Publications by authors named "Joao Paulo Oliveira-Costa"

13 Publications

  • Page 1 of 1

The Role of the LY294002 - A Non-Selective Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) Pathway- in Cell Survival and Proliferation in Cell Line SCC-25.

Asian Pac J Cancer Prev 2019 Nov 1;20(11):3377-3383. Epub 2019 Nov 1.

Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, University of São Paulo, Brazil.

The activation of PI3K further activates subsequent regulatory pathways, which are activated via AKT phosphorylation. AKT is closely related to the Bcl-2 family, a protein known to be involved in cell survival. AKT also has a relationship with inflammatory and glycolytic mediators. The present work aimed to evaluate the relationship between the PI3K/AKT pathway, cell survival/proliferation, inflammatory mediators and the glycolytic pathway in oral squamous cell carcinoma. All experiments were performed in the SCC25 oral squamous cell carcinoma cell line. In the presence or absence of PI3K pathway inhibitors, we analyzed the protein expression of pAKT and AKT; X-linked inhibitor of apoptosis protein; Bcl-2-associated death promoter; Bcl-2-like protein two inhibitor; cyclooxygenase 1; cyclooxygenase-2; and glycoprotein-associated glucose transporter 1. For the functional characterization of treated or untreated cells, we also performed matrix invasion assays, cell migration assays, and cell proliferation assays. Our results demonstrated that activation of the PI3K/AKT pathway is directly related to members of the Bcl-2 family and GLUT1, but not the inflammatory mediators COX1 and COX2. Our data suggest that the PI3K/AKT pathway is related to cell survival and proliferation in oral squamous cell carcinoma through its interaction with Bcl-2 family members.
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http://dx.doi.org/10.31557/APJCP.2019.20.11.3377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063005PMC
November 2019

Blood-based biomarkers for the diagnosis and monitoring of gliomas.

Neuro Oncol 2018 08;20(9):1155-1161

Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Monitoring patient response to treatment is challenging for most cancers, but it is particularly difficult in glioblastoma multiform, the most common and aggressive form of malignant brain tumor. These tumors exhibit a high degree of heterogeneity which may not be reflected in a biopsy. To determine if the current standard of care is effective, glioma patients are monitored using MRI or CT scans, an effective but sometimes misleading approach due to the phenomenon of pseudoprogression. As such, there is incredible need for a minimally invasive "liquid biopsy" to assist in molecularly characterizing the tumors while also aiding in the identification of true progression in glioblastoma. This review details the status and potential impact for circulating tumor cells, extracellular vesicles, ctDNA, and ctRNA, putative circulating biomarkers found in the blood in glioblastoma patients. As mutation-based therapy becomes more prevalent in gliomas, blood-based analyses may offer a non-invasive method of identifying mutations. The ability to obtain serial "liquid biopsies" will provide unique opportunities to study the evolution of tumors and mechanisms of treatment resistance and monitor for mutational changes in response to therapy.
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http://dx.doi.org/10.1093/neuonc/noy074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071656PMC
August 2018

Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells.

Oncotarget 2015 Aug;6(25):20902-20

Department of Pathology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil.

Oral squamous cell carcinoma (OSCC) is the most common tumor of the oral cavity and has been associated with poor prognosis. Scarce prognostic markers are available for guiding treatment and/or sub-classifying patients. This study aims to identify biomarkers by searching for genes whose expression is increased or decreased during tumor progression (through T1 to T4 stages). Thirty-six samples from all tumor size stages (from T1 to T4) were analyzed using cDNA microarrays. Selected targets were analyzed by immunohistochemistry and in circulating tumor cells by immunofluorescence and Nanostring. Correlation was shown between PD-L1 and tumor size and lymph node metastasis, HOXB9 and tumor size, BLNK and perineural invasion, and between ZNF813 and perineural invasion. PD-L1 positivity was an independent prognostic factor in this cohort (p = 0.044, HH = 0.426). In CTCs from patients with locally advanced OSCC, we found a strong cytoplasmatic expression of PD-L1. PD-L1 is a ligand of PD-1 and is believed to limit T cell activity in inflammatory responses and limit autoimmune diseases. We demonstrated an important role for PD-L1 in primary tumors according to tumor size, and in disease specific survival. Therefore, we could further determine individuals with PD-L1+ CTCs, and possibly follow treatment using CTCs.
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http://dx.doi.org/10.18632/oncotarget.3939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673238PMC
August 2015

BRCA1 and γH2AX as independent prognostic markers in oral squamous cell carcinoma.

