RESUMO
AIMS: To assess the risk, for patients with thymoma, of developing an additional malignancy (AM). METHODS AND RESULTS: We studied 68 patients with thymomas. Based on the World Health Organization classification, the tumours were categorised as A, AB or B (B1, B2, B3) thymomas. Control populations comprised 114 patients with colorectal cancer, 108 patients with lymphoma and 123 patients with thyroid carcinoma. Patients with thymomas showed a higher risk of developing an AM (22 of 68 patients versus 11 of 114, eight of 108, and eight of 123 patients, respectively; P = 0.0002). The association between thymomas and AMs was related to the thymoma histotype, with B1, B2, B3 and AB tumours showing a higher risk of developing an AM than A thymomas (P = 0.0474). CONCLUSIONS: Patients affected by thymomas showed a significantly higher risk of developing additional malignancies than those in the control groups, and cases that exhibited a predominantly cortical component were more likely to develop other neoplasms. This may be related to the functions of cortical thymic epithelial cells in providing for T lymphocyte maturation through interaction with major histocompatibility complexes.
Assuntos
Hospedeiro Imunocomprometido , Vigilância Imunológica/imunologia , Neoplasias Primárias Múltiplas/imunologia , Timoma/imunologia , Neoplasias do Timo/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/imunologia , Timoma/patologia , Neoplasias do Timo/patologia , Adulto JovemRESUMO
Analyses of the tumour immunoglobulin (Ig) gene (IG) heavy (H) and light chains show heterogeneity of mutational status, but reveal common features of ongoing IGH isotype-switching with multiple IGH isotype expression and preference of IG lambda (IGL) light chain with selective use of IGLJ3. Phenotypic and immunogenetic analyses were performed in a series of 105 HCL patients to estimate prevalence of multiple IG light chain expression by the tumour cells. By phenotype, 3/105 HCL (2.9%) expressed double tumour-related Ig kappa (K) and L light chain proteins. By immunogenetic analysis, functional mutated double IGK(I) /IGK(II) , IGK(I) /IGL(I) and IGL(I) /IGL(II) transcripts were cloned and sequenced in 3/71 (4.2%) HCL. These latter three HCL expressed multiple IGH isotypes with mutated IGHVDJ rearrangements at the time of AID transcript expression. Most interestingly, the three cases had reinduced RAG1 transcript. In the double IGL expresser, single-cell analysis documented co-expression of the tumour-related IGLs in 5/6 cells (83%). In the IGK/IGL co-expresser, evidence of surface IgK/IgL isotype proteins confirmed functionality of the tumour-derived transcripts. The evidence of double light chain expression in single HCs and the new observation of RAG re-induction suggest ongoing selective influences on the BCR that may promote or maintain the HCL clone in the periphery.
Assuntos
Rearranjo Gênico de Cadeia Leve de Linfócito B , Leucemia de Células Pilosas/genética , Receptores de Antígenos de Linfócitos B/genética , Alelos , Proteínas de Homeodomínio/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia de Células Pilosas/imunologiaRESUMO
Recent studies suggest that Epstein-Barr virus (EBV) can infect naïve B cells, driving them to differentiate into resting memory B cells via the germinal center reaction. This hypothesis has been inferred from parallels with the biology of normal B cells but has never been proven experimentally. Rag2(-/-) gamma(c)(-/-) mice that were transplanted with human CD34(+) cord blood cells as newborns were recently shown to develop human B, T, and dendritic cells, constituting lymphoid organs in situ. Here we used this model to better define the strategy of EBV infection of human B cells in vivo and to compare this model system with different conditions of EBV infection in humans. Our results support the model of EBV persistence in vivo in cases that were characterized by follicular hyperplasia and a relatively normal CD4(+) and CD8(+) T-cell distribution. Intriguingly, in cases that were characterized by nodular and diffuse proliferation with a preponderance of CD8(+) T cells, similar to infectious mononucleosis, EBV still infects naïve B cells but also induces clonal expansion and ongoing somatic mutations without germinal center reactions. Our results reveal different strategies of EBV infection in B cells that possibly result from variations in the host immune response. Future experiments might allow understanding of the mechanisms responsible for persistent EBV infection and provide targets for more highly tailored therapeutic interventions.
