Understanding the role of Cripto-1 in cancer progression and therapeutic strategies.

During the initial stages of gastrulation during embryonic differentiation and wound healing, Cripto-1 is a critical protein for human growth. The epithelial adhesion molecules' downregulation, the mesenchymal overexpression, and mobile proteins are important mechanisms by which Cripto-1 initiates epithelial to mesenchymal transition (EMT). As a result, the function of Cripto-1 for inducing EMT to increase cell migration is advantageous during embryogenesis; however, it is deleterious during the formation, growth, and malignant tumor metastasis. The majority of malignancies are reported to have elevated levels of Cripto-1. Cripto-1 can modify cancerous cells through its function in EMT, which enables these cells to migrate via the extracellular matrix, bloodstream, and lymphatic vessels, on their way for metastasizing to other organs. The goal of this review is to explain what role Cripto-1 plays in common cancers and to summarize how therapeutic strategies are used to interfere with this molecule to target cancers.

Investigating the role of EGF-CFC gene family in recurrent pregnancy loss through bioinformatics and molecular approaches.

Recurrent pregnancy loss (RPL) is the most common reproductive failure, reaching 1-5% of women throughout their lives, and having unknown etiology in 50% of the cases. In humans, EGF-CFC1 (Epidermal Growth Factors & Cripto/FRL-1/Cryptic) gene family is composed by TDGF1 and CFC1, two developmental genes. The aim of this study was to investigate the role of EGF-CFC on RPL. To this, multiple approaches were performed; we conducted an expression analysis of TDGF1 and CFC1 using publicly available data from Gene Omnibus Expression (GEO), systems biology analyses and functional prediction; and a molecular analysis carried out in a case-control study. Our GEO analysis showed a decrease in TDGF1 expression in the endometrium (p=0.049) and CFC1 expression in placenta (p=0.015) of women with RPL. Network analysis, gene ontology and literature pointed to a strong connection between EGF-CFC1 gene family to pathways that play key roles during pregnancy, including TGF-ß, c-Src/MAPK/AKT, Notch, TNFα, IFNγ and IL-6. A pathogenicity score developed for this gene family showed that the c.-14+1429T>C (rs3806702) variant in the TDGF1 and the p.Arg47Gln (rs201431919) variant in CFC1 gene would be the ones with the highest deleterious effect for RPL. In the case-control study, which involved 149 women with RPL and 159 controls, no statistical difference was observed in the allele and genotype distributions of the variants studied in the two groups. In this study, we performed extensive bioinformatics analysis for biomarker prioritization followed by experimental validation of proposed selected markers. Although there is no statistical difference in the frequencies of these variants between RPL and controls, the expression analysis results suggest that TDGF1 and CFC1 genes might play a role in RPL. In addition, systems biology analyzes raise the hypothesis that genes in other signaling pathways that may be related to RPL as good candidates for future studies.Abbreviations RPL: recurrent pregnancy loss; EGF-CFC1: Epidermal Growth Factors - Cripto/FRL-1; GEO: Gene Omnibus Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes.

In vivo and in vitro study of co-expression of LMP1 and Cripto-1 in nasopharyngeal carcinoma / Estudo in vivo e in vitro da coexpressão de LMP1 e Cripto-1 em carcinoma nasofaríngeo

Abstract Introduction: Nasopharyngeal carcinoma, an epithelial-derived malignant tumor which because of its anatomical location and atypical early symptoms, when diagnosed invasion and metastasis often have occurred. This requires a better understanding of the development mechanism, identifying diagnostic markers, and developing new treatment strategies. Objective: To study the relationship of LMP1 and Cripto-1 in nasopharyngeal carcinoma. Methods: The expression of LMP1 and Cripto-1 in specimens obtained from nasopharyngeal carcinoma patients (n = 42) and nasopharyngitis patients (n = 22) were examined. The expression of LMP1 and Cripto-1 in LMP1-negative and LMP1-positive (CNE1-LMP1) cells were also examined. Results: The expression of LMP1 and Cripto-1 was significantly higher in nasopharyngeal carcinoma than in nasopharyngitis (p < 0.05). Their expression in nasopharyngeal carcinoma with metastasis were significantly higher than that without metastasis (p < 0.05), which was correlated with TNM staging (p < 0.05). High Cripto-1 expression and high proliferation rate were seen in CNE1-LMP1 cells. Conclusions: The expression of LMP1 and Cripto-1 in nasopharyngeal carcinoma is positively related. Their co-expression might contribute to the proliferation and metastasis of nasopharyngeal carcinoma.