Oncoscience 2014 1;1(5):383-91. Epub 2014 Jun 1.

Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.

Oral squamous cell carcinomas (OSCC) are believed to originate from sequential mutations that can develop as a consequence of genetic instability acquired over time. BRCA1 are linked to DNA recombination and repair processes, being of importance for its role in regulation of RAD51 and H2AX (γH2AX). The aim of this study was to investigate the relationship between BRCA1 expression status and evaluate its prognostic impact. We selected from 150 OSCC patients, and evaluated BRCA1 expression in OSCC by immunohistochemistry and qRT-PCR, comparing its expression with homologous recombination markers (RAD51, γH2AX and p53), clinicopathological and survival data. Expression of BRCA1 was observed in 61 cases (43.88%) and was related to tumor size (T stage) (p=0.001), and gender (p=0.017). mRNA from BRCA1 showed a borderline relationship with perineural invasion (p=0.053). BRCA1 [p=0.030; HR: 2.334 (C.I.: 1.087-5.012)], γH2AX [p=0.045; HR: 0.467 (C.I.: 0.222-0.628)] and gender [p=0.001; HR: 10.386 [(C.I.: 2.679-10.623)] were independent prognostic factors for DSS. BRCA1 and γH2AX expression by OSCC cells are associated with reduced overall survival time, independent of other variables in patients, as well as gender, and our findings shed some light about DSB markers in OSCC and its role as prognostic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278309PMC
http://dx.doi.org/10.18632/oncoscience.47DOI Listing
January 2015

CD44+/CD133+ immunophenotype and matrix metalloproteinase-9: Influence on prognosis in early-stage oral squamous cell carcinoma.

Head Neck 2014 Dec 29;36(12):1718-26. Epub 2014 Jan 29.

Vale do Rio Verde University (UninCor), Tres Coraçoes, Minas Gerais, Brazil.

Background: The purpose of this study was to investigate the expression of CD44 and/or CD133 immunophenotypes and the associated effects of matrix metalloproteinase-9 (MMP-9) in early-stage oral squamous cell carcinomas (SCC) to assess their influence on tumor prognosis.

Methods: The following data were derived from 150 patients: age, sex, primary anatomic site, smoking status, alcohol intake, recurrence, metastases, histological classification, treatment, disease-free survival (DFS), and overall survival (OS). Immunohistochemical study of CD44, CD133, and MMP-9 expression was performed on a tissue microarray of 150 paraffin blocks of oral SCCs.

Results: The predominant immunophenotype identified to exhibit a significant correlation with MMP-9 was the CD44+/CD133+. Multivariate analyses identified a significant correlation of OS with surgical treatment and with CD44+/CD133+ immunophenotype.

Conclusion: This investigation demonstrated the prognostic importance of CD44/CD133 expression, which can help improve the prognostic value of surgical treatment for oral SCCs when diagnosed in early stages.
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http://dx.doi.org/10.1002/hed.23527DOI Listing
December 2014

The relationship between lymphatic vascular density and vascular endothelial growth factor A (VEGF-A) expression with clinical-pathological features and survival in pancreatic adenocarcinomas.

Diagn Pathol 2013 Oct 18;8:170. Epub 2013 Oct 18.

Departament of Pathology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil.

