using shRNAs or GRP78 immunoneutralization precludes Cripto activation of MAPK/PI3K pathways and modulation of activin-A, activin-B, Nodal and transforming growth factor-β1 signaling. We further demonstrate that blockade of Cripto binding to cell surface GRP78 prevents Cripto from increasing cellular proliferation, downregulating E-Cadherin, decreasing cell adhesion and promoting pro-proliferative responses to activin-A and Nodal. Thus, disrupting the Cripto/GRP78 binding interface blocks oncogenic Cripto signaling and may have important therapeutic value in the treatment of cancer.

Caterina Bianco - One of the best experts on this subject based on the ideXlab platform.

  • Cripto 1 ablation disrupts alveolar development in the mouse mammary gland through a progesterone receptor mediated pathway
    American Journal of Pathology, 2015
    Co-Authors: Malgorzata Klauzinska, Caterina Bianco, David Mccurdy, Maria Cristina Rangel, Arun Vaidyanath, Nadia P Castro, Michael M Shen, Monica Gonzales, Daniel Bertolette, Robert Callahan
    Abstract:

    Cripto-1, a member of the epidermal growth factor–Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo . Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways.

  • role of Cripto 1 during epithelial to mesenchymal transition in development and cancer
    American Journal of Pathology, 2012
    Co-Authors: Maria Cristina Rangel, Nadia P Castro, David S Salomon, Tadahiro Nagaoka, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Epithelial-to-mesenchymal transition (EMT) is a critical multistep process that converts epithelial cells to more motile and invasive mesenchymal cells, contributing to body patterning and morphogenesis during embryonic development. In addition, both epithelial plasticity and increased motility and invasiveness are essential for the branching morphogenesis that occurs during development of the mammary gland and during tumor formation, allowing cancer cells to escape from the primary tumor. Cripto-1, a member of the epidermal growth factor–Cripto-1/FRL-1/Cryptic (EGF/CFC) gene family, together with the transforming growth factor (TGF)-β family ligand Nodal, regulates both cell movement and EMT during embryonic development. During postnatal development, Cripto-1 regulates the branching morphogenesis of the mouse mammary gland and enhances both the invasive and migratory properties of mammary epithelial cells in vitro. Furthermore, transgenic mouse models have shown that Cripto-1 promotes the formation of mammary tumors that display properties of EMT, including the down-regulation of the cell surface adherens junctional protein E-cadherin and the up-regulation of mesenchymal markers, such as vimentin, N-cadherin, and Snail. Interestingly, Cripto-1 is enriched in a subpopulation of embryonal, melanoma, prostate, and pancreatic cancer cells that possess stem-like characteristics. Therefore, Cripto-1 may play a role during developmental EMT, and it may also be involved in the reprogramming of differentiated tumor cells into cancer stem cells through the induction of an EMT program.

  • an evolving web of signaling networks regulated by Cripto 1
    Growth Factors Journal, 2012
    Co-Authors: Tadahiro Nagaoka, Maria Cristina Rangel, Nadia P Castro, David S Salomon, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Over the past few decades, our understanding of the embryonic gene Cripto-1 has considerably advanced through biochemical, cell biology, and animal studies. Cripto-1 performs key functions during embryonic development, while it dramatically disappears in adult tissues, except possibly in adult tissue stem cells. Cripto-1 is re-expressed in human tumors promoting cell proliferation, migration, invasion, epithelial to mesenchymal transition, and tumor angiogenesis. This diversity of biological effects is dependent upon interaction of Cripto-1 with an extensive array of signaling molecules. In fact, Cripto-1 modulates signaling of transforming growth factor-β family members, including Nodal, GDF-1/-3, Activin, and TGF-β1, activates c-src/MAPK/Protein Kinase B (AKT) pathway in a Glypican-1 and GRP78-dependent manner, and cross-talks with erbB4, Wnt/β-catenin, Notch, Caveolin-1, and Apelin/putative receptor protein related to Angiotensin-type I receptor (APJ) pathways. This article provides an updated survey o...

