RESUMO
BACKGROUND: Thrombospondin-1 (TSP-1) is an extracellular matrix component glycoprotein, which is known to be a potent inhibitor of angiogenesis and may be important in cancer invasiveness. We examined the TSP-1 expression in correlation with conventional clinicopathological parameters to clarify its prognostic significance in bladder cancer. In addition, the possible correlation of TSP-1 expression with microvessel count, VEGF expression, p53 expression as well as with the expression of the extracellular matrix components was studied to explore its implication in vascularization and tumour stroma remodeling. METHODS: The immunohistochemical expression of TSP-1 in tumour cells and in the tumour stroma was studied in 148 formalin-fixed paraffin-embedded urothelial cell carcinoma tissue samples. RESULTS: TSP-1 was detected in perivascular tissue, at the epithelial-stromal junction, in the stroma and in tumour cells in the majority of the cases. In tumour cells, low TSP-1 expression was observed in 43% of the cases, moderate and high in 7%, while 50% showed absence of TSP expression. A higher TSP-1 immunoreactivity in well and moderately differentiated tumours compared to poorly differentiated was noted. PT1 tumours showed decreased TSP-1 expression in comparison to pTa and pT2-4 tumours. Increased tumour cell TSP-1 expression was related to increased microvessel density. In the tumour stroma, 37% of the cases showed small amount of TSP-1 expression, 7.5% moderate and high, while 55% of the cases showed absence of TSP-1 stromal immunoreactivity. Stromal TSP-1 expression was inversely correlated with tumour stage and tumour size. This expression was also positively correlated with microvessel density, VEGF expression and extracellular matrix components tenascin and fibronectin. Using univariate and multivariate analysis we didn't find any significant correlation of TSP-1 expression in superficial tumours in both tumour cells and tumour stroma in terns of the risk of recurrence and disease progression CONCLUSION: Our data suggest that both tumour and stromal TSP-1 expression may play a role in tumour aggressiveness and angiogenesis. In addition, the correlation of stromal TSP-1 expression with extracellular matrix components fibronectin and tenascin indicate its possible implication in tumour stroma remodeling.
Assuntos
Carcinoma/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Neovascularização Patológica/metabolismo , Trombospondina 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Carcinoma/patologia , Contagem de Células , Progressão da Doença , Feminino , Fibronectinas/metabolismo , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Tenascina/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: The migration, proliferation, differentiation, and adhesion of cells and other cellular functions are influenced by the surrounding extracellular matrix in normal and wound healing conditions. The formation of epiretinal membranes, a wound healing process, is a serious complication of retinal diseases, the most important being proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). In the present study, the authors investigated the expression of various extracellular matrix components and in particular tenascin, fibronectin, laminin, collagen IV, and MMP-3 glycoprotein as well as the expression of glial fibrillary acidic protein in each type of epithelial membrane in order to elucidate the role of these molecules in the formation of these two types of membranes. METHODS: The authors performed immunohistochemistry in 14 PVR and 14 PDR membranes, using antibodies against the above mentioned extracellular matrix components. Tenascin and fibronectin were observed as major components in the extracellular matrix, while laminin and collagen type IV were detected as minor components in both types of membranes. A higher fibronectin expression in PVR compared with PDR membranes was found (p=0.0035). A positive relationship of its expression with the proliferative activity (p=0.15) and collagen type IV expression (p<0.0001) was also observed. RESULTS: Tenascin expression was positively correlated with glial fibrillary acidic protein positive cells in PDR membranes (p=0.04). Collagen type IV localized around vessels was observed with high levels in PDR membranes (p=0.0031). CONCLUSIONS: The results indicated that the extracellular matrix components seem to be involved in PVR and PDR, contributing to tissue remodeling and perhaps by different pathogenetic pathways, which could reflect different stages of development in these two types of membranes.