Background: Pancreatic cancer is a rare tumor with an extremely low survival rate. Its known risk factors include the chronic use of tobacco and excessive alcohol consumption and the presence of chronic inflammatory diseases, such as pancreatitis and type 2 diabetes. Angiogenesis and lymphangiogenesis, which have been the focus of recent research, are considered prognostic factors for cancer development. Knowing the angiogenic and lymphangiogenic profiles of a tumor may provide new insights for designing treatments according to the different properties of the tumor. The aim of this study was to evaluate the density of blood and lymphatic vessels, and the expression of VEGF-A, in pancreatic adenocarcinomas, as well as the relationship between blood and lymphatic vascular density and the prognostically important clinical-pathological features of pancreatic tumors.

Methods: Paraffin blocks containing tumor samples from 100 patients who were diagnosed with pancreatic cancer between 1990 and 2010 were used to construct a tissue microarray. VEGF expression was assessed in these samples by immunohistochemistry. To assess the lymphatic and vascular properties of the tumors, 63 cases that contained sufficient material were sectioned routinely. The sections were then stained with the D2-40 antibody to identify the lymphatic vessels and with a CD34 antibody to identify the blood vessels. The vessels were counted individually with the Leica Application Suite v4 program. All statistical analyses were performed using SPSS 18.0 (Chicago, IL, USA) software, and p values ≤ 0.05 were considered significant.

Results: In the Cox regression analysis, advanced age (p=0.03) and a history of type 2 diabetes (p=0.014) or chronic pancreatitis (p=0.02) were shown to be prognostic factors for pancreatic cancer. Blood vessel density (BVD) had no relationship with clinical-pathological features or death. Lymphatic vessel density (LVD) was inversely correlated with death (p=0.002), and by Kaplan-Meyer survival analysis, we found a significant association between low LVD (p=0.021), VEGF expression (p=0.023) and low patient survival.

Conclusions: Pancreatic carcinogenesis is related to a history of chronic inflammatory processes, such as type 2 diabetes and chronic pancreatitis. In pancreatic cancer development, lymphangiogenesis can be considered an early event that enables the dissemination of metastases. VEGF expression and low LVD can be considered as poor prognostic factors as tumors with this profile are fast growing and highly aggressive.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5113892881028514.
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http://dx.doi.org/10.1186/1746-1596-8-170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816792PMC
October 2013

Relationship between B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) and homologous recombination regulatory genes in invasive ductal breast carcinomas.

Histol Histopathol 2012 10;27(10):1353-9

Department of Pathology, Riberão Preto Medical School, University of São Paulo, Riberão Preto, São Paulo, Brazil.

B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is a Polycomb group protein that is able to induce telomerase activity, enabling the immortalization of epithelial cells. Immortalized cells are more susceptible to double-strand breaks (DSB), which are subsequently repaired by homologous recombination (HR). BRCA1 is among the HR regulatory genes involved in the response to DNA damage associated with the RAD51 protein, which accumulates in DNA damage foci after signaling H2AX, another important marker of DNA damage. Topoisomerase IIIß (topoIIIß) removes HR intermediates before chromosomal segregation, preventing damage to cellular DNA structure. In breast carcinomas positive for BMI-1 the role of proteins involved in HR remains to be investigated. The aim of this study was to evaluate the association between BMI-1 and homologous recombination proteins. Using tissue microarrays containing 239 cases of primary breast tumors, the expression of Bmi-1, BRCA-1, H2AX, Rad51, p53, Ki-67, topoIIIß, estrogen receptors (ER), progesterone receptors (PR), and HER-2 was analyzed by immunohistochemistry. We observed high Bmi-1 expression in 66 cases (27.6%). Immunohistochemical overexpression of BMI-1 was related to ER (p=0.004), PR (p<0.001), Ki-67 (p<0.001), p53 (p=0.003), BRCA-1 (p= 0.003), H2AX (p=0.024) and topoIIIß (p<0,001). Our results show a relationship between the expression of BMI-1 and HR regulatory genes, suggesting that Bmi-1 overexpression might be an important event in HR regulation. However, further studies are necessary to understand the mechanisms in which Bmi-1 could regulate HR pathways in invasive ductal breast carcinomas.
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http://dx.doi.org/10.14670/HH-27.1353DOI Listing
October 2012

Topoisomerase expression in oral squamous cell carcinoma: relationship with cancer stem cells profiles and lymph node metastasis.

