ROGER CHAMMAS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Radiologia, Faculdade de Medicina - Docente
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
15 resultados
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- Endostatin gene therapy stimulates upregulation of ICAM-1 and VCAM-1 in a metastatic renal cell carcinoma model(2012) CHAVES, K. C. B.; PERON, J. P. S.; CHAMMAS, R.; TURACA, L. T.; PESQUERO, J. B.; BRAGA, M. S.; FOGUER, K.; SCHOR, N.; BELLINI, M. H.One of the greatest challenges in urological oncology is renal cell carcinoma (RCC), which is the third leading cause of death in genitourinary cancers. RCCs are highly vascularized and respond positively to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential of ES-based antiangiogenic therapy to activate tumor-associated endothelial cells in metastatic RCC (mRCC). Balb/c-bearing Renca cells were treated with NIH/3T3-LendSN or, as a control, with NIH/3T3-LXSN cells. The T-cell subsets and lymphocyte populations of tumors, mediastinal lymph nodes and the spleen were assessed by flow cytometry. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was assessed by real-time PCR, flow cytometry and immunohistochemistry analysis. ES gene therapy led to an increase in the percentage of infiltrating CD4-interferon (IFN)-gamma cells (P<0.05), CD8-IFN-gamma cells (P<0.01) and CD49b-tumor necrosis factor-alpha cells (P<0.01). In addition, ES therapy caused an increase at the mRNA level of ICAM-1 (1.4-fold; P<0.01) and VCAM-1 (1.5-fold) (control vs treated group; P<0.001). Through flow cytometry, we found a significant increase in the CD34/ICAM-1 cells (8.1-fold; P<0.001) and CD34/VCAM-1 cells (1.6-fold; P<0.05). ES gene therapy induced a significant increase in both T CD4 and CD8 cells in the lymph nodes and the spleen, suggesting that ES therapy may facilitate cell survival or clonal expansion. CD49b cells were also present in increased quantities in all of these organs. In this study, we demonstrate an antitumor inflammatory effect of ES in an mRCC model, and this effect is mediated by an increase in ICAM-1 and VCAM-1 expression in tumor-associated endothelial cells.
- Endostatin neoadjuvant gene therapy extends survival in an orthotopic metastatic mouse model of renal cell carcinoma(2012) BRAGA, Marina de Souza; CHAVES, Karen Barbosa; CHAMMAS, Roger; SCHOR, Nestor; BELLINI, Maria HelenaDespite recent advances in targeted therapy, renal cell carcinoma (RCC) remains one of the most lethal urologic malignancies. Approximately 30% of patients with localised RCC will develop metastases after curative surgery. Presurgical therapy has been explored for treatment of localised RCC. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential use of an antiangiogenic agent as a neoadjuvant therapy in an orthotopic metastatic mouse model of RCC. BALB/c mice bearing Renca cells were treated before nephrectomy with NIH/3T3-LendSN cells. At the end of the experiment, ES serum levels were measured. Primary and metastatic tumour area and microvascular area were determined. In the survival studies, mice were monitored daily until they died. ES serum levels in treated mice were higher in the control group (P < 0.05). The median primary tumour area and the mean microvascular area were significantly lower in the ES-treated group compared to control group (P < 0.05). The proliferation of Renca cells in the ES-treated group was significantly reduced compared with the control group (P < 0.01). ES therapy led to a significant reduction in the number of pulmonary metastatic nodules compared with the control group (P < 0.01). Kaplan-Meier survival curves showed that the probability of survival was significantly higher in mice receiving ES therapy (P = 0.0243, Log-Rank test). Our results indicated that neoadjuvant ES gene therapy has the potential to decrease tumour burden, extend survival, and may have clinical benefit in the management of RCC.
