RESUMO
Oesophageal cancer is one of the most aggressive malignancies with limited treatment options, thus resulting in a high morbidity and mortality. With 5year survival rates of only 510%, oesophageal cancer holds a dismal prognosis for patients. In order to improve overall survival, the early diagnosis and tools for patient stratification for personalized treatment are urgent needs. A minority of oesophageal cancers belong to the spectrum of Lynch syndromeassociated cancers and are characterized by microsatellite instability (MSI). Microsatellite instability is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumours, such as colorectal and gastric cancer. In the latter, high levels of MSI are associated with a better prognosis and with an increased benefit to immunebased therapies. Therefore, similar therapeutic approaches could offer an opportunity of treatment for oesophageal cancer patients with MSI. Apart from immune checkpoint inhibitors, other immunotherapies such as adoptive Tcell transfer, peptide vaccine and oncolytic viruses are under investigation in oesophageal cancer patients. In the present review, the rationale and current knowledge about immunotherapies in oesophageal cancer are summarised.
Assuntos
Neoplasias Esofágicas/terapia , Imunoterapia/métodos , Animais , Vacinas Anticâncer/uso terapêutico , Neoplasias Esofágicas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia Viral Oncolítica/métodosRESUMO
Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2-9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Imunoterapia/métodos , Instabilidade de Microssatélites , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Pancreáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Intervalo Livre de Doença , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Pancreatectomia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Seleção de Pacientes , Medicina de Precisão/métodos , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. METHODS: In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip. FINDINGS: We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma. INTERPRETATION: DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma. FUNDING: German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.
Assuntos
Metilação de DNA , Neoplasias Meníngeas/classificação , Neoplasias Meníngeas/genética , Meningioma/classificação , Meningioma/genética , Recidiva Local de Neoplasia/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Genoma , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Neurofibromina 2/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-akt/genética , Estudos Retrospectivos , Análise de Sequência de RNA , Receptor Smoothened/genética , Taxa de Sobrevida , Fatores de Transcrição/genética , Transcriptoma , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade MPNST, three malignant Triton tumors, six low-grade MPNST, four epithelioid MPNST, 33 neurofibromas (15 dermal, 8 intraneural, 10 plexiform), six atypical neurofibromas, 43 schwannomas (including 5 NF2 and 5 schwannomatosis associated cases), 11 cellular schwannomas, 10 melanotic schwannomas, 7 neurofibroma/schwannoma hybrid tumors, 10 nerve sheath myxomas and 10 ganglioneuromas. Schwannomas formed different epigenomic subgroups including a vestibular schwannoma subgroup. Cellular schwannomas were not distinct from conventional schwannomas. Nerve sheath myxomas and neurofibroma/schwannoma hybrid tumors were most similar to schwannomas. Dermal, intraneural and plexiform neurofibromas as well as ganglioneuromas all showed distinct methylation profiles. Atypical neurofibromas and low-grade MPNST were indistinguishable with a common methylation profile and frequent losses of CDKN2A. Epigenomic analysis finds two groups of conventional high-grade MPNST sharing a frequent loss of neurofibromin. The larger of the two groups shows an additional loss of trimethylation of histone H3 at lysine 27 (H3K27me3). The smaller one retains H3K27me3 and is found in spinal locations. Sporadic MPNST with retained neurofibromin expression did not form an epigenetic group and most cases could be reclassified as cellular schwannomas or soft tissue sarcomas. Widespread immunohistochemical loss of H3K27me3 was exclusively seen in MPNST of the main methylation cluster, which defines it as an additional useful marker for the differentiation of cellular schwannoma and MPNST.
Assuntos
Neoplasias de Bainha Neural/patologia , Neurilemoma/patologia , Neurofibromatoses/patologia , Neoplasias Cutâneas/patologia , Humanos , Metilação , Neoplasias de Bainha Neural/classificação , Neoplasias de Bainha Neural/metabolismo , Neurilemoma/classificação , Neurilemoma/diagnóstico , Neurilemoma/metabolismo , Neurofibromatoses/classificação , Neurofibromatoses/metabolismo , Neurofibromina 1/metabolismo , Sarcoma/patologia , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/metabolismoRESUMO
The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher's exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression (P < .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma.
