Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood–brain barrier and treatment strategies

Breast cancer (BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis (BM) reported in 17–20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood–brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC(AU)

Serum ADAM metallopeptidase domain 12 as a promising diagnostic biomarker for breast and liver cancer

Background ADAM metallopeptidase domain 12 (ADAM12) is generally upregulated in tissues of various tumors, emerging as a prognostic biomarker. However, the clinical significance of serum ADAM12 in tumors still remains to be fully elucidated. The present study aimed to investigate the expression and prognostic value of serum ADAM12 in tumor patients. Materials and methods Serum samples were collected from healthy doners (HDs; n = 87) and patients (n = 238) with a clinical diagnosis of breast, liver, lung, stomach and esophageal (STES) and thyroid cancer. Serum ADAM12 protein and mRNA expression was detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR), respectively. Receiver–operator characteristic (ROC) analysis was performed to explored the prognostic value of serum ADAM12 expression. Results The expression of serum ADAM12 in breast and liver cancer patients was significantly upregulated compared with HDs. In patients with breast cancer, the levels of serum ADAM12 protein and mRNA were significantly higher in tumor stages than that in HDs (p < 0.05), with AUC value of 0.82. In liver cancer, elevated levels of serum ADAM12 protein were significantly correlated with clinical stage (r = 0.74; p = 6.9e−4) and T stage (r = 0.74, p = 7.6e−4), and attained AUC value of 1. However, the clinical significance of serum ADAM12 expression in lung, STES and thyroid cancer had not been found. Conclusions Serum ADAM12 expression showed high degree of tumor heterogeneity, and may be a valuable noninvasive diagnostic and prognostic biomarker for breast and liver cancer (AU)

Is there a relationship between infertility and fertilin β protein distribution? / ¿Existe relación entre la infertilidad y la distribución de la proteína fertilin β?

Introduction: Fertilin β is a sperm surface protein that can mediate sperm-egg membrane interaction. This study was conducted to determine whether the expression of fertilin β after intrauterine insemination (IUI) in donors with normal parameters after standard semen analysis is related to low success rate or failure of fertilization. Methods: We examined the sperm of 30 male donors who have normal as controls, oligozoospermia, and unexplained infertility as the clinically indication for IUI. Fertilin β has been labeled with the ADAM2 antibody by indirect immunofluorescence (IF) assay. To evaluate the reproducibility of the test, we selected four sperm samples scale of 0 to +++ according to the distribution of fluorescence label. Results: The results were highly correlated with the corrected total cell fluorescence (CTCF) (Rp=0.9972, P<0.05). We suggest that the relationship between infertility and fertilin β may be due to the distribution of this protein on the sperm surface. Male partners of couples with unexplained infertility showed a low distribution of fertilin β by a decrease of the fluorescence signal in the IF labeling (scale of +++ by 7.4±10.32%, P<0.0001, ±SD). Discussion: Abnormal fertilin β function may be a potential mechanism that could lead to fertilization failure. (AU)

Introducción: La fertilinβ es una proteína de la superficie del esperma que puede mediar entre la interacción del espermatozoide y la membrana del óvulo. Este estudio se realizó para determinar si la expresión de fertilinβ después de la inseminación intrauterina (IIU) en donantes con parámetros normales después del análisis estándar de semen está relacionada con una baja tasa de éxito o fracaso de la fertilización. Métodos: Examinamos los espermatozoides de 30 donantes masculinos que tenían controles normales, oligozoospermia e infertilidad inexplicable como indicación clínica de IIU. La fertilinβ ha sido etiquetada con el anticuerpo ADAM2 mediante un ensayo de inmunofluorescencia indirecta (IF). Para evaluar la reproducibilidad de la prueba, seleccionamos cuatro muestras de esperma en una escala de 0 a +++ según la distribución de la etiqueta de fluorescencia. Resultados: Los resultados estuvieron altamente correlacionados con la fluorescencia celular total corregida (Rp=0,9972, p<0,05). Sugerimos que la relación entre la infertilidad y la fertilinβ puede deberse a la distribución de esta proteína en la superficie del esperma. Los compañeros masculinos de parejas con infertilidad inexplicable mostraron una baja distribución de fertilinβ por una disminución de la señal de fluorescencia en el etiquetado IF (escala de +++ en 7,4 ±10,32%, p<0,0001, ±DE). Conclusión: La función anormal de la fertilinβ puede ser un mecanismo potencial que podría conducir al fracaso de la fertilización. (AU)

Disintegrin and metalloproteinases (ADAMs) expression in gastroesophageal reflux disease and in esophageal adenocarcinoma

Background. Clinically useful marker molecules for the progression of gastroesophageal reflux disease and Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) are lacking. Many adenocarcinomas and inflammatory conditions exhibit increased expression of ADAMs, ‘a disintegrin and metalloproteinases’. Methods. We assessed the expression of five ADAMs (9, 10, 12, 17, 19) in three esophageal cell lines (Het-1A, OE19, OE33) by RT-PCR and Western blotting, and in human samples of normal esophagus, esophagitis, BE, Barrett’s dysplasia, and EAC by RT-PCR, and in selected samples by immunohistochemistry. Results. EAC patients showed increased mRNA expression of ADAMs 9, 12, 17 and 19, as compared to controls. At immunohistochemistry, ADAM9 and ADAM10 proteins were increased in EAC. Patient samples also showed increased mRNA expression of ADAM12 in esophagitis, of ADAM9 in BE, and of ADAMs 9, 12 and 19 in Barrett’s dysplasia, as compared to controls. Two EAC cell lines showed increased ADAM9 mRNA. Conclusions. ADAM9 expression is increased in EAC. Its predecessors show increased ADAM9 mRNA expression. The importance of the alterations in ADAM expression for the development of EAC, and their use as marker molecules, warrant further studies (AU)

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Association between ADAM33 S2 and V4 polymorphisms and susceptibility to allergic rhinitis: A meta-analysis

BACKGROUND: It has been reported that ADAM33 (a disintegrin and metalloproteinase domain 33) polymorphisms might be associated with susceptibility to allergic rhinitis (AR). OBJECTIVE: Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarise and clarify the association between ADAM33 S2, V4, T1, T2 and T + 1 polymorphisms and AR risk. Methods/results: A systematic search of studies on the association of ADAM33 polymorphisms with susceptibility to AR was conducted in Pubmed and Embase. A total of five case-control studies with 1251 patients and 1634 controls were included. Meta-analysis indicated an association between the ADAM33 S2 and AR in allele comparison (G/C:OR = 1.40, 95% CI 1.08-1.82, P = 0.012), heterozygote comparison (CG/CC:OR = 1.24, 95% CI 1.04-1.48, P = 0.015), and dominant comparison (CG+GG/CC:OR = 1.39, 95% CI 1.05-1.85, P = 0.023). The meta-analysis also revealed an association between the ADAM33 V4 and AR in allele comparison (G/C:OR = 1.67, 95% CI 1.01-2.75, P = 0.044). However, no association was found between AR and the ADAM33 T1, T2 and T + 1 polymorphisms in any gene model comparison. CONCLUSIONS: This meta-analysis demonstrates that the ADAM33 S2 and V4 polymorphisms confer susceptibility to AR. However, these results should be interpreted with caution due to limited sample and heterogeneity. Large-scale and well-designed studies are needed to validate our findings

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