Assuntos
Antígenos CD34/metabolismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Proteínas de Ligação a DNA/deficiência , Infecções por Vírus Epstein-Barr/patologia , Sangue Fetal/citologia , Sangue Fetal/transplante , Imunoglobulina G/genética , Animais , Linfócitos B/virologia , Contagem de Células Sanguíneas , Proliferação de Células , Células Clonais , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Humanos , Imunofenotipagem , Lasers , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Camundongos , Microdissecção , Proteínas Virais/metabolismo , Latência Viral/genéticaRESUMO
Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by in vitro studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro, to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites.
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Cdk9/Cyclin T1 complex is very important in controlling specific differentiative pathways of several cell types. Limited data are available regarding the expression of Cdk9/Cyclin T1 in hematopoietic and lymphoid tissues. Cdk9/Cyclin T1 expression seems to be related to particular stages of lymphoid differentiation/activation. In this study, we observed that the expression level of Cdk9/Cyclin T1 in vivo increases in memory B cells compared to naïve B cells, and in activated B cells, compared to non-activated ones. The expression level of the Cdk9/Cyclin T1 complex does not increase in cells induced to differentiate in vitro. In addition, we showed that Cdk9 interacts with E12 and E47, specifically activated during Germinal Center (GC) reaction. Taken together this data suggests an active role for the Cdk9/Cyclin T1 complex during lymphoid differentiation through germinal center reaction.
Assuntos
Linfócitos B/citologia , Linfócitos B/enzimologia , Diferenciação Celular , Quinase 9 Dependente de Ciclina/metabolismo , Ciclinas/metabolismo , Ativação Linfocitária/imunologia , Linfócitos B/metabolismo , Sobrevivência Celular , Ciclina T , Quinase 9 Dependente de Ciclina/genética , Ciclinas/genética , Regulação da Expressão Gênica , Centro Germinativo/enzimologia , Humanos , Células Jurkat , Linfonodos/enzimologia , Microscopia Confocal , Ligação Proteica , Transporte Proteico , Fatores de Transcrição TCF/metabolismo , Proteína 1 Semelhante ao Fator 7 de TranscriçãoRESUMO
The immunohistochemical expression of phosphorylated (activated) Akt (pAkt) in 50 advanced gastric carcinomas has been analyzed and the results correlated with age, sex, location in the stomach, histotype, stage, survival, mitotic and apoptotic index, some cell cycle regulators (cyclin D1, cyclin E, p34/cdc2, p27/kip1), and cell proliferation. There was a statistically significant direct correlation between pAkt expression (both cytoplasmatic and nuclear) and depth of infiltration of the tumor, number of infiltrated lymph nodes and p34/cdc2 expression, and between prevalently nuclear pAkt and cyclin D1 and cyclin E. Conversely, there was a significant inverse correlation between nuclear pAkt and apoptotic index and between cytoplasmatic and nuclear pAkt and patient survival. No correlation was found between pAkt and sex, age, tumor location, histotype, mitotic index, and cell proliferation. These findings suggest that pAkt may be considered an indicator of tumor progression and patient survival in gastric cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Proteína Quinase CDC2/metabolismo , Proliferação de Células , Ciclina D1/metabolismo , Ciclina E/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Análise de Sobrevida , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Data are controversial as to the role of menarche age as a risk factor of high-risk human papillomavirus (HR-HPV) infections. The objective of this study was to analyse the risk estimates for age at menarche as determinant of cervical intraepithelial neoplasia (CIN) and HR-HPV infections. A cohort of 3187 women were stratified into three groups according to their age at menarche: (i) women <13 years of age; (ii) those between 13 and 14 years and (iii) women >15 years of age. These groups were analysed for predictors of (a) HR-HPV, (b) high-grade CIN and (c) outcome of HR-HPV and cytological abnormalities during prospective follow-up. All the three groups had identical prevalence of HR-HPV, Papanicolaou smear abnormalities and CIN grades. In contrast to menarche age itself, the time from menarche to the first intercourse (TMI), to the first pregnancy (TMP) and to the first delivery (TMD) were all significant (P = 0.0001) predictors of HR-HPV (but not CIN2) in univariate analysis, but lost their significance in a multivariate model. Outcome of cervical disease and HR-HPV infection was unrelated to menarche age, the latter and the three intervals being not predictors of CIN2 in a multivariate model. In conclusion, age at menarche and the intervals between menarche and (i) onset of sexual activity, (ii) first pregnancy and iii) first delivery, are not independent predictors of HR-HPV infections and CIN2 in multivariate analysis.
