Browsing by Author "Baltazar, F"
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- Hotspot TERT promoter mutations are rare events in testicular germ cell tumorsPublication . Cárcano, FM; Vidal, DO; van Helvoort Lengert, A; Neto, CS; Queiroz, L; Marques, H; Baltazar, F; da Silva Martinelli, CM; Soares, P; da Silva, EC; Lopes, LF; Reis, RMThe abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at -245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.
- Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomasPublication . Pinheiro, C; Longatto-Filho, A; Scapulatempo, C; Mesquita-Rodrigues, A; Alves, VA; Schmitt, F; Baltazar, FTumour cells are known to be highly glycolytic, thus producing high amounts of lactic acid. Monocarboxylate transporters (MCTs), by promoting the efflux of the accumulating acids, constitute one of the most important mechanisms in the maintenance of tumour intracellular pH. Since data concerning MCT expression in colorectal carcinomas (CRC) are scarce and controversial, the present study aimed to assess the expressions of MCT1, 2, and 4 in a well characterized series of CRC and assess their role in CRC carcinogenesis. CRC samples (126 cases) were analyzed for MCT1, MCT2, and MCT4 immunoexpression and findings correlated with clinico-pathological parameters. Expression of all MCT isoforms in tumour cells was significantly increased when compared to adjacent normal epithelium. Remarkably, there was a significant gain of membrane expression for MCT1 and MCT4 and loss of plasma membrane expression for MCT2 in tumour cells. Plasma membrane expression of MCT1 was directly related to the presence of vascular invasion. This is the larger study on MCT expression in CRC and evaluates for the first time its clinico-pathological significance. The increased expression of these transporters suggests an important role in CRC, which might justify their use, especially MCT1 and MCT4, as targets in CRC drug therapy.
- Rational Identification of a Colorectal Cancer Targeting Peptide through Phage DisplayPublication . Ferreira, D; Silva, AP; Nobrega, FL; Martins, IM; Barbosa-Matos, C; Granja, S; Martins, SF; Baltazar, F; Rodrigues, LRColorectal cancer is frequently diagnosed at an advanced stage due to the absence of early clinical indicators. Hence, the identification of new targeting molecules is crucial for an early detection and development of targeted therapies. This study aimed to identify and characterize novel peptides specific for the colorectal cancer cell line RKO using a phage-displayed peptide library. After four rounds of selection plus a negative step with normal colorectal cells, CCD-841-CoN, there was an obvious phage enrichment that specifically bound to RKO cells. Cell-based enzyme-linked immunosorbent assay (ELISA) was performed to assess the most specific peptides leading to the selection of the peptide sequence CPKSNNGVC. Through fluorescence microscopy and cytometry, the synthetic peptide RKOpep was shown to specifically bind to RKO cells, as well as to other human colorectal cancer cells including Caco-2, HCT 116 and HCT-15, but not to the normal non-cancer cells. Moreover, it was shown that RKOpep specifically targeted human colorectal cancer cell tissues. A bioinformatics analysis suggested that the RKOpep targets the monocarboxylate transporter 1, which has been implicated in colorectal cancer progression and prognosis, proven through gene knockdown approaches and shown by immunocytochemistry co-localization studies. The peptide herein identified can be a potential candidate for targeted therapies for colorectal cancer.
- Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapiesPublication . Martins, SF; Reis, RM; Mesquita-Rodrigues, A; Baltazar, F; Filho, ALColorectal cancer (CRC) is one of the cancer models and most of the carcinogenic steps are presently well understood. Therefore, successful preventive measures are currently used in medical practice. However, CRC is still an important public health problem as it is the third most common cancer and the fourth most frequent cause of cancer death worldwide. Nowadays, pathologic stage is a unique and well-recognized prognostic indicator, however, more accurate indicators of the biologic behavior of CRC are expected to improve the specificity of medical treatment. Angiogenesis plays an important role in the growth and progression of cancer but its role as a prognostic factor is still controversial. Probably the most important clinical implication of tumor angiogenesis is the development of anti-angiogenic therapy. The goal of this review is to critically evaluate the role of angiogenic markers, assessed by either endoglin-related microvessel density or expression of vascular endothelial growth factor family members in the CRC setting and discuss the role of these angiogenic markers in anti-angiogenic therapies.
- Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapiesPublication . Martins, SF; Reis, RM; Rodrigues, AM; Baltazar, F; Filho, ALColorectal cancer (CRC) is one of the cancer models and most of the carcinogenic steps are presently well understood. Therefore, successful preventive measures are currently used in medical practice. However, CRC is still an important public health problem as it is the third most common cancer and the fourth most frequent cause of cancer death worldwide. Nowadays, pathologic stage is a unique and well-recognized prognostic indicator, however, more accurate indicators of the biologic behavior of CRC are expected to improve the specificity of medical treatment. Angiogenesis plays an important role in the growth and progression of cancer but its role as a prognostic factor is still controversial. Probably the most important clinical implication of tumor angiogenesis is the development of anti-angiogenic therapy. The goal of this review is to critically evaluate the role of angiogenic markers, assessed by either endoglin-related microvessel density or expression of vascular endothelial growth factor family members in the CRC setting and discuss the role of these angiogenic markers in anti-angiogenic therapie
- Significance of glycolytic metabolism-related protein expression in colorectal cancer, lymph node and hepatic metastasisPublication . Martins, SF; Amorim, R; Viana-Pereira, M; Pinheiro, C; Costa, RA; Silva, P; Couto, C; Alves, S; Fernandes, S; Vilaça, S; Falcão, J; Marques, H; Pardal, F; Rodrigues, M; Preto, A; Reis, RM; Longatto-Filho, A; Baltazar, FBACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer death worldwide. Most cancer cells display high rates of glycolysis with production of lactic acid, which is then exported to the microenvironment by monocarboxylate transporters (MCTs). The main aim of this study was to evaluate the significance of MCT expression in a comprehensive series of primary CRC cases, lymph node and hepatic metastasis. METHODS: Expressions of MCT1, MCT4, CD147 and GLUT1 were studied in human samples of CRC, lymph node and hepatic metastasis, by immunohistochemistry. RESULTS: All proteins were overexpressed in primary CRC, lymph node and hepatic metastasis, when compared with non-neoplastic tissue, with exception of MCT1 in lymph node and hepatic metastasis. MCT1 and MCT4 expressions were associated with CD147 and GLUT1 in primary CRC. These markers were associated with clinical pathological features, reflecting the putative role of these metabolism-related proteins in the CRC setting. CONCLUSION: These findings provide additional evidence for the pivotal role of MCTs in CRC maintenance and progression, and support the use of MCTs as biomarkers and potential therapeutic targets in primary and metastatic CRC.