Resumo Introdução: O carcinoma nasofaríngeo é um tumor maligno derivado do epitélio de localização anatômica recôndita e sintomas iniciais atípicos; quando diagnosticado, frequentemente invasão e metástases já ocorreram. Isso requer uma melhor compreensão do seu mecanismo de desenvolvimento, identificação dos marcadores diagnósticos e desenvolvimento de novas estratégias de tratamento. Objetivo: Estudar a relação de LMP1 e Cripto-1 no carcinoma nasofaríngeo. Método: A expressão de LMP1 e Cripto-1 em espécimes obtidos de pacientes com carcinoma de nasofaringe (n = 42) e pacientes com nasofaringite (n = 22) foi analisada. A expressão de LMP1 e Cripto-1 em células LMP1-negativas e LMP1-positivas (CNE1-LMP1) também foi analisada. Resultados: A expressão de LMP1 e Cripto-1 foi significantemente maior na presença de carcinoma nasofaríngeo do que na nasofaringite (p < 0,05). Sua expressão em carcinomas com metástase foi significantemente maior do que em casos sem metástase (p < 0,05), o que se correlacionou com o estadiamento TNM (p < 0,05). Uma alta expressão de Cripto-1 e alta taxa de proliferação foram observadas nas células CNE1-LMP1. Conclusões: A expressão de LMP1 e Cripto-1 é positivamente relacionada com carcinoma nasofaríngeo. Sua coexpressão pode ser atribuída à proliferação e metástase do tumor.

Teratocarcinoma-derived growth factor-1 (Cripto-1) is overexpressed in epithelial odontogenic lesions displaying more aggressive behaviour.

PURPOSE: Cripto-1 also known as teratoma-derived growth factor 1 (TDGF-1) belongs to the EGF-CFC family of growth factor-like molecules. Cripto-1 is involved with embryonic development and not expressed in adult tissue, but some tumours are accompanied by reactivation. METHODS: The aim of this study was to evaluate the immunohistochemical expression of Cripto-1 in most common odontogenic cysts and tumours. Thirty ameloblastomas, 30 keratocysts, 30 dentigerous cysts and two ameloblastic carcinomas were evaluated using the polymeric immunoperoxidase technique. Immunohistochemical expressions were analysed by the IRS (immunoreactive score). Statistical analyses were performed by the Kruskal-Wallis and Mann-Whitney tests (p ≤ 0.05). RESULTS: Age ranged from 9 to 75 years old, with a prevalence of females (n = 49/53.3%). The mandible was the most affected anatomical site (n = 69/75.0%). Cripto-1 immunoexpression was observed in all ameloblastoma, keratocyst and ameloblastic carcinoma cases, although nine dentigerous cyst cases (30%) were negative. Expression scores were higher in ameloblastoma, keratocyst and ameloblastic carcinoma cases (median ranging from 8 to 11) when compared with dentigerous cyst cases (median of 2), with a statistically significant difference (p < 0.001). CONCLUSIONS: Cripto-1 is critically important in the progression of several tumours since it is related to significant cell survival and differentiation pathways. The high expression of Cripto-1 in more aggressive odontogenic lesions suggests that this molecule may be involved in the activation of important pathways related to the etiopathogenesis of these lesions.

In vivo and in vitro study of co-expression of LMP1 and Cripto-1 in nasopharyngeal carcinoma.