Assuntos
Menarca , Infecções por Papillomavirus/epidemiologia , Displasia do Colo do Útero/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Parto Obstétrico/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Teste de Papanicolaou , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Gravidez/estatística & dados numéricos , Fatores de Risco , Comportamento Sexual/estatística & dados numéricos , Fatores de Tempo , Esfregaço Vaginal , Displasia do Colo do Útero/patologiaRESUMO
Beclin 1 is is an autophagy gene, the role of which as a tumour suppressor has recently been recognized in a few studies. We examined the expression of Beclin 1 protein in 212 primary human brain tumours, including 97 high-grade glial tumours, 29 low-grade glial tumours, 4 grade III meningiomas, 19 grade II meningiomas, 52 grade I meningiomas, and 11 medulloblastomas. In 94 cases, including 56 glial tumours, 35 meningiomas, and 3 medulloblastomas we also assessed Beclin 1 mRNA expression by real-time RT-PCR. In most high-grade astrocytic, ependymal neoplasms and atypical meningiomas we found a decrease of cytoplasmic protein expression that was, instead, high in the majority of low-grade tumours and in medulloblastomas. The expression level of Beclin 1 mRNA was significantly lower in glioblastomas than in grade II (p=0.04) and grade I (p=0.01) astrocytomas; in grade III than in grade I astrocytomas (p=0.01); in grade II than in grade I meningiomas (p=0.03); and in all glial tumours when compared to all meningiomas (p<0.0001). Cytoplasmic expression is thought to be linked to the functional protein. Our observations are in line with studies that demonstrated decreased expression of Beclin 1 in human breast, ovarian, prostate and ovarian cancer and furtherly support its involvement also in brain tumours, which had previously been demonstrated in a few experimental studies, both in spontaneous and in therapy-induced autophagy. Furthermore, our study suggests possible differences of Beclin 1 involvement and its role among the different histotypes of brain neoplasms. Further studies are needed to highlight Beclin 1 function in tumour suppression and/or in tumour survival through autophagy and other related programmed cell death processes in brain tumours.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica , Meduloblastoma/metabolismo , Proteínas de Membrana/biossíntese , Meningioma/metabolismo , Oligodendroglioma/metabolismo , RNA Mensageiro/metabolismo , Proteínas Reguladoras de Apoptose/fisiologia , Autofagia , Proteína Beclina-1 , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Meduloblastoma/patologia , Proteínas de Membrana/fisiologia , Meningioma/patologia , Oligodendroglioma/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Vascular Endothelial Growth Factor (VEGF)-D is a member of the VEGF family of angiogenic growth factors that activate the Vascular Endothelial Growth Factor Receptor (VEGFR)-2 and VEGFR-3, which are mainly expressed in blood and lymphatic vessels. Here we have analyzed by using monoclonal antibodies, the expression of VEGF-D and its cognate receptor VEGFR-3 in normal and pathologic bone marrow and lymph node biopsies. This analysis revealed that VEGF-D is expressed in B cells of the germinal centers, scattered B and T blasts, myeloid progenitors, acute leukemia, several types of non Hodgkin lymphoma, and classical Hodgkin's lymphoma. In normal tissues VEGFR-3 was only expressed in fenestrated capillaries of bone marrow and in lymphatic vessels of lymph nodes, while in VEGF-D expressing tumors newly formed vessels, but not malignant cells, showed high VEGFR-3 expression. These data suggest that VEGF-D could contribute to leukemia and lymphoma growth via the induction of angiogenesis in bone marrow and lymphoid tissues.