Assuntos
Retinopatia Diabética/metabolismo , Membrana Epirretiniana/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Vitreorretinopatia Proliferativa/metabolismo , Antígenos/imunologia , Biomarcadores/metabolismo , Adesão Celular , Diferenciação Celular , Movimento Celular , Colágeno Tipo IV/biossíntese , Colágeno Tipo IV/imunologia , Retinopatia Diabética/complicações , Retinopatia Diabética/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Membrana Epirretiniana/etiologia , Membrana Epirretiniana/patologia , Fibronectinas/biossíntese , Fibronectinas/imunologia , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/imunologia , Humanos , Imuno-Histoquímica/métodos , Laminina/biossíntese , Laminina/imunologia , Metaloproteinase 3 da Matriz/biossíntese , Metaloproteinase 3 da Matriz/imunologia , Epitélio Pigmentado Ocular/metabolismo , Epitélio Pigmentado Ocular/patologia , Índice de Gravidade de Doença , Tenascina/biossíntese , Tenascina/imunologia , Vitreorretinopatia Proliferativa/complicações , Vitreorretinopatia Proliferativa/patologiaRESUMO
The most important cellular protective mechanisms against oxidative stress are antioxidant enzymes. Their action is based on decomposal of reactive oxygen species (ROS) and their transformation to H2O2. Within the mitochondria manganese superoxide dismutase (MnSOD) affords the major defense against ROS. In this study we investigated tissue sections from 101 breast carcinomas for the immunohistochemical expression of MnSOD protein and these results were assessed in relation to various clinicopathological parameters, in order to clarify the prognostic value of this enzyme. The possible relationship to hormone receptor content, anti-apoptotic protein bcl-2, p53 and cell proliferation was also estimated. High expression levels were observed, as 79/101 (78,2%) cases expressed strong immunoreactivity. In this study MnSOD increased in a direct relationship with tumor grade and is therefore inversely correlated with differentiation (p=0.0004). Furthermore, there was a strong positive correlation between MnSOD expression and p53 protein immunoreactivity (p=0.0029). The prognostic impact of MnSOD expression in determining the risk of recurrence and overall survival with both univariate (long-rang test) and multivariate (Cox regression) methods of analysis was statistically not significant. These results indicate that neoplastic cells in breast carcinomas retain their capability to produce MnSOD and thus protected from the possible cellular damage provoked by reactive oxygen species. In addition, MnSOD content varies according to the degree of differentiation of breast carcinoma.
Assuntos
Antioxidantes/metabolismo , Neoplasias da Mama/enzimologia , Carcinoma/enzimologia , Superóxido Dismutase/metabolismo , Distribuição por Idade , Neoplasias da Mama/patologia , Carcinoma/patologia , Divisão Celular , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Invasividade Neoplásica , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/análise , Superóxido Dismutase/genética , Proteína Supressora de Tumor p53/análiseRESUMO
In the present study 79 cases of de novo Diffuse Large B-cell Lymphomas (DLBCL) were studied in order: a) to analyse the expression of cyclin D3, cyclin E and cyclin D1 in relation to other proliferative features (expression of Ki67, cyclin A and cyclin B1), the apoptosis status and the expression of p53, Rb, p16 and p27; and b) to determine whether distinct clusters of proliferation and apoptosis could be identified in DLBCL. Overexpression of cyclin D3 and cyclin E was found in 35/79 (43%) and 18/79 (22%) cases, respectively, whereas overexpression of cyclin D1 was not detected in any case. In most cases (39/46) overexpression of cyclin D3 and cyclin E was mutually exclusive possibly reflecting different underlying pathways inducing deregulated expression of these cyclins. In most cases (29/35) overexpression of cyclin D3 was mutually exclusive with Rb/p16 aberrant expression status supporting an oncogenic role for cyclin D3 and suggesting that the pathogenetic effect of cyclin D3 overexpression occurs through perturbation of the Rb1 pathway. Combined alterations of the P53 and the Rb/p16/cyclin D3 expression status were significantly associated with higher mean values of cyclin A (p=0.023) and cyclin B1 (p=0.033) indicating that concurrent impairment of the p53 and Rb1 pathways induces increased tumour cell proliferation in DLBCL. Cluster analysis of the apoptosis and the proliferation status permitted separation of DLBCL into distinct groups with low (44 cases) and high (18 cases) apoptotic activity and into distinct groups with low (32 cases), intermediate (36 cases) and high (11 cases) proliferative activity. The identification of distinct clusters with respect to the proliferation and the apoptosis status indicates that groups with distinct cellular kinetic properties can be defined in the histological group of DLBCL.