Assuntos
Neoplasias Meníngeas/genética , Meningioma/genética , Mutação , Recidiva Local de Neoplasia/genética , Regiões Promotoras Genéticas , Telomerase/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Progressão da Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Prognóstico , Regiões Promotoras Genéticas/genética , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Smooth muscle cells (SMC) are common components of endometriotic lesions. SMC have been characterized previously in peritoneal, ovarian and deep infiltrating endometriotic lesions and adenomyosis. The aim of this retrospective study was to investigate the extent of differentiation in endometriosis-associated SMC (EMaSMC) in peritoneal endometriotic lesions. METHODS: We obtained biopsies from peritoneal endometriotic lesions (n = 60) and peritoneal sites distant from the endometriotic lesion (n = 60), as well as healthy peritoneum from patients without endometriosis (control tissue, n = 10). These controls were hysterectomy specimens from patients without endometriosis or adenomyosis. Histopathological examination of peritoneal specimens using antibodies against oxytocin receptor (OTR), vasopressin receptor (VPR), smooth muscle myosin heavy chain (SM-MHC), estrogen receptor (ER) or progesterone receptor (PR) was performed. To identify SMC and their level of differentiation, antibodies for smooth muscle actin desmin and caldesmon were used. RESULTS: SMC were detected in all endometriotic lesions. SMC were more abundant in unaffected peritoneum of women with endometriosis (38%) compared with women without endometriosis (6%; P < 0.0001). Depending on the level of differentiation, SMC stained for SM-MHC, OTR, VPR, ER and PR. OTR was only detected in fully differentiated SMC. CONCLUSIONS: Identification of OTR, VPR, ER and PR leads to the hypothesis that the EMaSMC might be functionally active and possibly involved in the generation of pain associated with endometriosis.
Assuntos
Endometriose/patologia , Regulação da Expressão Gênica , Imuno-Histoquímica/métodos , Músculo Liso/metabolismo , Peritônio/patologia , Adulto , Biópsia/métodos , Diferenciação Celular , Feminino , Humanos , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/metabolismo , Pré-Menopausa , Receptores de Estrogênio/metabolismo , Receptores de Ocitocina/metabolismo , Receptores de Progesterona/metabolismo , Estudos RetrospectivosRESUMO
The transcription factor Ets-1 plays several distinct critical roles in tumour development and progression by acting both in neoplastic cells and in the tumour stroma. Increased expression of Ets-1 in tumours is often associated with a worse prognosis. Stromal fibroblasts attribute an important part to the behaviour of malignant tumours. In this study we investigated the role of Ets-1 in the tumour stroma. It is well known that ets-1 expression in fibroblasts--one of the main components of the tumour stroma--can be induced by basic fibroblast growth factor (bFGF). We applied suppression subtractive hybridization (SSH) to identify genes that are differentially expressed between bFGF stimulated wild-type fibroblasts and fibroblasts with reduced Ets-1 expression. We selected clones up- or down-regulated in bFGF stimulated wild-type fibroblasts using SSH and functionally characterized them by reference to public databases using NCBI BLAST tools. Expression levels of genes corresponding to subtracted clones were analyzed using RT-PCR. Known genes were associated with diverse functions; novel Ets-1 regulated genes identified by SSH not only encoded components involved in matrix degradation (as cathepsin and PAI-2) but also constituents of the extracellular matrix (ECM) including α-2-Type I collagen, TGF-ß induced protein, lumican and decorin. Our findings identify several potential novel target genes of Ets-1, and they provide potentially important insights into the role of Ets-1 in stromal fibroblasts for both remodelling and different functionalities of the ECM.
Assuntos
Fibroblastos/metabolismo , Regulação da Expressão Gênica , Proteína Proto-Oncogênica c-ets-1/metabolismo , Sítios de Ligação , Linhagem Celular , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Regiões Promotoras Genéticas/genética , Proteína Proto-Oncogênica c-ets-1/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Transcription factors are an important group of proteins. Changes in expression or activity of transcription factors result in diverse and manifold effects on the whole transcriptome of the cell. Therefore transcription factors are of special interest in physiological as well as pathological processes particularly tumour development and progression. In this review we focus on Ets-1, the prototype of the ETS family of transcription factors. ETS family members play important roles in development, differentiation and proliferation of cells in general and they are involved in apoptosis and tissue remodelling as well. Most of them are downstream nuclear targets of Ras-MAP kinase signalling and the deregulation of ets genes results in malignant transformation of different cells. Several ets genes are rearranged in human leukaemia, Ewing tumours and prostate cancer to produce chimeric oncoproteins. Furthermore, an aberrant expression of several ets genes is often observed in various types of human malignant tumours. With regard to the involvement of some ETS transcription factors, especially Ets-1, in malignant transformation and tumour progression (including invasion, metastasis and neoangiogenesis) through transactivation of cancer related genes, they are potential molecular targets for selective cancer therapy. In this review we focus on the roles of Ets-1 for tumour development and progression with special emphasis on tumour vascularization and invasion. We then discuss specific strategies for Ets-1 inhibition as a potential tool for cancer treatment.
Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Proteína Proto-Oncogênica c-ets-1/antagonistas & inibidores , Proteína Proto-Oncogênica c-ets-1/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neovascularização Patológica/metabolismo , Proteína Proto-Oncogênica c-ets-1/genéticaRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n = 37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor alpha and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Receptores ErbB/genética , Neoplasias de Bainha Neural/genética , Receptor ErbB-2/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Dosagem de Genes , Genes p16 , Genes p53 , Humanos , Imuno-Histoquímica , Neoplasias de Bainha Neural/metabolismo , PTEN Fosfo-Hidrolase/genética , Polimorfismo Conformacional de Fita Simples , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador alfa/genética , Fator de Crescimento Transformador alfa/metabolismo , TrastuzumabRESUMO
The description of neuroglia by Virchow in 1848 may be considered the starting point of our understanding of primary brain tumors. At the beginning of the 20th century, surgical removal of primary brain tumors became possible, and therefore, tissue for microscopic analysis and clinical data on survival became available. During this time, research on gliomas beyond improving surgical procedures focused on their classification. The classification schemes developed emphasized parameters for sorting tumors with regard to (i) cytological aspects; (ii) presumed tumor cell origin; (iii) histological appearance of the tissue; or (iv) clinical outcome. Over the years, experimental studies have greatly improved our knowledge on gliomas. Gliomas induced by viruses, chemicals, radiation, transgenes and knock-out technology contributed to the understanding of their pathogenesis and still serve as preclinical models for the testing of novel therapies. Recent advances in developmental neurobiology and the identification of stem cells provided new insights into the origin of brain tumors and the molecular mechanisms of tumor formation. This review briefly compiles the evolution of our concepts on gliomas, focusing on the latest developments.
Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/etiologia , Glioma/classificação , Glioma/etiologia , Animais , Neoplasias Encefálicas/patologia , Glioma/patologia , HumanosRESUMO
Malignant peripheral nerve sheath tumors (MPNST) are sarcomas with poor prognosis and limited treatment options. Factors contributing to tumor progression are largely unknown. We therefore examined MPNST from 22 neurofibromatosis type 1 (NF1) patients, 14 non-NF1 patients, and 14 neurofibroma patients for matrix metalloproteinase 13 (MMP-13) expression. Because wild-type and mutant p53 were shown to differentially regulate MMP-13 expression, TP53 status and protein levels were also determined. MMP-13 expression was detected in 58% of MPNST and was significantly associated with recurrent MPNST (P = .019). p53 was observed in 78% of MPNST and was found to be strongly associated with MMP-13 expression (P = .005). In contrast, 14 neurofibromas lacked MMP-13 and p53 expressions. TP53 mutations were found in only 11% of MPNST and were associated with high tumor grades (P = .029). No significant association between mutant TP53 and MMP-13 was observed, indicating that other factors drive MMP-13 expression in MPNST. The presence of metastasis was linked to p53Pro(72) polymorphism (P = .041) and shorter survival. In summary, our data suggest that MMP-13 expression in nerve sheath tumors is coupled with malignant progression. Therefore, MMP-13 may serve as a marker for progression and as a therapeutic target.
Assuntos
Biomarcadores Tumorais/fisiologia , Genes p53/fisiologia , Metaloproteinase 13 da Matriz/fisiologia , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Progressão da Doença , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes p53/genética , Humanos , Masculino , Metaloproteinase 13 da Matriz/biossíntese , Metaloproteinase 13 da Matriz/genética , Pessoa de Meia-Idade , Mutação , Neoplasias de Bainha Neural/genética , Neurofibroma/genética , Neurofibroma/metabolismo , Neurofibroma/patologiaRESUMO
BACKGROUND: The transcription factor avian erythroblastosis virus E26 (V-Ets) oncogene homolog 1 (Ets-1) is involved in tumor development and progression through the transcriptional regulation of several matrix-degrading enzyme systems, including matrix metalloproteinases (MMPs). It has been demonstrated that the MMPs are expressed strongly in high-grade meningiomas. To determine the biologic significance of Ets-1 in the progression of benign meningiomas, the authors investigated the expressions of Ets-1 and its target genes MMP-2 and MMP-9 in primary and recurrent, Grade 1 meningiomas. METHODS: The expression levels of Ets-1, MMP-2, and MMP-9 were examined by immunohistochemistry in 70 Grade 1 meningiomas, including 36 primary tumors without recurrence after 5 years of follow-up and 17 pairs of primary tumors and subsequent recurrences. RESULTS: The results demonstrated higher expression of Ets-1, MMP-2, and MMP-9 proteins in meningiomas with subsequent recurrences compared with meningiomas from patients who had no recurrences (P < .001). In addition, Ets-1 expression was correlated with the expression of both MMP-2 and MMP-9. CONCLUSIONS: Ets-1 may be involved in meningioma recurrence by up-regulating MMP-2 and MMP-9. Increased expression of these genes in World Health Organization grade 1 meningiomas may serve as an indicator for a high risk of recurrence.