conferenceObject ERCC1 AND BETA-TUBULIN III IN ADVANCED NSCLC PATIENTS TREATED WITH CISPLATIN-VINORELBINE(2012) CASTRO JR., G. de; VICTOR, C. R.; BIGATON, F. J.; TAKAHASHI, T. K.; FEHER, O.; SABER, A. M. Ab'; TAKAGAKI, T. Y.; SIQUEIRA, S. A. C.; CHAMMAS, R.; HOFF, P. M. G.Background: Platinum-containing chemotherapy remains as the standard treatment in advanced/metastatic non-small-cell lung cancer (NSC LC) patients (pts). Increased ERCC 1 expression has been associated with resistance to platinum-based therapies, and beta-tubulin III (TUBB 3) was shown to be involved in resistance to antimicrotubule agents. Here we studied these tumor markers in NSC LC pts treated with cisplatin-vinorelbine and correlated their expression with survival. Methods: It is a retrospective study on pts diagnosed with advanced/metastatic NSC LC (TNM 6th ed), consecutively identified. All pts were treated with cisplatin 80 mg/m2 d1 and vinorelbine 30 mg/m2 d1, d8, d15, every 21 days, 4–6 cycles, in our Institution, between Sep/2002 and Oct/2008. ERCC 1 (clone 8F1) and TUBB 3 (clone TUJ1) expression were evaluated by immunohistochemistry, and biomarker expression was considered as high when more than 10% of tumor cells presented moderate to strong staining, nuclear or cytoplasmic, respectively. Overall survival (OS) was estimated by the Kaplan-Meier method and curves were compared with log-rank. Results: 142 pts were studied; median age 63 y (34-87), 67% male and 86% current smokers. Adenocarcinoma (ADC, 58 pts, 43%), followed by squamous cell carcinoma (SCC , 50 pts, 37%) were the most frequent histologic types. 100 pts (71%) were staged as IV and 34 pts (24%) as IIIB. The median number of cycles was 4 (1-7). Median OS was 7.9 mo. Overall, high ERCC 1 expression was observed in 61/104 pts (59%) and high TUBB 3 expression in 55/109 pts (51%). According to histologic types, low ERCC 1 expression was observed in 7/42 SCC pts (16%) and in 35/63 ADC pts (56%) (p=0.0004). Among ADC pts, 1-y OS rate was 28% and 47% in pts which tumors presented with high and low ERCC 1 expression, respectively (HR 1.57, 95% CI 0.9-2.7, p=0.08). TUBB 3 expression neither presented any difference between SCC and ADC types, nor any prognostic impact in terms of OS. Conclusions: Low ERCC 1 expression was observed more frequently in pts with advanced lung ADC and it was a favorable prognostic factor in ADC pts treated with cisplatin-vinorelbine.- Ethnicity and Cutaneous Melanoma in the City of Sao Paulo, Brazil: A Case-Control Study(2012) LUIZ, Olinda C.; GIANINI, Reinaldo Jose; GONCALVES, Fernanda T.; FRANCISCO, Guilherme; FESTA-NETO, Cyro; SANCHES, Jose Antonio; GATTAS, Gilka J. F.; CHAMMAS, Roger; ELUF-NETO, JoseBackground: Over the last century the incidence of cutaneous melanoma has increased worldwide, a trend that has also been observed in Brazil. The identified risk factors for melanoma include the pattern of sun exposure, family history, and certain phenotypic features. In addition, the incidence of melanoma might be influenced by ethnicity. Like many countries, Brazil has high immigration rates and consequently a heterogenous population. However, Brazil is unique among such countries in that the ethnic heterogeneity of its population is primarily attributable to admixture. This study aimed to evaluate the contribution of European ethnicity to the risk of cutaneous melanoma in Brazil. Methodology/Principal Findings: We carried out a hospital-based case-control study in the metropolitan area of Sao Paulo, Brazil. We evaluated 424 hospitalized patients (202 melanoma patients and 222 control patients) regarding phenotypic features, sun exposure, and number of grandparents born in Europe. Through multivariate logistic regression analysis, we found the following variables to be independently associated with melanoma: grandparents born in Europe-Spain (OR = 3.01, 95% CI: 1.03-8.77), Italy (OR = 3.47, 95% CI: 1.41-8.57), a Germanic/Slavic country (OR = 3.06, 95% CI: 1.05-8.93), or >= 2 European countries (OR = 2.82, 95% CI: 1.06-7.47); eye color-light brown (OR = 1.99, 95% CI: 1.14-3.84) and green/blue (OR = 4.62; 95% CI 2.22-9.58); pigmented lesion removal (OR = 3.78; 95% CI: 2.21-6.49); no lifetime sunscreen use (OR = 3.08; 95% CI: 1.03-9.22); and lifetime severe sunburn (OR = 1.81; 95% CI: 1.03-3.19). Conclusions: Our results indicate that European ancestry is a risk factor for cutaneous melanoma. Such risk appears to be related not only to skin type, eye color, and tanning capacity but also to others specific characteristics of European populations introduced in the New World by European immigrants.
- Expression of PAFR as Part of a Prosurvival Response to Chemotherapy: A Novel Target for Combination Therapy in Melanoma(2012) ONUCHIC, Ana Claudia; MACHADO, Camila M. L.; SAITO, Renata F.; RIOS, Francisco J.; JANCAR, Sonia; CHAMMAS, RogerMelanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas.