Assuntos
Regulação Leucêmica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Linfócitos/metabolismo , Fator D de Crescimento do Endotélio Vascular/biossíntese , Anticorpos Monoclonais/química , Biópsia , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Células HL-60 , Humanos , Células K562 , Linfonodos/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Tumour-infiltrating lymphocytes (TILs) represent the local immune response to cancer, however, their correlation with tumour behaviour is not unanimously considered in the literature. Most studies have not characterized TILs, that are known to comprise distinct subsets, bearing different roles in the complex tumour microenvironment. Characterization of patient lymphocytes has been mainly performed in peripheral blood, that is not always representative of the local immune status. Only few investigations have been performed at the tissue level in cancer, including melanoma. TILs encompass different populations of effector and regulatory T cells (Tregs), and the relevance of the latter in tumour progression is widely accepted. The transcription factor gene product FOXP3 is considered the most reliable marker of Tregs. However, it has not been extensively evaluated in primary cutaneous melanoma. We analyzed 66 vertical growth phase primary cutaneous melanomas, aiming at finding differences in TIL subsets between two groups of cases, that behaved differently in terms of local recurrence. In our study, the percentage of Tregs, as characterized by CD25 and FOXP3 expression, both among tumour cells, inside tumour parenchyma and at its periphery, and among TILs, at the tumour-stroma boundary, was significantly higher in cases that recurred than in those that did not (p=0.00065; p=0.00014; p<0.00001, respectively). TIL characterization by immunohistochemistry in melanoma diagnostic reports, could add further information. The analysis of a larger series of patients and correlation with other clinical parameters, such as distant metastases and/or patient survival, are mandatory for validating its use as a prognostic indicator.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Recidiva Local de Neoplasia/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Feminino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/imunologiaRESUMO
BACKGROUND: The growth-controlling functions of the high-risk human papillomaviruses (HPV) depend on their ability to interact with several cellular proteins, including the key regulatory proteins of the cell cycle. We have examined the value of cell cycle regulatory proteins as predictors of the intermediate end point markers in cervical carcinogenesis: (a) grade of cervical intraepithelial neoplasia (CIN), (b) high-risk HPV type, (c) clearance/persistence of high-risk HPV, and (d) disease outcome in women participating in a multicenter follow-up study in three New Independent States countries. METHODS: Totally, 232 biopsy samples tested high-risk HPV-positive and/or Papanicolaou smear-positive women were immunohistochemically stained for the following cell cycle markers: p105, p107, p130, E2F4, p21(CIP1/WAF1/SDI1), cyclin A, and Ki-67. In addition, apoptotic index (AI) and mitotic index (MI) were determined in H&E-stained sections. Prospective follow-up data were available to disclose the clinical and virological outcome of the lesions. RESULTS: The expression of Ki-67, p21(CIP1/WAF1/SDI1), and cyclin A and AI and MI values were markedly increased in high-grade lesions, but only MI was an independent predictor of CIN3 in multivariate analysis. Cyclin A was the only independent predictor of high-risk HPV (odds ratio, 1.09; 95% confidence interval, 1.01-1.18; P = 0.021), exceeding the predictive power of CIN grade and high-grade squamous intraepithelial lesion Papanicolaou smears. None of these markers provided any useful predictive information as to the clinical and virological outcomes during the follow-up. Highly significant correlations (P = 0.0001) were found between AI and MI as well as between MI and cyclin A, Ki-67 and p21(CIP1/WAF1/SDI1), Ki-67 and cyclin A, and p21(CIP1/WAF1/SDI1) and cyclin A followed by that between p105 and cyclin A (P = 0.001) and p105 and p130 (P = 0.002). CONCLUSIONS: All tested factors related to cell cycle were increased, but only MI and cyclin A was an independent predictor of CIN3 and high-risk HPV carriage, respectively.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/metabolismo , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/metabolismo , Ciclo Celular , Estudos de Coortes , Estudos Transversais , Ciclina A/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , DNA Viral/genética , Fator de Transcrição E2F4/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Proteína do Retinoblastoma/metabolismo , Proteína p107 Retinoblastoma-Like/metabolismo , Proteína p130 Retinoblastoma-Like/metabolismo , Fatores de Risco , U.R.S.S. , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologiaRESUMO
Macrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in various biological processes. Although MIF's functions in cancer have not been completely elucidated, its expression has usually been correlated with tumour progression and aggressiveness, and it is currently discussed as a new promising target for novel therapies. Recent studies seem to confirm its active role in melanoma pathobiology; however, its expression has not yet been extensively studied in melanocytic tumours. We evaluated MIF protein expression in 126 skin lesions, including benign and atypical nevi, melanoma and melanoma metastases. In 55 cases, we also assessed MIF mRNA expression by real-time RT-PCR. Benign nevi were subdivided into nevocytic and Spitz/blue types; and melanomas into the radial, and vertical growth phase. A strong cytoplasmic MIF positivity was found in most samples, although it was more heterogeneous in malignant tumours; MIF nuclear expression characterized Spitz/blue nevi, atypical nevi, melanomas and metastases. All samples expressed MIF mRNA but it was significantly lower in benign nevi vs atypical nevi, melanomas and metastases (p=0.001; p<0.0001; p=0.002, respectively). Our study shows a widespread distribution of MIF among melanocytic tumours. Whereas we observed a trend towards higher expression levels of mRNA in atypical and malignant tumours, MIF protein was highly expressed in all lesions, although limited to the cytoplasm in most benign nevi. These observations suggest differences in MIF protein storage, subcellular location and properties in most benign nevi vs atypical and malignant tumours that should be confirmed by further investigation and correlation with clinical outcome.
