Papers by Cristina Rangel
Frontiers in Oncology
Cancer is a major public health concern worldwide responsible for high morbidity and mortality ra... more Cancer is a major public health concern worldwide responsible for high morbidity and mortality rates. Alternative therapies have been extensively investigated, and plant-derived compounds have caught the attention of the scientific community due to their chemopreventive and anticancer effects. Sulforaphane (SFN) is one of these naturally occurring agents, and studies have shown that it is able to target a specific cancer cell population displaying stem-like properties, known as cancer stem cells (CSCs). These cells can self-renewal and differentiate to form highly heterogeneous tumor masses. Notably, most of the conventional chemotherapeutic agents cannot target CSCs once they usually exist in a quiescent state and overall, the available cytotoxic drugs focus on highly dividing cells. This is, at least in part, one of the reasons why some oncologic patients relapse after standard therapy. In this review we bring together studies supporting not only the chemopreventive and anticancer...
Journal of Cellular Physiology, 2013
Human Cripto-1 (CR-1) plays an important role in regulating embryonic development while also regu... more Human Cripto-1 (CR-1) plays an important role in regulating embryonic development while also regulating various stages of tumor progression. However, mechanisms that regulate CR-1 expression during embryogenesis and tumorigenesis are still not well defined. In the present study, we investigated the effects of two nuclear receptors, liver receptor homolog (LRH)-1 and germ cell nuclear factor receptor (GCNF) and epigenetic modifications on CR-1 gene expression in NTERA-2 human embryonal carcinoma cells and in breast cancer cells. CR-1 expression in NTERA-2 cells was positively regulated by LRH-1 through direct binding to a DR0 element within the CR-1 promoter, while GCNF strongly suppressed CR-1 expression in these cells. In addition, the CR-1 promoter was unmethylated in NTERA-2 cells, while T47D, ZR75-1 and MCF7 breast cancer cells showed high levels of CR-1 promoter methylation and low CR-1 mRNA and protein expression. Treatment of breast cancer cells with a demethylating agent and histone deacetylase inhibitors reduced methylation of the CR-1 promoter and reactivated CR-1 mRNA and protein expression in these cells, promoting migration and invasion of breast cancer cells. Analysis of a breast cancer tissue array revealed that CR-1 was highly expressed in the majority of human breast tumors, suggesting that CR-1 expression in breast cancer cell lines might not be representative of in vivo expression. Collectively, these findings offer some insight into the transcriptional regulation of CR-1 gene expression and its critical role in the pathogenesis of human cancer.
Growth Factors, 2011
Over the past few decades, our understanding of the embryonic gene Cripto-1 has considerably adva... more 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 of the various signaling pathways modulated by Cripto-1 with a focus on mechanistic insights in our understanding of the biological function of Cripto-1 in eukaryotic cells.
A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER- bre... more A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER- breast cancer has been established. However, mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNg combined with IL1b or TNFa. Given that IFNg is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNg presents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8+ T cells werespatially analyzed in aggressive ER-, TNBC, and HER2+ breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma restricted CD8+ T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8+ T cell penetratio...
Nanomedicine: Nanotechnology, Biology and Medicine, 2021
Radiation induces the generation of Platelet-activating factor receptor (PAF-R) ligands, includin... more Radiation induces the generation of Platelet-activating factor receptor (PAF-R) ligands, including PAF and oxidized phospholipids. Alternatively, PAF is also synthesized by the biosynthetic enzymes lysophosphatidylcholine acyltransferases (LPCATs) which are expressed by tumor cells including melanoma. The activation of PAF-R by PAF and oxidized lipids triggers a survival response protecting tumor cells from radiation-induced cell death, suggesting the involvement of the PAF/PAF-R axis in radioresistance. Here, we investigated the role of LPCATs in the melanoma cell radiotherapy response. LPCAT is a family of four enzymes, LPCAT1-4, and modular nucleic acid nanoparticles (NANPs) allowed for the simultaneous silencing of all four LPCATs. We found that the in vitro simultaneous silencing of all four LPCAT transcripts by NANPs enhanced the therapeutic effects of radiation in melanoma cells by increasing cell death, reducing long-term cell survival, and activating apoptosis. Thus, we propose that NANPs are an effective strategy for improving radiotherapy efficacy in melanomas.
Frontiers in Oncology, 2020
The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact ... more The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of sene...
Clinical Cancer Research, 2018
The master regulators of embryonic development, Cripto and Notch, play key roles in modulating ma... more The master regulators of embryonic development, Cripto and Notch, play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells and in the adult organism particularly within the adult mammary stem cells, which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during mammary gland tumorigenesis to support the tumor-initiating cell/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of breast cancer. To investigate a possible interplay of Cripto and Notch pathways in mammary tumorigenesis and CSCs generation/maintenance, we developed a transgenic mouse model overexpressing Notch and lacking Cripto. We observed considerable tumor supp...
Breast cancer research and treatment, Jan 11, 2016
Cancer has been considered as temporal and spatial aberrations of normal development in tissues. ... more Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumo...