J Oral Pathol Med 2012 Nov 5;41(10):762-8. Epub 2012 Jun 5.

Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

Background: The relationship between predictive proteins and tumors presenting cancer stem cells (CSCs) profiles in oral tumors is still poorly understood. This study aims to identify the relationship between topoisomerases I, IIα, and IIIα and putative CSCs immunophenotype in oral squamous cell carcinoma (OSCC) and determine its influence on prognosis.

Methods: The following data were retrieved from 127 patients: age, gender, primary anatomic site, smoking and alcohol intake, recurrence, metastases, histologic classification, treatment, and survival. An immunohistochemical study for topoisomerases I, IIα, and IIIα was performed in a tissue microarray containing 127 paraffin blocks of OSCCs.

Results: In univariate analysis, topoisomerases expression showed significant differences according to CSCs profiles and p53 immunoexpression, but not with survival. Topoisomerases IIα and IIIα also showed significant relationship with lymph node metastasis. The multivariate test confirmed these associations.

Conclusions: The results that all topoisomerases correlates with OSCC CSCs may indicate a role for topoisomerases in head and neck carcinogenesis. Notwithstanding, it is plausible that other members of topoisomerases family could represent novel therapeutical targets in oral squamous cell carcinoma.
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http://dx.doi.org/10.1111/j.1600-0714.2012.01174.xDOI Listing
November 2012

The role of tumor hypoxia in MUC1-positive breast carcinomas.

Virchows Arch 2011 Oct 3;459(4):367-75. Epub 2011 Sep 3.

Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil.

Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell-cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1α) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1α and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1α (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-κB (IκBα), driving NF-κB to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-κB expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-κB to the nucleus. Our data also support the notion that activation of HIF-1α in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.
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http://dx.doi.org/10.1007/s00428-011-1142-6DOI Listing
October 2011

Differential expression of HIF-1α in CD44+CD24-/low breast ductal carcinomas.

Diagn Pathol 2011 Aug 8;6:73. Epub 2011 Aug 8.

Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.

Background: Cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of tumor. Stem cells renewal and differentiation can be directly influenced by the oxygen levels of determined tissues, probably by the reduction of oxidative DNA damage in hypoxic regions, thus leading to a friendlier microenvironment, regarding to clonal expansion and for resistance to chemotherapeutic regimens. Furthermore, there have been strong data indicating a pivotal role of hypoxic niche in cancer stem cells development. There are evidence that hypoxia could drive the maintenance of CSC, via HIF-1α expression, but it still to be determined whether hypoxia markers are expressed in breast tumors presenting CD44+CD24-/low immunophenotype.

Methods: Immunohistochemical analysis of CD44+CD24-/low expression and its relationship with hypoxia markers and clinical outcome were evaluated in 253 samples of breast ductal carcinomas. Double-immunolabeling was performed using EnVision Doublestain System (Dako, Carpinteria, CA, USA). Slides were then scanned into high-resolution images using Aperio ScanScope XT and then, visualized in the software Image Scope (Aperio, Vista, CA, USA).

Results: In univariate analysis, CD44+CD24-/low expression showed association with death due to breast cancer (p = 0.035). Breast tumors expressing CD44+CD24-/low immunophenotype showed relationship with HIF-1α (p = 0.039) and negativity for HER-2 (p = 0.013).

Conclusion: Considering that there are strong evidences that the fraction of a tumour considered to be cancer stem cells is plastic depending upon microenvironmental signals, our findings provide further evidence that hypoxia might be related to the worse prognosis found in CD44+CD24-/low positive breast tumors.
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http://dx.doi.org/10.1186/1746-1596-6-73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170242PMC
August 2011

Prognostic factors in patients with malignant salivary gland neoplasms in a Brazilian population.

Asian Pac J Cancer Prev 2011 ;12(2):363-8

Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.