  • Cripto 1 a common embryonic stem cell and cancer cell marker
    2012
    Co-Authors: Maria Cristina Rangel, Nadia P Castro, David S Salomon, Tadahiro Nagaoka, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Human Cripto-1 has been implicated in embryogenesis and tumorigenesis. During early embryonic development, Cripto-1 functions as a co-receptor for transforming growth factor-β family members, including Nodal/growth differentiation factors 1 and 3, and is essential for mesoderm and endoderm formation and anterior/posterior and left-right axis establishment. In normal adult tissues Cripto-1 is expressed at very low levels, while its expression significantly increases in approximately 50–80% of different types of human carcinomas. Overexpression of Cripto-1 in mouse mammary epithelial cells leads to their transformation in vitro and enhances migration, invasion, branching morphogenesis and epithelial to mesenchymal transition. Transgenic mouse studies have shown that overexpression of Cripto-1 in the mammary gland results in mammary hyperplasias and papillary adenocarcinomas. Furthermore, Cripto-1 is expressed at high levels in different types of human tumors. In conclusion, while during embryogenesis Cripto-1 performs specific and regulatory functions related to cell and tissue patterning, inappropriate expression of Cripto-1 in adult tissues leads to cell transformation and tumor progression.

  • Cripto-1: At the Crossroads of Embryonic Stem Cells and Cancer
    Embryonic Stem Cells - Basic Biology to Bioengineering, 2011
    Co-Authors: Nadia P Castro, Maria Cristina Rangel, David S Salomon, Tadahiro Nagaoka, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Human Cripto-1 is a member of the Epidermal Growth Factor-Cripto-FRL-1-cryptic (EGFCFC) family of peptides (Bianco et al., 2010; de Castro et al., 2010). During early vertebrate development, Cripto-1 functions as a co-receptor for transforming growth factor  (TGF-) ligands, such as Nodal and growth and differentiation factor-1 and -3 (GDF-1 and GDF-3), through an heteromeric complex composed of Activin type II and type I (ALK4) serine threonine kinase receptors in the plasma membrane. Genetic studies in zebrafish and mice have demonstrated that Cripto-1/Nodal signaling is essential for the formation of the primitive streak, patterning of the anterior/posterior (A/P) axis, specification of mesoderm and endoderm and establishment of left/right (L/R) asymmetry (Bianco et al., 2010; de Castro et al., 2010). In adult tissues, Cripto-1 is expressed at low levels in all stages of mammary gland development and its expression increases during pregnancy and lactation. Overexpression of Cripto-1 in mouse mammary epithelial cells leads to their transformation in vitro and can enhance migration, invasion, branching morphogenesis and epithelial to mesenchymal transition (EMT) (Bianco et al., 2010; de Castro et al., 2010). Furthermore, transgenic mouse studies have shown that overexpression of a human Cripto-1 transgene in the mouse mammary gland under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter results in mammary hyperplasias and papillary adenocarcinomas (Wechselberger et al., 2005). Cripto-1 is also expressed at high levels in approximately 5080% of different types of human carcinomas, including breast, colon, pancreas, lung and ovary (Bianco et al., 2010; de Castro et al., 2010). Cripto-1 is therefore an example of an embryonic gene that plays an important role not only during embryogenesis, but is also implicated in malignant progression. Furthermore, Cripto-1 signaling might represent a common signaling pathway shared by embryonic stem cells and cancer cells. Recent studies have shown that Cripto-1 is an important component of critical core pathways that regulate stem cell self-renewal and differentiation (Hough et al., 2009). Chromatin immunoprecipitation (ChiP) analysis has revealed the presence of Oct-4 and Nanog binding sites in the Cripto-1 promoter region, suggesting that Cripto-1 is a direct transcriptional target of Oct-4 and Nanog transcription factors (Loh et al., 2006). More importantly, several signaling pathways that are critical for early embryonic development and regulate stem cell