article 12 Citação(ões) na Scopus The inactive form of glycogen synthase kinase-3 beta is associated with the development of carcinomas in galectin-3 wild-type mice, but not in galectin-3-deficient mice(2012) MENDONCA, Daniella Fernandes; CHAMMAS, Roger; LIU, Fu-Tong; NONOGAKI, Suely; CARDOSO, Sergio Vitorino; LOYOLA, Adriano Mota; FARIA, Paulo Rogerio deGalectin-3 has been implicated in the tumor development via its mediation of the Wnt signaling pathway. Likewise, glycogen synthase kinase-3beta (GSK3 beta) also plays a role in the Wnt signaling pathway by controlling the levels of cytoplasmic beta-catenin. Altered GSK3 beta expression has been described in various tumors, but to date, there are no studies evaluating its expression in models of oral carcinogenesis. Additionally, it is unknown whether the absence of galectin-3 regulates the expression of GSK3 beta. To this end, Gal3-deficient (Gal3(-/-)) and wild-type (Gal3(+/+)) male mice were treated with 4NQO for 16 weeks and sacrificed at week 16 and 32. The tongues were removed, processed, and stained with H&E to detect dysplasias and carcinomas. An immunohistochemical assay was performed to determine the level of P-GSK3 beta-Ser9 expression in both groups. Carcinomas were more prevalent in Gal3(+/+) than Gal3(-/-) mice (55.5% vs. 28.5%), but no statistical difference was reached. In the dysplasias, the proportion of cells positive for P-GSK3 beta-Ser9 was slightly higher in Gal3(+/+) than Gal3(-/-) mice (63% vs. 61%). In the carcinomas, a significant difference between Gal3(+/+) and Gal3(-/-) mice was found (74% vs. 59%; p=0.02). P-GSK3 beta-Ser9-positive cells slightly decreased from the progression of dysplasias to carcinomas in Gal3(-/-) mice (61% vs. 59%; p>0.05). However, a significant increase in P-GSK3 beta-Ser9 expression was observed from dysplasias to carcinomas in Gal3(+/+) mice (63% vs. 74%; p=0.01). In conclusion, these findings suggest that fully malignant transformation of the tongue epithelium is associated with increased P-GSK3 beta-Ser9 expression in Gal3(+/+) mice, but not in Gal3(-/-) mice.article 20 Citação(ões) na Scopus The involvement of the spleen during chronic phase of Schistosoma mansoni infection in galectin-3(-/-) mice(2012) BRAND, Camila; OLIVEIRA, Felipe L.; TAKIYA, Christina M.; PALUMBO JR., Antonio; HSU, Daniel K.; LIU, Fu-Tong; BOROJEVIC, Radovan; CHAMMAS, Roger; EL-CHEIKH, Marcia C.Schistosoma mansoni synthesizes glycoconjugates which interact with galectin-3, eliciting an intense humoral immune response. Moreover, it was demonstrated that galectin-3 regulates B cell differentiation into plasma cells. Splenomegaly is a hallmark event characterized by polyclonal B cell activation and enhancement of antibody production. Here, we investigated whether galectin-3 interferes with spleen organization and B cell compartment during chronic schistosomiasis, using wild type (WT) and galectin-3(-/-) mice. In chronically-infected galectin-3(-/-) mice the histological architecture of the spleen, including white and red pulps, was disturbed with heterogeneous lymphoid follicles, an increased number of plasma cells (CD19(-)B220(-/low)CD138(+)) and a reduced number of macrophages (CD19(-)B220(-)Mac-1(+)CD138(-)) and B lymphocytes (CD19(+)B220(+/high)CD138(-)), compared with the WT infected mice. In the absence of galectin-3 there was an increase of annexin-V+PI- cells and a major presence of apoptotic cells in spleen compared with WT infected mice. In spleen of WT infected mice galectin-3 was largely expressed in lymphoid follicles and extrafollicular sites. Thus, we propose that galectin-3 plays a role in splenic architecture, controlling distinct events such as apoptosis, macrophage activity, B cell differentiation and plasmacytogenesis in the course of S. mansoni infection.conferenceObject Intratumoral Societies - Subpopulations of Tumor Cells Expressing Different Levels of ADAM23 Seems Responsible for Different Aspects of Malignancy(2012) BARNABE, G. F.; COSTA, E. T.; ASPRINO, P. F.; NAGAI, M. H.; MALNIC, B.; CHAMMAS, R.; CAMARGO, A. A.Background: Cancer evolve through the accumulation of genomic and epigenomic alterations that enable tumor progression towards malignancy. Epigenetic silencing of ADAM23 (A Desintegrin A nd Metalloprotease domain 23) gene is a recurrent event in a wide range of tumors, including pancreatic, breast, gastric and colorectal tumors. Hypermethylation of ADAM23 gene promoter has been associated with metastatic disease and poor overall survival in breast cancer patients (Verbisck et al. 2009). However the precise biological effects of ADAM23 down regulation during tumor progression is unknown. Here we sought to further clarify the role of ADAM23 in tumor progression through functional characterization of ADAM23 in vivo and in vitro. Material and Methods: We stably knocked down ADAM23 expression in MDA-MB-435 tumor cells using shRNA and