Assuntos
Fatores Inibidores da Migração de Macrófagos/metabolismo , Melanoma/metabolismo , Nevo Pigmentado/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Humanos , Imuno-Histoquímica , Fatores Inibidores da Migração de Macrófagos/genética , Melanoma/patologia , Metástase Neoplásica , Nevo Pigmentado/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/patologiaRESUMO
We set out to analyze the presence of Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) in different neoplasms occurring in East Africa, a region characterized by a high KSHV/HHV-8 seroprevalence rate and endemic Kaposi's sarcoma (KS). Our results suggest that, in endemic regions of Africa, KSHV/HHV-8 is predominantly associated with KS, independently of HIV status. During the course of this study, other important information came to light. We found the presence of KSHV/HHV-8 in 2 cases of lymph nodes partially involved by Burkitt's lymphoma and KS and in 1 case of multicentric Castleman disease. Our immunophenotypic and molecular data seem to suggest 2 different mechanisms of viral infection are at work in lymphoid cells. On one hand, when B cells show a latent phase infection with KSHV/HHV-8, after the germinal center reaction, naive B cells become resting memory B cells, similarly to Epstein-Barr virus-infected B cells. On the other hand, when lytic genes such as vIL6 are expressed in naive B cells, they may be driven to differentiate into plasmablasts without undergoing germinal center reaction. Interestingly, among KSHV/HHV-8-positive cases, in those in which there was also lymphoma, the neoplastic cells were negative for KSHV/HHV-8. This further confirms that KSHV/HHV-8 is involved in the neoplastic transformation of only certain types of lymphoma, probably in relation to their precursor infected cell. In conclusion, the maturation stage of KSHV/HHV-8-positive B cells as well as the type of viral infection may well determine the morphological, phenotypic, and clinical characteristics of KSHV/HHV-8-associated lymphomas.
Assuntos
Centro Germinativo/virologia , Herpesvirus Humano 8/isolamento & purificação , Linfoma/virologia , Sarcoma de Kaposi/virologia , Adulto , Antígenos Virais , Linfócitos B/patologia , Linfócitos B/virologia , Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/virologia , Transformação Celular Neoplásica , Criança , DNA Viral/análise , Feminino , Centro Germinativo/patologia , HIV/genética , HIV/isolamento & purificação , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares , RNA Viral/análise , Estudos Retrospectivos , Sarcoma de Kaposi/patologiaRESUMO
BACKGROUND: Oral contraception (OC) has been proclaimed by the IARC as a risk factor of cervical cancer (CC), on prolonged use by high-risk human papillomavirus (HPV) positive women. However, the available data are far from complete, and more evidence is necessary on the potential confounding effects of sexual behavior and HPV infection. The aim of the present was study to analyse the risk estimates for OC users in order to develop several intermediate end-point markers in cervical carcinogenesis. PATIENTS AND METHODS: A cohort of 3,187 women, enrolled in a multi-center screening trial in three New Independent States (NIS) of the former Soviet Union (the NIS Cohort Study), was stratified into three groups according to their contraception modes: i) non-users of contraception, ii) non-OC users and iii) OC users. These groups were analysed forpredictors of three outcome measures: a) exposure to HR-HPV; b) progression to high-grade cervical intraepithelial neoplasia (CIN2/3 and HSIL); and c) persistence/clearance of HR-HPV and cytological abnormalities during a prospective follow-up. RESULTS: All three groups had an identical prevalence of HR-HPV (HCII and PCR), Pap smear abnormalities and CIN histology, but differed significantly (p=0.0001) with regard to all key variables of sexual behaviour, known as risk factors for CC. Predictors of HR-HPV, CIN2/3 and HSIL were different in the three groups, reflecting these different sexual preferences. Use of OC was not a significant predictor of CIN2/3 or HSIL in HPV-positive or HPV-negative women. Outcomes of cervical disease and HR-HPV infection were unrelated to contraception. In a multivariate regression model mode of contraception was of no predictive value for either HR-HPV or high-grade CIN. CONCLUSION: Sexual behaviour is different among OC users, non-OC users and in nonusers of contraception; these risk factors predispose women to HR-HPV, high-grade CIN, and determine the outcome of their cervical disease/HR-HPV infection. The use of OC is not an independent risk factor for any of these intermediate end-point markers of cervical carcinogenesis. Failure to record these epidemiological data inevitably leads to erroneous conclusions about the role of OC as an independent risk factor of cervical cancer.