Assuntos
Ciclina E/biossíntese , Ciclinas/biossíntese , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Proteínas Musculares , Apoptose/fisiologia , Divisão Celular/fisiologia , Análise por Conglomerados , Ciclina A/biossíntese , Ciclina D1/biossíntese , Ciclina D3 , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Antígeno Ki-67/biossíntese , Proteínas dos Microfilamentos/biossíntese , Proteína do Retinoblastoma/biossíntese , Proteína Supressora de Tumor p53/biossínteseRESUMO
Expression of the hormone-related proteins hsp27, pS2, and also of cathepsin D (CD) and metallothionein (MT) was studied by immunohistochemistry and analyzed against clinical data in breast cancer. Archived material of paraffin-embedded breast carcinoma tissues from a cohort of 134 patients with primary invasive breast cancer was used. Hsp27 and pS2 (>10% of tumor cells stained) were found to be expressed in 63.6% and 37.6% of cases, respectively, and were correlated negatively with grading (P=0.006 and 0.01) and positively with estrogen receptors (ER) (P=0.04 and 0.04). pS2 expression was correlated with lymph node status (P=0.02), tumor size (P=0.01), progesterone receptor (PR) content (P=0.02), hsp27 (P=0.015) and bcl-2 protein (P=0.001). An inverse relationship between pS2 expression and the expression of p53 protein (P=0.005) and proliferation-associated index MIB1 (P<0.0001) was noted. Stromal cathepsin D was positively correlated with tumor grade (P=0.01), PCNA (P=0.007), MIB1 (P=0.001) and p53 (P=0.01), and negatively with ER (P=0.04) and bcl-2 (P<0.0001). MT was correlated positively with stromal CD (P=0.007) and inversely with PgR (P=0.04). Univariate analysis showed CD expression to be a positive prognostic factor for survival (P=0.035), with borderline significance, while MT was more strongly positive (P=0.01). However, none of the proteins studied was found to be related to disease outcome in univariate analysis. Our data show that hsp27, pS2 and stromal CD expression may reflect tumor differentiation and the functional status of ER in breast cancer, but stromal CD and tumor MT expression were the only factors found that may be of limited prognostic value.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Catepsina D/metabolismo , Proteínas de Choque Térmico/metabolismo , Metalotioneína/metabolismo , Proteínas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biópsia por Agulha , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Catepsina D/análise , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Proteínas de Choque Térmico/análise , Humanos , Imuno-Histoquímica , Metalotioneína/análise , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/metabolismo , Probabilidade , Prognóstico , Proteínas/análise , Sensibilidade e Especificidade , Análise de Sobrevida , Fator Trefoil-1 , Proteína Supressora de Tumor p53/análise , Proteínas Supressoras de TumorRESUMO
Syndecan-1, a cell surface proteoglycan found predominantly on epithelia of mature tissues, binds both extracellular matrix (ECM) components and basic fibroblast growth factor (bFGF) and is implicated in the restriction of growth and invasiveness of neoplastic cells, as it induces the adhesion capacity of neoplastic cells with the stroma. In this study we investigated breast carcinomas for the immunohistochemical expression of syndecan-1 protein and these results were assessed in relation to clinicopathological parameters, in order to clarify its prognostic value. The possible relationship with hormone receptors content, p53, cell proliferation markers, and extracellular matrix components was also estimated. Tissue sections from 102 breast carcinomas were used and immunostainings were performed on formalin-fixed, paraffin-embedded tissue sections by the labelled streptavidin avidin biotin (LSAB) method. High expression levels were observed, as 75/102 (73.5%) cases expressed immunoreactivity in more than 80% of neoplastic cells, while 67/102 (65.7%) exhibited high staining intensity. The survival analysis showed an increased mortality risk associated with high syndecan-1 staining intensity with borderline significance (p=0.041). In addition, there was a strong negative correlation between syndecan-1 protein expression and ECM, specifically collagen IV (p=0.026) and tenascin (p=0.0067). The results of the present study show the implication of this protein in the remodeling of breast cancer tissue, through the interaction with other extracellular matrix components, probably influences the tumour progression.