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  • role of Cripto 1 during epithelial to mesenchymal transition in development and cancer
    American Journal of Pathology, 2012
    Co-Authors: Maria Cristina Rangel, Nadia P Castro, David S Salomon, Tadahiro Nagaoka, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Epithelial-to-mesenchymal transition (EMT) is a critical multistep process that converts epithelial cells to more motile and invasive mesenchymal cells, contributing to body patterning and morphogenesis during embryonic development. In addition, both epithelial plasticity and increased motility and invasiveness are essential for the branching morphogenesis that occurs during development of the mammary gland and during tumor formation, allowing cancer cells to escape from the primary tumor. Cripto-1, a member of the epidermal growth factor–Cripto-1/FRL-1/Cryptic (EGF/CFC) gene family, together with the transforming growth factor (TGF)-β family ligand Nodal, regulates both cell movement and EMT during embryonic development. During postnatal development, Cripto-1 regulates the branching morphogenesis of the mouse mammary gland and enhances both the invasive and migratory properties of mammary epithelial cells in vitro. Furthermore, transgenic mouse models have shown that Cripto-1 promotes the formation of mammary tumors that display properties of EMT, including the down-regulation of the cell surface adherens junctional protein E-cadherin and the up-regulation of mesenchymal markers, such as vimentin, N-cadherin, and Snail. Interestingly, Cripto-1 is enriched in a subpopulation of embryonal, melanoma, prostate, and pancreatic cancer cells that possess stem-like characteristics. Therefore, Cripto-1 may play a role during developmental EMT, and it may also be involved in the reprogramming of differentiated tumor cells into cancer stem cells through the induction of an EMT program.

  • an evolving web of signaling networks regulated by Cripto 1
    Growth Factors Journal, 2012
    Co-Authors: Tadahiro Nagaoka, Maria Cristina Rangel, Nadia P Castro, David S Salomon, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Over the past few decades, our understanding of the embryonic gene Cripto-1 has considerably advanced through biochemical, cell biology, and animal studies. Cripto-1 performs key functions during embryonic development, while it dramatically disappears in adult tissues, except possibly in adult tissue stem cells. Cripto-1 is re-expressed in human tumors promoting cell proliferation, migration, invasion, epithelial to mesenchymal transition, and tumor angiogenesis. This diversity of biological effects is dependent upon interaction of Cripto-1 with an extensive array of signaling molecules. In fact, Cripto-1 modulates signaling of transforming growth factor-β family members, including Nodal, GDF-1/-3, Activin, and TGF-β1, activates c-src/MAPK/Protein Kinase B (AKT) pathway in a Glypican-1 and GRP78-dependent manner, and cross-talks with erbB4, Wnt/β-catenin, Notch, Caveolin-1, and Apelin/putative receptor protein related to Angiotensin-type I receptor (APJ) pathways. This article provides an updated survey o...

  • Cripto 1 a common embryonic stem cell and cancer cell marker
    2012
    Co-Authors: Maria Cristina Rangel, Nadia P Castro, David S Salomon, Tadahiro Nagaoka, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Human Cripto-1 has been implicated in embryogenesis and tumorigenesis. During early embryonic development, Cripto-1 functions as a co-receptor for transforming growth factor-β family members, including Nodal/growth differentiation factors 1 and 3, and is essential for mesoderm and endoderm formation and anterior/posterior and left-right axis establishment. In normal adult tissues Cripto-1 is expressed at very low levels, while its expression significantly increases in approximately 50–80% of different types of human carcinomas. Overexpression of Cripto-1 in mouse mammary epithelial cells leads to their transformation in vitro and enhances migration, invasion, branching morphogenesis and epithelial to mesenchymal transition. Transgenic mouse studies have shown that overexpression of Cripto-1 in the mammary gland results in mammary hyperplasias and papillary adenocarcinomas. Furthermore, Cripto-1 is expressed at high levels in different types of human tumors. In conclusion, while during embryogenesis Cripto-1 performs specific and regulatory functions related to cell and tissue patterning, inappropriate expression of Cripto-1 in adult tissues leads to cell transformation and tumor progression.