INTRODUCTION: Nasopharyngeal carcinoma, an epithelial-derived malignant tumor which because of its anatomical location and atypical early symptoms, when diagnosed invasion and metastasis often have occurred. This requires a better understanding of the development mechanism, identifying diagnostic markers, and developing new treatment strategies. OBJECTIVE: To study the relationship of LMP1 and Cripto-1 in nasopharyngeal carcinoma. METHODS: The expression of LMP1 and Cripto-1 in specimens obtained from nasopharyngeal carcinoma patients (n=42) and nasopharyngitis patients (n=22) were examined. The expression of LMP1 and Cripto-1 in LMP1-negative and LMP1-positive (CNE1-LMP1) cells were also examined. RESULTS: The expression of LMP1 and Cripto-1 was significantly higher in nasopharyngeal carcinoma than in nasopharyngitis (p<0.05). Their expression in nasopharyngeal carcinoma with metastasis were significantly higher than that without metastasis (p<0.05), which was correlated with TNM staging (p<0.05). High Cripto-1 expression and high proliferation rate were seen in CNE1-LMP1 cells. CONCLUSIONS: The expression of LMP1 and Cripto-1 in nasopharyngeal carcinoma is positively related. Their co-expression might contribute to the proliferation and metastasis of nasopharyngeal carcinoma.

Nódulo pulmonar solitario por Cryptococcus en paciente HIV positivo. Reporte de un caso / Solitary pulmonary nodule by c ryptoc oc cus in HIV pos itiv e patient. Case repor

Se presenta el caso de un paciente masculino VIH positivo con historia de cefalea y rigidez nucal. Dada su condición clínica el paciente es hospitalizado en sala. La radiografía de tórax es normal y se realiza tomografía de tórax de alta resolución debido a la historia clínica de VIH encontrándose un nódulo pulmonar solitario en el pulmón derecho con márgenes irregulares al cual se realiza biopsia dirigida por tomografía resultando un diagnóstico de micosis pulmonar.

A case of a positive VHI male patient with a history of headache and nuchal stiffness is reported. Gi­ven his clinical condition, the patient is hospitalized in the emergency room. The chest x­ray is nor­mal and a high­resolution chest tomography is performed due to the clinical history of HIV, finding a solitary pulmonary nodule in the right lung with irregular margins to which a biopsy directed by tomo­graphy is performed, resulting in a diagnosis of pulmonary mycosis.

Expression of Nodal, Cripto, SMAD3, phosphorylated SMAD3, and SMAD4 in the proliferative endometrium of women with endometriosis.

BACKGROUND: Nodal is a growth factor of the transforming growth factor ß superfamily that is expressed in high turnover tissues, such as the human endometrium, and in several malignancies. The effects of Nodal are modulated by the coreceptor Cripto and mediated by SMAD proteins. This study evaluated the gene and protein expression of Nodal, Cripto, total and phosphorylated (p) SMAD3, and SMAD4 in the proliferative endometrium of women with and without endometriosis. METHOD: Total RNA was isolated and complementary DNA synthesized from eutopic endometrium of women with (n = 15) and without (n = 12) endometriosis, followed by quantitative real-time polymerase chain reaction (PCR) to evaluate the gene expression of Nodal, Cripto, SMAD3, and SMAD4. Western blot was used to evaluate the protein levels of Nodal and Cripto, and immunohistochemistry was performed to localize SMAD3, pSMAD3, and SMAD4. RESULTS: Although Nodal expression was unchanged in women with endometriosis, real-time PCR indicated lower gene expression of Cripto (fold change 0.27, P < .05) in the endometriosis group. This difference, however, was not maintained at protein expression level as assessed by Western blot. The immunostaining of total SMAD3 was reduced in the endometriosis group (P < .01), but the localization of pSMAD3 and the nuclear staining of SMAD4 were unchanged. CONCLUSION: These findings suggest that the Nodal signaling pathway has subtle changes in the endometrium of women with endometriosis, but this imbalance may not cause functional damage as it seems not to affect the nuclear expression of SMAD4.