MicroRNAs and exosomes: promising new biomarkers in acute myeloid leukemias?

Despite advances in understanding of carcinogenesis and of treatment of acute myeloid leukemia, this neoplasm still has a lethality of at least 30%. The search for biomarkers that can predict the response to treatment in the early stages of the disease is still necessary. In recent years, a new form of cellular communication between tumor and non-neoplastic cells has been discovered: the exchange of information through extracellular vesicles. These are small vesicles released by membrane-coated cells that carry proteins, lipids, messenger RNAs, microRNA and DNA, which can be internalized and promote biological changes in target cells. Exosomes are qualified as a type of extracellular vesicle and, in tumors, carry immunoinhibitory signals that promote the escape of immune control. Recent studies have showed their involvement in communication with the cells of the tumor microenvironment and with chemoresistance in several tumors. To date, there is no information about immunoregulatory microRNAs transported by exosomes and their correlation with clinical evolution during chemotherapy for acute myeloid leukemia. Knowledge about immunomodulatory microRNAs obtained by leukemic cells and transported by exosomes can direct us towards the design of new diagnostic and treatment tools in this type of leukemia.

MicroRNAs and exosomes: promising new biomarkers in acute myeloid leukemias?

ABSTRACT Despite advances in understanding of carcinogenesis and of treatment of acute myeloid leukemia, this neoplasm still has a lethality of at least 30%. The search for biomarkers that can predict the response to treatment in the early stages of the disease is still necessary. In recent years, a new form of cellular communication between tumor and non-neoplastic cells has been discovered: the exchange of information through extracellular vesicles. These are small vesicles released by membrane-coated cells that carry proteins, lipids, messenger RNAs, microRNA and DNA, which can be internalized and promote biological changes in target cells. Exosomes are qualified as a type of extracellular vesicle and, in tumors, carry immunoinhibitory signals that promote the escape of immune control. Recent studies have showed their involvement in communication with the cells of the tumor microenvironment and with chemoresistance in several tumors. To date, there is no information about immunoregulatory microRNAs transported by exosomes and their correlation with clinical evolution during chemotherapy for acute myeloid leukemia. Knowledge about immunomodulatory microRNAs obtained by leukemic cells and transported by exosomes can direct us towards the design of new diagnostic and treatment tools in this type of leukemia.

Altered Expression of PRKX, WNT3 and WNT16 in Human Nodular Basal Cell Carcinoma.

BACKGROUND/AIM: Nodular and superficial are the most common subtypes of basal cell carcinoma (BCC). Signaling pathways such as Hedgehog (HH) and Wingless (WNT) signaling are associated with BCC phenotypic variation. The aim of the study was to evaluate of the expression profiles of 84 genes related to the WNT and HH signaling pathways in patients with nodular and superficial BCC. MATERIALS AND METHODS: A total of 58 BCCs and 13 samples of normal skin were evaluated by quantitative real-time polymerase chain reaction (qPCR) to detect the gene-expression profile. RESULTS: qPCR array showed segregation in BCC subtypes compared to healthy skin. PRKX, WNT3 and WNT16 were significantly (p<0.05) altered: PRKX was up-regulated, and WNT3 and WNT16 were down-regulated in nodular BCC. CONCLUSION: PRKX, WNT3 and WNT16 genes, belonging to the WNT signaling pathway, are involved in the tumorigenic process of nodular BCC.

SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although several clinical characteristics can be associated with worse prognosis, more robust biological markers still remains uncovered. SMYD2, a member of SMYD protein family, regulates the activity of several proteins through methylation. In this study, we performed quantitative real time PCR to compare the expression of SMYD2 in 83 pediatric ALL patients and non-neoplastic bone marrow samples (BMS). The study revealed that SMYD2 expression is altered in ALL BMS and its high expression was correlated with a bad prognosis. Moreover, we also revealed that SMYD2 expression level significantly decreases in patients that respond to chemotherapy treatment.