  • Cripto-1: At the Crossroads of Embryonic Stem Cells and Cancer
    Embryonic Stem Cells - Basic Biology to Bioengineering, 2011
    Co-Authors: Nadia P Castro, Maria Cristina Rangel, David S Salomon, Tadahiro Nagaoka, Hideaki Karasawa, Caterina Bianco
    Abstract:

    Human Cripto-1 is a member of the Epidermal Growth Factor-Cripto-FRL-1-cryptic (EGFCFC) family of peptides (Bianco et al., 2010; de Castro et al., 2010). During early vertebrate development, Cripto-1 functions as a co-receptor for transforming growth factor  (TGF-) ligands, such as Nodal and growth and differentiation factor-1 and -3 (GDF-1 and GDF-3), through an heteromeric complex composed of Activin type II and type I (ALK4) serine threonine kinase receptors in the plasma membrane. Genetic studies in zebrafish and mice have demonstrated that Cripto-1/Nodal signaling is essential for the formation of the primitive streak, patterning of the anterior/posterior (A/P) axis, specification of mesoderm and endoderm and establishment of left/right (L/R) asymmetry (Bianco et al., 2010; de Castro et al., 2010). In adult tissues, Cripto-1 is expressed at low levels in all stages of mammary gland development and its expression increases during pregnancy and lactation. Overexpression of Cripto-1 in mouse mammary epithelial cells leads to their transformation in vitro and can enhance migration, invasion, branching morphogenesis and epithelial to mesenchymal transition (EMT) (Bianco et al., 2010; de Castro et al., 2010). Furthermore, transgenic mouse studies have shown that overexpression of a human Cripto-1 transgene in the mouse mammary gland under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter results in mammary hyperplasias and papillary adenocarcinomas (Wechselberger et al., 2005). Cripto-1 is also expressed at high levels in approximately 5080% of different types of human carcinomas, including breast, colon, pancreas, lung and ovary (Bianco et al., 2010; de Castro et al., 2010). Cripto-1 is therefore an example of an embryonic gene that plays an important role not only during embryogenesis, but is also implicated in malignant progression. Furthermore, Cripto-1 signaling might represent a common signaling pathway shared by embryonic stem cells and cancer cells. Recent studies have shown that Cripto-1 is an important component of critical core pathways that regulate stem cell self-renewal and differentiation (Hough et al., 2009). Chromatin immunoprecipitation (ChiP) analysis has revealed the presence of Oct-4 and Nanog binding sites in the Cripto-1 promoter region, suggesting that Cripto-1 is a direct transcriptional target of Oct-4 and Nanog transcription factors (Loh et al., 2006). More importantly, several signaling pathways that are critical for early embryonic development and regulate stem cell

  • targeting the embryonic gene Cripto 1 in cancer and beyond
    Expert Opinion on Therapeutic Patents, 2010
    Co-Authors: Caterina Bianco, David S Salomon
    Abstract:

    Importance of the field: Emerging evidence has clearly implicated an inappropriate activation of embryonic regulatory genes during cell transformation in adult tissues. An example of such a case is the embryonic gene Cripto-1. Cripto-1 is critical for embryonic development and is considered a marker of undifferentiated embryonic stem cells. Critpo-1 is expressed at low levels in adult tissues, but is re-expressed at a high frequency in a number of different types of human carcinomas, therefore, representing an attractive therapeutic target in cancer. Area covered in this review: This review surveys different approaches that have been used to target Cripto-1 in cancer as reflected by the relevant patent literature as well as peer-reviewed publications. Potential involvement and targeting of Cripto-1 in neurodegenerative and degenerative muscle diseases are also discussed. What the reader will gain: The reader will gain an overview of different mAbs, vaccines or oligonucleotides antisense targeting Cripto-1...