Assuntos
Anticoncepcionais Orais/efeitos adversos , Infecções por Papillomavirus/complicações , Displasia do Colo do Útero/etiologia , Neoplasias do Colo do Útero/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Fatores de Risco , Neoplasias do Colo do Útero/induzido quimicamente , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/induzido quimicamente , Displasia do Colo do Útero/virologiaRESUMO
Tat protein is an early nonstructural protein necessary for virus replication, which is secreted by infected cells and taken up by uninfected cells. Extensive evidence indicates that Tat may be a cofactor in the development of AIDS-related neoplasms. The molecular mechanism underlying Tat's oncogenic activity may include deregulation of cellular genes. Among these genes, it has recently been shown that pRb2/p130 oncosuppressor protein is one of the targets in the interaction between HIV gene product Tat and host proteins. However, whether the HIV-1 gene product Tat may inactivate the oncosuppressive function of pRb2/p130 has not yet been elucidated. Here, we show that mRNA levels of pRb2/p130 increase in the presence of Tat, whereas no change in the phosphorylation status of pRb2/p130 is observed. In addition, Tat can inhibit the growth control activity exerted by pRb2/p130 in the T98G cell line. Finally, Tat does not compete with E2F-4 in binding to pRb2/p130. The interaction between Tat and pRb2/p130 seems to result in the deregulation of the control exerted by pRb2/p130 on the cell cycle. Taken together, these results open a window on the role of pRb2/p130 in AIDS-related oncogenesis.
Assuntos
Produtos do Gene tat/metabolismo , HIV-1/metabolismo , Linfoma Relacionado a AIDS/etiologia , Fosfoproteínas/metabolismo , Proteínas , Proteína do Retinoblastoma/metabolismo , Linhagem Celular , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Humanos , Linfoma Relacionado a AIDS/metabolismo , Proteína p130 Retinoblastoma-Like , Transfecção , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
OBJECTIVE: In the present study we evaluated the protein distribution and mRNA levels of inhibin alpha-subunit and its coreceptor betaglycan in endometrial adenocarcinoma. DESIGN: Two groups of postmenopausal women were studied: the first group had recently diagnosed endometrial adenocarcinoma (n = 16; age range 61-79 years), and the second group (n = 12; age range 64-78 years) had undergone hysterectomy for uterine prolapse and served as control. METHODS: Inhibin alpha-subunit and betaglycan gene expression and tissue distribution were evaluated by semiquantitative RT-PCR and immunohistochemistry respectively. RESULTS: Inhibin alpha-subunit and betaglycan mRNAs were expressed by both healthy and tumoral endometria, but their expression was significantly lower in endometrial carcinoma (P < 0.001, based on Student's t test). Inhibin alpha-subunit expression was much weaker in the glands of tumours than in non-neoplastic specimens. Betaglycan protein was identified in the epithelial cells lining non-tumoral endometrium, and in endothelial cells of both normal and tumoral endometria. Well-differentiated neoplastic cells had a faint and scarce betaglycan staining, and poorly differentiated cells did not express betaglycan at all. CONCLUSIONS: The lower inhibin alpha and betaglycan expression in endometrial adenocarcinoma suggests that the inhibin action may be disrupted. However, the expression of betaglycan in the endothelia of the tumour vasculature suggests that a selective vascular response to inhibin may be possible in these tumours.