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Matriz Extracelular/metabolismo , Glicoproteínas de Membrana/biossíntese , Proteoglicanas/biossíntese , Avidina/química , Membrana Basal/metabolismo , Biotina/química , Neoplasias da Mama/patologia , Carcinoma/patologia , Carcinoma Ductal de Mama/patologia , Adesão Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proliferação de Células , Estudos de Coortes , Colágeno Tipo IV/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Metástase Linfática , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/metabolismo , Receptores de Progesterona/metabolismo , Estreptavidina/química , Sindecana-1 , Sindecanas , Tenascina/metabolismo , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Cell cycle progression and transition of cells from the first gap phase (G1) to the DNA replication phase (S) depend on a finely tuned balance between the levels of cyclins, cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs). MATERIALS AND METHODS: We analyzed 57 squamous cell invasive carcinomas of the larynx, 10 in situ carcinomas, 56 cases of dysplasia, 11 papillomas and 26 keratosis. We investigated: a) the immunohistochemical expression of CDKIs, p21 and p27, b) any possible relation between normal and abnormal immunoprofiles of these proteins and p53 protein and proliferation status as determined by the expression of Ki67 and PCNA, and c) their presence in pre-malignant and malignant laryngeal lesions. RESULTS: Expression of p21 and p27 was observed in 58.9% and 89.5% of the laryngeal carcinomas, respectively. High levels of p21 were significantly correlated with increased cyclin D (p=0.001), cyclin E (p<0.001) and Ki67 (p<0.001), while increased expression levels of p27 were associated with p53 accumulation (p=0.02) and with increased proliferation status as expressed by Ki67 (p=0.05). CONCLUSION: Due to the increased expression levels of CDKIs in laryngeal carcinomas, we suggest the existence of a mechanism by which tumor cells tolerate the inhibitory effect of these proteins on cell cycle progression.
Assuntos
Carcinoma in Situ/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Laríngeas/metabolismo , Lesões Pré-Cancerosas/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Inibidor de Quinase Dependente de Ciclina p21 , Inibidor de Quinase Dependente de Ciclina p27 , Humanos , Imuno-Histoquímica/métodos , Neoplasias Laríngeas/patologia , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologiaRESUMO
Thrombospondin (TSP-1) is a 450-kd adhesive glycoprotein that was initially discovered in platelets and subsequently in a variety of cell types. Several reports suggest that TSP-1 possesses tumour suppressor function, through its ability to inhibit tumour neovascularization. In this study we investigated tissue sections from 124 breast carcinomas for the immuno-histochemical expression of TSP-1 protein and its relationship to several clinicopathological parameters. The possible relationship to hormone receptors content, p53 protein, proliferation associated indices, angiogenesis, VEGF expression and extracellular matrix components (tenascin, fibronectin, laminin, collagen type IV and syndecan-1) was also estimated. TSP-1 was detected in the perivascular tissue, at the epithelial-stromal junction, in the stroma and in the tumour cells. High tumour cell TSP-1 expression was observed in 9.7%, moderate in 17.7%, mild in 10.5%, while 62.1% of the cases were negative for TSP-1 expression. The survival analysis showed an increased risk of recurrence associated with low TSP-1 tumour cell expression. High stromal TSP-1 expression was observed in 3.2% of the cases, moderate in 3.3%, mild in 27.4%, while 63.6% of the cases showed absence of TSP-1 expression. This expression was higher in invasive lobular type of breast cancer and inversely correlated with the lymph node involvement and the estrogen receptor content. Stromal TSP-1 expression was also positively correlated with extracellular matrix components expression, tenascin, fibronectin, collagen type IV, laminin, and syndecan-1. The relationship of TSP-1 expression with tumor angiogenesis, growth fraction and p53 protein expression was not significant. Our data suggest that TSP-1 expression seems to be associated with favorable biological behavior and may have clinical value in terms of predicting the risk of recurrence. In addition, TSP-1 might not be a direct anti-angiogenic factor, although it seems to be implicated in the remodeling of breast cancer tissue through interaction with other extracellular matrix components.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Matriz Extracelular/metabolismo , Neovascularização Patológica/metabolismo , Trombospondina 1/biossíntese , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Neovascularização Patológica/patologia , Prognóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
We review the available information regarding the role of adhesive molecules as potential participants in the complex events of fertilization, embryogenesis, implantation and placentation. Studies that specifically relate to the expression and modulation of adhesive molecules in fertilization, embryogenesis, and implantation have been identified in the literature and by Medline searches. Cell-cell and cell-extracellular matrix interactions play a critical role in various developmental processes and in the cascade of events that lead to implantation and to the normal development of the fetus during pregnancy. Adhesion molecules influence, directly or indirectly, numerous aspects of cell behaviour, cell migration, cell growth, cell survival, cell proliferation, angiogenesis, invasion and metastasis.