Due to the difficulty of follow-up for long periods, information about the survival rates of malignant salivary gland tumors is deficient in the global scientific literature. This study was aimed at investigating the epidemiological profile and prognostic factors that might affect survival in patients with primary malignant salivary gland tumors in Brazil. Patients were investigated regarding histopathological subtypes, age, gender, anatomic localization, smoking and alcohol intake, tumor size, clinical stage, histological grade, recurrence, metastasis, and treatment on clinicopathological outcomes. Survival curves were generated using the Kaplan-Meier method, and both univariate and multivariate analyses were performed using the log rank test and Cox regression, respectively. A total of 63 cases were analyzed, females being slightly predominant (50.8%), with ages ranging from 13 to 87 years. The most common diagnosis was adenoid cystic carcinoma and the most affected anatomical location was the parotid. Tumors were predominantly classified as stage I and high-grade at the diagnosis. The 5- and 10-year overall survival rates were 84.6% and 74.7%, respectively. Disease-free survival (DFS) rates were 71.6% (5 years) and 56.6% (10 years). Univariate analysis showed significant effects of tumor size and clinical stage on the DFS (P<0.0001 for both), and Cox regression analysis confirmed clinical stage as an independent prognostic factor (P = 0.035). Our results highlight the relevance of clinical stage as an independent prognostic parameter for malignant salivary gland tumors.
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August 2011

Significance of topoisomerase IIIβ expression in breast ductal carcinomas: strong associations with disease-specific survival and metastasis.

Hum Pathol 2010 Nov;41(11):1624-30

Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.

Topoisomerases are ubiquitous nuclear enzymes that regulate DNA structure in eukaryotic cells. The role of topoisomerase IIIβ, the newest member of the topoisomerase family, in the clinical outcome of breast cancer is still poorly understood. This study aims to investigate the immunoexpression of topoisomerase IIIβ in breast cancer and its relationships with clinicopathologic features and immunohistochemical markers of prognostic significance in breast pathology. Using tissue microarrays containing 171 cases of primary invasive breast cancer, we analyzed the immunoexpression of topoisomerase IIIβ, estrogen receptor, progesterone receptor, HER-2, BRCA-1, p53, and Ki67. Immunostaining for topoisomerase IIIβ was found in 33.9% of breast carcinomas, and immunopositivity was correlated with distant metastasis (P = .036) and death (P = .006). Decreased expression of topoisomerase IIIβ correlated with low expression of Ki67 (P < .001) and negativity for HER-2 (P < .001), BRCA-1 (P = .001), and p53 (P < .001). In the multivariate analysis, topoisomerase IIIβ expression was a significant predictor of survival (hazard ratio, 3.006 [95% confidence interval, 1.582-5.715]; P = .001). In conclusion, topoisomerase IIIβ expression can be a useful marker in assessing the prognosis of patients with breast cancer and is an independent predictor of survival.
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http://dx.doi.org/10.1016/j.humpath.2010.01.027DOI Listing
November 2010

Prognostic factors and survival analysis in a sample of oral squamous cell carcinoma patients.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 Nov 30;106(5):685-95. Epub 2008 Aug 30.

Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.

Objectives: The aims of this report were to describe the 5-year overall survival (OS) in a group of oral squamous cell carcinoma (OSCC) patients and to investigate the effects of age, gender, anatomic localization, tumor evolution time, smoking and alcohol intake, nodal status, tumoral recurrences, histologic classification, p53 and p63 immunoexpression, human papillomavirus DNA presence, and treatment on the prognostic outcome.

Study Design: Survival curves were generated using Kaplan-Meier method, and univariate and multivariate analyses were made using the log rank test and Cox regression, respectively.

Results: The 5-year OS was 28.6%, and the univariate analysis showed significant results for p53 and p63 immunoexpression, age, and anatomic localization. The Cox regression demonstrated poor OS for tumors with p53 immunoexpression and for patients aged over 60 years. There were also significant differences in survival depending on the anatomic localizations.

Conclusion: These results highlight the influence of p53 immunoexpression, age, and anatomic localization in OSCC evolution.
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http://dx.doi.org/10.1016/j.tripleo.2008.07.002DOI Listing
November 2008