Connective tissue research, 2015
Cripto-1 (CR-1) is a multifunctional embryonic protein that is re-expressed during inflammation, ... more Cripto-1 (CR-1) is a multifunctional embryonic protein that is re-expressed during inflammation, wound repair, and malignant transformation. CR-1 can function either as a tethered co-receptor or shed as a free ligand underpinning its flexible role in cell physiology. CR-1 has been shown to mediate cell growth, migration, invasion, and induce epithelial to mesenchymal transition (EMT). The main signaling pathways mediating CR-1 effects include Nodal-dependent (Smad2/3) and Nodal-independent (Src/p44/42/Akt) signaling transduction pathways. In addition, there are several naturally occurring binding partner proteins (BPPs) for CR-1 that can either agonize or antagonize its bioactivity. We will review the collective role of CR-1 as an extracellular protein, discuss caveats to consider in developing a quantitation assay, define possible mechanistic avenues applicable for drug discovery, and report on our experimental approaches to overcome these problematic issues.
Embryonic Stem Cells - Basic Biology to Bioengineering, 2011
Human Cripto-1 is a member of the Epidermal Growth Factor-Cripto-FRL-1-cryptic (EGF-CFC) family o... more Human Cripto-1 is a member of the Epidermal Growth Factor-Cripto-FRL-1-cryptic (EGF-CFC) family of peptides (Bianco 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;. 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;. 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 . Cripto-1 is also expressed at high levels in approximately 50-80% of different types of human carcinomas, including breast, colon, pancreas, lung and ovary (Bianco 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 . 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 . More importantly, several signaling pathways that are critical for early embryonic development and regulate stem cell www.intechopen.com Embryonic Stem Cells -Basic Biology to Bioengineering
Rajasekhar/Cancer Stem Cells, 2014
Seminars in cancer biology, 2014
Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphospha... more Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that can function either in cis (autocrine) or in trans (paracrine). The cell membrane cis form is found in lipid rafts and endosomes while the trans acting form lacking the GPI anchor is soluble. As a member of the epidermal growth factor (EGF)/Cripto-1-FRL-1-Cryptic (CFC) family, CR-1 functions as an obligatory co-receptor for the transforming growth factor-β (TGF-β) family members, Nodal and growth and differentiation factors 1 and 3 (GDF1/3) by activating Alk4/Alk7 signaling pathways that involve Smads 2, 3 and 4. In addition, CR-1 can activate non-Smad-dependent signaling elements such as PI3K, Akt and MAPK. Both of these pathways depend upon the 78kDa glucose regulated protein (GRP78). Finally, CR-1 can facilitate signaling through the canonical Wnt/β-catenin and Notch/Cbf-1 pathways by functioning as a chaperone protein for LRP5/6 and Notch,...
Journal of Cell Biology, 2009
Nodal and Notch signaling pathways play essential roles in vertebrate development. Through a yeas... more Nodal and Notch signaling pathways play essential roles in vertebrate development. Through a yeast two-hybrid screening, we identified Notch3 as a candidate binding partner of the Nodal coreceptor Cripto-1. Coimmunoprecipitation analysis confirmed the binding of Cripto-1 with all four mammalian Notch receptors. Deletion analyses revealed that the binding of Cripto-1 and Notch1 is mediated by the Cripto-1/FRL-1/Cryptic domain of Cripto-1 and the C-terminal region of epidermal growth factor–like repeats of Notch1. Binding of Cripto-1 to Notch1 occurred mainly in the endoplasmic reticulum–Golgi network. Cripto-1 expression resulted in the recruitment of Notch1 protein into lipid raft microdomains and enhancement of the furin-like protein convertase-mediated proteolytic maturation of Notch1 (S1 cleavage). Enhanced S1 cleavage resulted in the sensitization to ligand-induced activation of Notch signaling. In addition, knockdown of Cripto-1 expression in human and mouse embryonal carcinoma...
Cancer Research, 2010
Human Cripto-1 (CR-1) is a membrane bound protein that belongs to the epidermal growth factor (EG... more Human Cripto-1 (CR-1) is a membrane bound protein that belongs to the epidermal growth factor (EGF)-CFC family. CR-1 plays an important role in regulating embryonic development while also having significant implications in various forms of carcinogenesis. Previous studies have shown that germ cell nuclear factor (GCNF), a member of the nuclear receptor superfamily of transcription factors, inhibits CR-1 expression in human embryonal carcinoma NTERA-2 cells following retinoic acid-induced differentiation due to direct binding to a DR0 element within the CR-1 promoter. In the present study, we investigated the effects on CR-1 gene expression of another member of the nuclear receptor superfamily, liver receptor homologue-1 (LRH-1), which can bind to the same GCNF-binding site within the promoter of several genes. NTERA-2 cells transfected with a CR-1 promoter luciferase reporter vector showed substantially increased CR-1 promoter activity in the presence of LRH-1 and decreased CR-1 pro...