Assuntos
Moléculas de Adesão Celular/biossíntese , Regulação da Expressão Gênica/fisiologia , Gravidez/metabolismo , Animais , Movimento Celular/fisiologia , Proliferação de Células , Sobrevivência Celular/fisiologia , Implantação do Embrião/fisiologia , Feminino , Desenvolvimento Fetal/fisiologia , Humanos , Neovascularização Fisiológica/fisiologia , Placentação/fisiologiaRESUMO
PURPOSE: This retrospective study aims to elucidate the role of angiogenesis in the pathogenesis of pterygium. We evaluated microvessel density (MVD), and expression of vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1). METHODS: Fifty-two surgically excised pterygia and seven normal conjunctivae were immunohistochemically studied applying the streptavidin-biotin method in paraffin-embedded tissue sections. Monoclonal antibodies were targeted against CD31, VEGF, and TSP-1 proteins. RESULTS: Pterygium presented with statistically significant higher average count of microvessels compared to normal conjunctivae (17.97+/-8.5 vs5.72+/-5 per high power field, P=0.001). In 24/52 (46.2%) cases of pterygium, high expression levels for VEGF were demonstrated, whereas the mean percentage of VEGF-positive epithelial cells was 58.03%. Furthermore, normal conjunctival presented statistically significant higher expression levels for VEGF in epithelial cells (83.14+/-36.08 vs58.03+/-31.23%, P=0.007). On the contrary, the presence of VEGF immunoreactivity in vascular endothelial and stromal cells was significantly higher in pterygium tissues (P<0.0001). Stromal staining for TSP-1 was detected in only 29/52 (55.8%) of the cases and no correlation with normal conjunctivae was found. Finally, statistically significant positive correlation between MVD values and stromal VEGF expression was found (P=0.049). CONCLUSION: The angiogenesis-related factors that were studied proved to be highly expressed in pterygium tissue. On the contrary, TSP expression level was low, allowing inducers of angiogenesis to act uninhibited. This phenomenon could provide the pathogenic basis of pterygium formation.