Assuntos
Adenocarcinoma/fisiopatologia , Neoplasias do Endométrio/fisiopatologia , Inibinas/genética , Proteoglicanas/genética , Receptores de Peptídeos/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Ativinas , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Regulação para Baixo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inibinas/metabolismo , Pessoa de Meia-Idade , Pós-Menopausa , Proteoglicanas/metabolismo , RNA Mensageiro/análise , Receptores de Peptídeos/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
Prostate cancer is the second leading cause of cancer-related death. The androgen deprivation therapy is the standard treatment for advanced stages. Unfortunately, virtually all tumors become resistant to androgen withdrawal. The progression to castration-resistance is not fully understood, although a recent paper has suggested translationally controlled tumor protein to be implicated in the process. The present study was designed to investigate the role of this protein in prostate cancer, focusing on the correlation between its expression level with tumor differentiation and response to treatment. We retrieved 292 prostatic cancer specimens; of these 153 had been treated only by radical prostatectomy and 139 had undergone radical prostatectomy after neoadjuvant treatment with combined androgen blockade therapy. Non-neoplastic controls were represented by 102 prostatic peripheral zone specimens. In untreated patients, the expression of the protein, evaluated by RT-qPCR and immunohistochemistry, was significantly higher in tumor specimens than in non-neoplastic control, increasing as Gleason pattern and score progressed. In treated prostates, the staining was correlated with the response to treatment. An association between protein expression and the main clinicopathological factors involved in prostate cancer aggressiveness was identified. These findings suggest that the protein may be a promising prognostic factor and a target for therapy.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Adenocarcinoma/tratamento farmacológico , Idoso , Androgênios/uso terapêutico , Progressão da Doença , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Gradação de Tumores/métodos , Prostatectomia/métodos , Neoplasias da Próstata/tratamento farmacológico , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Rim/metabolismo , Biomarcadores Tumorais/metabolismo , Western Blotting , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Rim/patologia , Reação em Cadeia da Polimerase em Tempo Real , Coloração e Rotulagem , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Hurthle cell adenomas and carcinomas, characterized by the presence of oncocytic cells, are unusual thyroid neoplasms, the treatment of which is still controversial. We analyzed specimens from 49 patients with oncocytic cell nodular lesions including 20 adenomas, 19 carcinomas, and 10 hyperplasias for RET/PTC (papillary thyroid carcinoma) activation, which is the most frequent genetic alteration in PTCs. RET/PTC activation was detected in a significant number of cases of Hurthle cell adenomas and carcinomas, but in 0 of 10 patients with hyperplastic nodules. In particular, the RET/PTC1 isoform was found in 7 of 12 adenomas and 4 of 7 carcinomas. These results would indicate that RET/PTC is a genetic event common to papillary carcinomas and to Hurthle cell neoplasias.
Assuntos
Adenoma Oxífilo/metabolismo , Carcinoma/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adenoma Oxífilo/patologia , Carcinoma/patologia , Humanos , Hiperplasia/metabolismo , Imuno-Histoquímica , Proteínas Tirosina Quinases , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
PURPOSE: Although the retinoblastoma gene (RB/p105) has been intensely investigated as a prototype suppressor gene in humans, mutational data on the Rb family member pRb2/p130 (p130) has only recently been reported. A protective role against apoptosis has been suggested for pRb/p105, both in vitro and in vivo. However, only limited information is available on the role of pRb2/p130 in controlling apoptosis. The purpose of this study was to determine the extent of a role of this gene in the neoplasms that give the Rb family its name. METHODS: Forty-two human retinoblastomas were retrospectively examined by immunohistochemical labeling of the Rb-related proteins and the results compared with cellular kinetic characteristics: the apoptotic index (AI) and the mitotic index (MI). RESULTS: The retinoblastomas that did not express p130 showed a significantly lower AI than those that expressed p130. This result was also supported by flow cytometry on a human Saos-2 cell line that was transiently transfected with RB2/p130. The p130(-) tumors displayed a lesser degree of differentiation than the p130(+) ones. CONCLUSIONS: These observations give evidence that expression of p130 is inversely correlated with higher rates of apoptosis in human retinoblastomas and give an additional example of this regulator's role in cellular differentiation.