The American Journal of Pathology, 2010
Cripto-1 is critical for early embryonic development and , together with its ligand Nodal , has b... more Cripto-1 is critical for early embryonic development and , together with its ligand Nodal , has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes , Cripto-1 performs important roles in the formation and progression of several types of human tumors , stimulating cell proliferation , migration , epithelial to mesenchymal transition , and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways , suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells , which may re-express embryonic genes , Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore , the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer , leading to the elimination of undifferentiated stem-like tumor initiating cells.
Cancer Research, 2011
Cripto-1 (CR-1) is a cell-membrane protein that is overexpressed in several different types of hu... more Cripto-1 (CR-1) is a cell-membrane protein that is overexpressed in several different types of human carcinomas. We have previously shown that TGFβ1 and Activins can enhance CR-1 expression while BMP2 and BMP4 can inhibit CR-1 expression in NTERA-2 embryonal carcinoma cells and in LS174T colon cancer cells. Nevertheless, there is still a very incomplete picture as to the nature of the epigenetic, transcriptional and hormonal factors that might be involved in regulating Cripto-1 expression under different conditions. Previous studies have demonstrated that activation of p38 MAPK can regulate expression of Nodal, a Cripto-1 ligand, during early embryogenesis and is necessary for the specification of mouse cardiomyocytes from embryonic stem cells, which depends upon a Nodal-dependent signaling pathway involving Cripto-1. We therefore evaluated if activation of p38 MAPK might be involved in regulating Cripto-1 expression and Cripto-1 dependent signaling in human embryonal carcinoma cells. In undifferentiated NTERA-2 and NCCIT embryonal carcinoma cells two p38 MAPK inhibitors PD169316 and SB20358 completely inhibited the basal levels of CR-1 mRNA and protein expression in both cell lines. A JNK inhibitor SP600125 had only minor effects on CR-1 mRNA and protein expression whereas the p44/42 MAPK inhibitor U0126 showed no effect. Transfection of specific siRNA against p38 MAPK was also able to significantly interfere with CR-1 mRNA and protein expression in NTERA2 and NCCIT embryonal carcinoma cells. In contrast, knockdown of p44/42 MAPK or JNK with specific siRNA did not significantly affect CR-1 expression in embryonal carcinoma cells. We therefore evaluated whether CR-1 might trigger activation of p38 MAPK in embryonal carcinoma cells and in mouse mammary epithelial cells. Recombinant CR-1 protein was found to stimulate in a delayed fashion (after 50-60 minutes) p38 MAPK phosphorylation in mouse mammary epithelial cells and in embryonal carcinoma cells suggesting a feed-forward activation loop. Whether p38 MAPK functions in undifferentiated embryonal carcinoma cells to regulate CR-1 expression and/or signaling involving regulation of invasion, migration and epithelial to mesenchymal transition in human embryonal carcinoma cells and in mouse mammary epithelial cells is under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2175. doi:10.1158/1538-7445.AM2011-2175
Cancer Research, 2015
Approximately 10-20% of breast cancer consists of triple-negative tumors, which present the poore... more Approximately 10-20% of breast cancer consists of triple-negative tumors, which present the poorest prognosis among the different subtypes. The triple-negative breast cancer (TNBC) tumors are known to be enriched with stem-like cells that are resistant to standard targeted drugs. Thus, it is extremely important to develop new agents that are non-toxic and specifically efficacious against these cancer stem-like cells (CSCs) that are suggested to be responsible for the initiation and maintenance of tumors. Here, we show that sulforaphane (SFN), a dietary component abundant in broccoli and broccoli sprouts, inhibits cell proliferation and sphere formation of the CSC population in TNBC cells. TNBC stem-like cells were isolated from MDA-MB-231 Luci D3H1human triple negative breast cancer cells using fluorescently activated cell sorting (FACS) analysis. Six week old BalbC/nude mice were purchased from Jackson laboratory and fed with an AIN-96G-purified diet containing no SFN (Harlan Teklad Inc) until the end of experiments. The mice (n = 40) were treated with or without daily i.p. injection of 50mg SFN/kg b.w. for 2 weeks prior to the inoculation with MDA-MB-231 Luci D3H1 cells. The tumor cells were planted into both sides of the 4 th inguinal mammary fat pads. The SFN treatment was continued for 3 additional weeks after the tumor cell xenografts. Our results revealed that the CSC population isolated with CD49f+, CD24-/CD44high showed the ability to form mammoshperes, which is a characteristic of stemness. When these cells were treated with natural dietary constituent SFN at the concentration of 7.5 μM, they lost the property of mammosphere formation in vitro. Furthermore, SFN pre-treated animals (n = 20) exhibited a thirty percent reduction in tumor volume compared with control (saline 0.9%) at day 30 after the tumor cell inoculation. These data indicate that SFN suppresses triple negative mammary tumor formation both in vitro (7.5uM) and in vivo (50mg/kg bw) by targeting a CSC population. Further analysis on gene expression and protein profiles are being performed to elucidate whether stem-related developmental signaling pathways are being modulated by SFN. Citation Format: Nadia P. Castro, Cristina M. Rangel, David Salomon, Karen Saylor, Young S. Kim. Sulforaphane suppresses the growth of triple-negative breast cancer stem-like cells in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2015-912
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Papers by Cristina Rangel