Assuntos
Túnica Conjuntiva/química , Neovascularização Patológica/patologia , Pterígio/etiologia , Trombospondina 1/metabolismo , Fatores de Crescimento do Endotélio Vascular/análise , Idoso , Idoso de 80 Anos ou mais , Túnica Conjuntiva/irrigação sanguínea , Feminino , Humanos , Masculino , Microcirculação/patologia , Pessoa de Meia-Idade , Pterígio/metabolismo , Pterígio/patologia , Estudos RetrospectivosRESUMO
The aim of the study was to investigate angiogenesis in patients with advanced-stage ovarian carcinoma. We used paraffin-embedded tumor tissues from 33 patients diagnosed with FIGO III ovarian cancer who had optimal surgery and received platinum-based chemotherapy. The tissue expression of CD34, vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1) was assessed immunohistochemically. CD34 stained hot spot areas were used to evaluate tumor microvessel density (MVD). VEGF and TSP-1 were assessed by semiquantitative methods. The studied molecules were investigated for relationship with standard clinicopathologic parameters. MVD count was high: median value of 39, range 12-143 microvessels/mm2. VEGF was present in all cases and stained strong in 91%. Stroma staining for TSP-1 was weak in 79% of the cases, strong in 6%, and absent in five (15%). We did not find correlations between the three studied markers and histologic type or tumor grade. MVD score did not relate to VEGF or TSP-1. We only observed a trend toward a longer survival in patients with tumors expressing high TSP-1 (60 vs. 36 months, P= 0.1). Proangiogenetic factor VEGF is highly expressed in advanced-stage ovarian carcinomas. The findings of this study may offer support for considering VEGF-targeted therapeutics in ovarian cancer treatment research.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antígenos CD34/biossíntese , Neovascularização Patológica/fisiopatologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Trombospondina 1/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adenocarcinoma/química , Adenocarcinoma/terapia , Adulto , Idoso , Antígenos CD34/análise , Antineoplásicos/uso terapêutico , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Microcirculação , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/química , Neoplasias Ovarianas/terapia , Compostos de Platina/uso terapêutico , Trombospondina 1/análise , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
The matrix metalloproteinases (MMPs) are a family of proteolytic zinc-containing enzymes, which are responsible for the breakdown of the extracellular matrix components in pathological and physiological conditions. They are involved in basement membrane disruption, stroma and blood vessel penetration, metastasis and more recently there is evidence that they participate in tumor growth and angiogenic events. Matrix metalloproteinase 2 and 9 (MMP 2 and 9) belong to the gelatinases, a subgroup of MMPs, and have the capacity to degrade the triple helix type IV collagen of basal lamina of the basement membrane. With the present study, we tried to demonstrate the expression of MMP-9 immunohistochemically, comparatively in benign, premalignant and malignant lesions of the larynx. We studied 154 laryngeal lesions including 55 squamous cell carcinomas, 8 in situ carcinomas, 54 cases of dysplasia (of low and intermediate grade), 13 papillomas and 24 cases of keratosis. Overexpression of MMP 9 was observed in 74.4% and 50% in invasive and in situ squamous cell carcinomas respectively. In dysplastic cases, in papillomas and in keratoses the percentage of overexpression was 62.9%, 61.53% and 54.16% respectively and the expression of MMP-9 was significantly higher in invasive squamous cell carcinomas compared to dysplasias (p=0.000004). Also significantly higher was the expression of MMP-9 in dysplastic cases compared to papillomas (p=0.023). The MMP-9 expression was related neither to survival nor to the other available clinicopathological parameters (tumor size, grade, clinical stage, lymph node status and patient age). In conclusion, our study indicates that the expression of MMP-9 is up-regulated in a stepwise fashion, with two main steps, the first one, when a dysplastic lesion evolves and the next one, when the dysplasia progresses to invasive carcinoma.
Assuntos
Neoplasias Laríngeas/química , Laringe/química , Metaloproteinase 9 da Matriz/análise , Lesões Pré-Cancerosas/química , Carcinoma in Situ/química , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Ceratose/metabolismo , Ceratose/patologia , Doenças da Laringe/metabolismo , Doenças da Laringe/patologia , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Laringe/citologia , Laringe/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Papiloma/química , Papiloma/metabolismo , Papiloma/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Regulação para CimaRESUMO
Formation of epiretinal membranes (ERMs) is a serious complication of retinal diseases, the most important being proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). In this study, our goal was to (i) calculate the microvessel density (MVD), (ii) evaluate vascular endothelial growth factor (VEGF) expression and (iii) correlate angiogenesis with the proliferative activity as expressed by the expression of Ki67 marker, in both membrane types. We performed immunohistochemistry in 14 PVR and eight PDR membranes, using antibodies against CD34, VEGF, Ki67 and glial fibrillary acidic protein. PDR membranes presented higher average count of microvessels compared with PVR membranes (p = 0.0015). No differences were observed concerning VEGF expression (p = 0.1). The expression of Ki67 was not correlated with microvessel number or VEGF expression. Our study confirms the presence of vascularisation in PDR membranes, as well as the presence of VEGF even in avascular PVR membranes, suggesting that immunoreactivity for VEGF may not be accompanied by angiogenesis.