ectopically expressed human ADAM23 in CMS5a, a mouse fibrosarcoma cell line. Cells transfected with empty vectors were used as controls in all comparisons. Invasion assays were performed embedding cell spheroids in a tri-dimensional collagen-type I matrix. Soft-agar and tumorigenesis assays were performed according to standardprotocols. ADAM23 expression in primary tumors displaying ADAM23 promoter hypermethylation was analyzed by in situ hybridization (approved ethics committee). Results: We demonstrated that, in both the human and murine models, reduced levels of ADAM23 correlate with a 3-fold increase in the average speed of cellular invasion through collagen matrix. By contrast, in soft-agar assays these fast invasive cells displayed a decrease of 50−70% in the colony sizes, with no changes in colony numbers. In vivo, ADAM23-positive human cells efficiently formed tumors (93%), while the tumorigenesis rate of ADAM23-negative cells was only 33%. In situ hybridization of ADAM23 hypermethylated tumors revealed the co-existence of ADAM23 negative cell clusters and clusters expressing high levels of ADAM23. Conclusions: Our results demonstrate that ADAM23 can act as a pleiotropic molecule by stimulating growth and tumorigenesis, but inhibiting invasion and suggest that the invasive phenotype is more likely to evolve after ADAM23 silencing in primary tumors. Finally, we hypothesize that the co-existence of tumor cell subpopulations expressing different level sof ADAM23 with in primary tumors may contribute to malignancy given that association of both proliferative and invasive phenotypes facilitate accomplishment of metastatic cascade.- Fibronectin expression is decreased in metastatic renal cell carcinoma following endostatin gene therapy(2012) CHAVES, Karen Cristina Barbosa; TURACA, Lauro Thiago; PESQUERO, Joao Bosco; MENNECIER, Gregory; DAGLI, Maria Lucia Zaidan; CHAMMAS, Roger; SCHOR, Nestor; BELLINI, Maria HelenaTumor cells induce the disruption of homeostasis between cellular and extracellular compartments to favor tumor progression. The expression of fibronectin (FN), a matrix glycoprotein, is increased in several carcinoma cell types, including renal cell carcinoma (RCC). RCC are highly vascularized tumors and are often amenable to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the modulation of FN gene expression by ES gene therapy in a murine metastatic renal cell carcinoma (mRCC) model. Balb/C mice bearing Renca cells were treated with NIH/3T3-LXSN cells or NIH/3T3-LendSN cells. At the end of the experiment, the ES serum levels were measured, and the FN gene expression was assessed using real-time PCR. The tissue FN was evaluated by western blotting and by immunofluorescence analysis. The ES serum levels in treated mice were higher than those in the control group (P < 0.05). ES treatment led to significant decreases at the FN mRNA (P < 0.001) and protein levels (P < 0.01). Here, we demonstrate the ES antitumor effect that is mediated by down-regulation of FN expression in mRCC.
conferenceObject Activated Wnt signaling pathway is not influenced by absence of galectin-3 in mice during tongue malignant transformation(2012) SOUZA, M. V. R.; CHAMMAS, R.; SANT'ANA, J. M. A.; LOYOLA, A. M.; CARDOSO, S. V.; FARIA, P. R.Introduction: Oncogenic role for galectin-3 (GAL3) is due to its involvement in the Wnt signaling. Altered expression of Wnt-target proteins like cyclin D1 and APC promote malignant transformation. However, no study has hitherto showed whether GAL3 interferes in the expression of both proteins during oral carcinogenesis. This study reports cyclin D1 and APC expression in dysplasias and carcinomas induced in the tongue of galectin-3 deficient (GAL3)/)) and wild-type (GAL3+/+) mice. Material and Methods: Sixty GAL3)/) and GAL3 +/+ mice were treated with 4NQO for 16 weeks and killed at week 16 and week 32. The tongues were removed and processed for paraffin embedding. Sections were stained with Haematoxylin and Eosin to identify dysplasias and carcinomas. An immunohistochemical assay was applied to evaluate the expression of cyclin D1 and APC protein. Results: Oral carcinogenesis occurred in both groups (P> 0.05). In GAL3)/) mice, the percentage of cyclin D1-positive cells was 36% for both dysplasias and carcinomas; in GAL3 +/+ mice, it was 28% and 34%, respectively. The intensity of APC expression in dysplasias from GAL3)/) mice ranged from weak (31.7%), moderate (12.2%) to strong (2.4%); in carcinomas from the same group, 48.1% and 7.4% of cases respectively exhibited a weak and moderate expression. In GAL3 +/+ mice, 59.4% and 28.1% of dysplasias and 50% and 40% of carcinomas presented a weak and moderate APC expression, respectively. However, no statistical significance was found. Conclusion: The absence of GAL3 does not interfere in the oral carcinogenesis and activated Wnt signaling was observed in both groups of mice (FAPEMIG).