Avaliação do perfil de metilação da região promotora de genes em hepatoblastoma / Gene promoter hypermethylation pattern in patients with hepatoblastoma

O hepatoblastoma é o tumor maligno hepático mais comum em crianças, entretanto constitui apenas 1% do total de neoplasias na infância. Sua baixa freqüência, portanto, dificulta a realização de estudos clínicos e pesquisas de novas estratégias terapêuticas. Os fatores prognósticos relevantes para essa doença estão relacionados, quase exclusivamente, ao grau de ressecabilidade tumoral, não existindo, até o momento, dados suficientes para a inclusão de fatores biológicos na estratificação dos pacientes por grupos de risco. Estudos de microarray que compararam o perfil de expressão de hepatoblastomas com tecido hepático normal, mostraram que grande parte dos genes diferencialmente expressos estava, de fato, hipoexpressa, o que pode, hipoteticamente, sugerir a interferência de mecanismos de silenciamento genético como, por exemplo, a hipermetilação do DNA. A técnica de MSP-Q foi utilizada na avaliação do perfil de metilação de 25 genes em 20 amostras parafinadas de hepatoblastomas. Observou-se a presença de hipermetilação de ilhas CpG em mais de 25% das amostras para 8 genes (APC, CCND2, CDH1, COX2, HIN1, MT1G, RASSF1A e SOCS1). A análise dos dados clínicos em conjunto com a pesquisa de metilação mostrou não haver correlação entre a presença de metilação em APC, RASSF1A, SOCS1 e MT1G e variáveis clínicas clássicas. No entanto, tanto a presença quanto o nível de metilação de MT1G apresentou uma correlação inversa com as taxas de sobrevida globais dos pacientes em questão. À saber, este foi o primeiro relato de hipermetilação da região promotora de MT1G em hepatoblastomas e de sua associação com o prognóstico da doença.

Hepatoblastoma is the most common malignant liver tumor in childhood. Nevertheless, it comprises 1% of all cancers in this age group. Because its low frequency, there are few clinical trials and new drugs research. Few prognostic factors were related to hepatoblastoma. Most of them are related to resectability. Microarray studies comparing different expression patterns in hepatoblastoma samples and normal liver tissue show that most of differentially expressed genes are hipoexpressed in tumors. Aberrant DNA hypermethylation might be the cause of this gene silence or hipoexpression. We evaluated the methylation pattern of 25 genes in 20 paraffin-embedded hepatoblastoma specimens by MSP-Q. DNA hypermethylation of CpG island in more than 25% of samples was observed in 8 genes (APC, CCND2, CDH1, COX2, HIN1, MT1G, RASSF1A and SOCS1). The statistical analysis of clinical data and methylation pattern showed that there are no correlation between APC, RASSF1A, SOCS1 and MT1G methylation and clinical characteristics. Nevertheless, both the methylation positivity and methylation level of MT1G showed inverse correlation with overall survival in these patients. This was the first report of CpG island hypermethylation in MT1G gene in hepatoblastoma and the first study that showed its association with prognosis

Trilateral retinoblastoma.

BACKGROUND: Trilateral retinoblastoma (TRB) is a syndrome consisting of unilateral or bilateral hereditary retinoblastoma (Rb) associated with an intracranial neuroblastic tumor. Although its incidence is low, the prognosis is very poor. This article reports four cases of TRB and discusses the role of neuroimaging screening for early detection. PROCEDURE: From January 1986 to December 2003, 470 children with Rb were admitted to the Pediatrics and Ophthalmology Departments, A C Camargo Hospital, São Paulo, Brazil. RESULTS: There were four patients with pineoblastoma, two of whom had a positive familial history. The age at diagnosis of Rb was 4, 6, 10, and 24 months while the age of diagnosis of TRB was 10, 25, 57, and 72 months. One patient presented TRB at initial diagnosis of Rb. Three patients had bilateral disease and all of them had one eye enucleated, followed by chemotherapy and/or external beam radiation therapy (EBRT). One child with unilateral disease was only submitted to enucleation. In spite of intensive treatment, all patients died with progressive disease within 7, 8, 12, and 12 months after diagnosis of TRB. CONCLUSIONS: Early diagnosis as well as new therapeutic approaches are needed to achieve better results.

Bilateral renal metastases from osteosarcoma: A case report and review of the literature.

Improvements in multimodal therapy for osteosarcoma (OS) have increased event-free and overall survival. But have also led to a greater number of recurrences in uncommon sites. We report a young adult with OS who developed late bilateral renal relapse. Late recurrences to the kidneys have a more aggressive clinical behavior and poor prognosis documented by 15 cases of OS metastastic to the kidney in the literature. Two of those patients had a long survival after chemotherapy and surgery. This suggests that the disease can be controlled with early detection and treatment.