Assuntos
Membrana Epirretiniana/patologia , Neovascularização Retiniana/patologia , Proliferação de Células , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Membrana Epirretiniana/metabolismo , Humanos , Técnicas Imunoenzimáticas , Antígeno Ki-67/metabolismo , Neovascularização Retiniana/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vitreorretinopatia Proliferativa/metabolismo , Vitreorretinopatia Proliferativa/patologiaRESUMO
There is increasing evidence that bcl6 and CD10 expression may be related to apoptosis and cell cycle progression. Therefore, 79 cases of de novo diffuse large B-cell lymphomas were studied for the expression of bcl6 and CD10 proteins in relation to 1) the apoptotic index; 2) the proliferation-associated proteins Ki67, cyclin A, and cyclin B1; and 3) the expression of the bcl2, p53, Rb, p16, and p27 proteins. Expression of bcl6, CD10, and bcl2 proteins was found in 54/79 (68%), 28/79 (35%), and 47/74 (63%) cases, respectively. The bcl6/CD10 patterns were as follows: bcl6+/CD10+ (26 cases, 32%), bcl6+/CD10- (28 cases, 33%), bcl6-/CD10- (23 cases, 31%), and bcl6-/CD10+ (2 cases, 4%). Significant positive correlations were found between bcl6/Ki67 (r =.328, P =.003), bcl6/cyclin A (r =.265, P =.018), bcl6/apoptotic index (r =.327, P =.010), CD10/Ki67 (r =.296, P =.008), and CD10/apoptotic index (r =.397, P =.001). In addition, high expression of bcl6 showed significant correlation with negative (null/low) bcl2 expression (chi(2) test, P =.002). The above findings indicate that increased expression of the bcl6 and CD10 proteins is associated with increased apoptosis and proliferation in diffuse large B-cell lymphomas. The association between increased bcl6 expression and enhanced apoptosis might be due, at least in part, to the null/low bcl2 expression because previous in vitro data showed that bcl6 overexpression induces apoptosis accompanied by bcl2 and bcl-xl downregulation. Moreover, significant correlation was found between increased apoptotic index and the bcl6+/CD10+ pattern (t test: P =.014, Mann-Whitney test: P =.046). This finding and the positive correlation of the apoptotic index with bcl6 and CD10 expression may be related to previous results showing that the expression of these proteins has favorable effects on the clinical outcome of diffuse large B-cell lymphomas.
Assuntos
Apoptose , Proteínas de Ligação a DNA/metabolismo , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Neprilisina/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais , Contagem de Células , Divisão Celular , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-6RESUMO
The expression of the cyclin-dependent kinase inhibitor (CDKI) p27 protein was investigated in relation to (1) the expression of the cell cycle regulators p53, Rb and p16 and (2) the proliferation profile as determined by the expression of Ki67, cyclin A, and cyclin B1 in 80 cases of de novo diffuse large B-cell lymphomas (DLBCL). P27 expression was low/null in large tumor cells in 58/80 cases and intermediate/high in 22/80 cases. Increased expression of p53 protein was observed in 39/80 cases. Decreased expression of Rb and p16 proteins was mutually exclusive and was observed in 5/80 and 14/80 cases, respectively. The analysis of the p27 expression status (low/null versus intermediate/high) with respect to the p53 and/or Rb/p16 expression status showed that low/null p27 expression was significantly correlated with increased p53 expression (P =.018) and showed a strong trend for correlation with concurrent increased p53 expression and decreased Rb or p16 expression (P =.050). These findings suggest a tendency for concurrent alterations of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL, which might result in impaired tumor growth control. Indeed, the analysis of the combined p27/p53/Rb/p16 expression status with respect to the proliferation profile showed that (1) three alterations in the combined p27/p53/Rb/p16 status (i.e., low/null P27 expression, increased expression of p53, and decreased expression of Rb or p16) were significantly correlated with increased expression of cyclin B1 (P =.005) and (2) two or three alterations were significantly correlated with increased expression of cyclin A (P =.014). These findings suggest combined impairment of a complex cell-cycle control network involving the CDK inhibitor p27, the P53 pathway, and the Rb1 pathway, which exerts a cooperative effect resulting in enhanced tumor cell proliferation.