Assuntos
Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Proteína Proto-Oncogênica c-ets-1/biossíntese , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fatores de Risco , Organização Mundial da SaúdeRESUMO
Matrix-degrading proteases play a key role in normal development, wound healing, many diseases such as rheumatoid arthritis and, in particular, tumour invasion. In invasive tumours, these enzymes are expressed by fibroblasts of the tumour stroma. Their expression and activity are tightly regulated at several levels, an important one being transcription. Previous in vitro and in vivo findings pointed to a major role of the Ets-1 transcription factor for this level of regulation. In the present study, we tried to prove this role in fibroblasts. We stimulated wild-type mouse fibroblasts with physiological doses of basic fibroblast growth factor (bFGF, known to induce different proteases and expressed by tumour cells) and compared the results to those obtained in Ets-1 -/- fibroblasts derived from Ets-1 knock-out mice. We found that basal Ets-1 levels are necessary not only for a fast induction of MMPs 2, 3 and 13 by bFGF but also for maintenance of the bFGF-induced expression of tissue inhibitors of metalloproteinases (TIMPs) 1, 2 and 3, which are known not only to inhibit but also participate as activators of certain pro-MMPs.
Assuntos
Fibroblastos/metabolismo , Metaloproteinases da Matriz/genética , Proteína Proto-Oncogênica c-ets-1/genética , Inibidores Teciduais de Metaloproteinases/genética , Animais , Células Cultivadas , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Knockout , Proteína Proto-Oncogênica c-ets-1/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
Platelet-derived growth factor receptor alpha (PDGFRalpha) and c-Kit are receptor tyrosine kinases. Both are targets of the tyrosine kinase inhibitor imatinib mesylate which is approved for treatment of some cancers. In order to assess the role of PDGFRalpha and c-Kit in malignant peripheral nerve sheath tumours (MPNST) we examined human tumours for structural alterations, protein and ligand expression. We investigated 34 MPNST, 6 corresponding plexiform neurofibromas (pNF) and 1 MPNST cell culture from 31 patients for mutations and polymorphisms in PDGFRA (exon 2-21) and KIT (exon 9, 11, 13, 17). PDGFRA was amplified in seven tumours from six patients and MPNST cell culture S462. KIT was amplified in five tumours from four patients and in the cell culture. Two MPNST carried somatic PDGFRA mutations in exons coding for the extracellular domain. In addition we detected several polymorphisms in PDGFRA. No point mutations or polymorphisms were detected in the four KIT exons analysed. PDGFRalpha expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFRalpha ligands in MPNST and neurofibromas revealed that PDGF-A was more widely expressed than PDGF-B. Focal c-Kit expression was detected in 2 of 29 (7%) MPNST patients. Imatinib treatment of MPNST cell culture S462 exerted a growth inhibitory effect and prevented PDGF-AA induced PDGFRalpha phosphorylation. In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib.
Assuntos
Antineoplásicos/farmacologia , Neoplasias de Bainha Neural/genética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-kit/biossíntese , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/biossíntese , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Benzamidas , Éxons , Amplificação de Genes , Perfilação da Expressão Gênica , Humanos , Mesilato de Imatinib , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/fisiopatologia , Polimorfismo Genético , Células Tumorais CultivadasRESUMO
The authors report the case of a 23-year-old man who presented with a C1-3 spinal mass. Following intraspinal decompression the tumor was histologically classified as an atypical meningioma (World Health Organization grade II). Two further surgical interventions resulted in almost total removal of the meningioma. In addition, radiotherapy was performed. During the 1.5-year follow-up period the diagnostic examinations identified a local tumor recurrence, an intraspinal C-6 metastasis, and a segmental instability with anterior C2-3 slippage and C3-4 kyphosis. The tumor was resected and occipitocervical stabilization was performed. Histological examination showed no change in malignancy. Despite additional hydroxyurea-based chemotherapy, the patient presented 4 months later with a hemiparesis and a massive recurrence of the tumor mass involving the posterior fossa and the upper thoracic spine. Because there were no further therapeutical options, the patient died. The authors discuss more aggressive therapeutic options in addition to surgery in patients with metastatic atypical meningiomas. The results in the reported case indicate that meningiomas associated with cerebrospinal fluid metastasis may represent a higher grade of malignancy.
Assuntos
Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Neoplasias da Medula Espinal/cirurgia , Adulto , Antineoplásicos/uso terapêutico , Vértebras Cervicais , Descompressão Cirúrgica , Progressão da Doença , Evolução Fatal , Humanos , Hidroxiureia/uso terapêutico , Instabilidade Articular/etiologia , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/secundário , Meningioma/líquido cefalorraquidiano , Meningioma/diagnóstico , Meningioma/secundário , Mielografia , Metástase Neoplásica , Recidiva Local de Neoplasia , Procedimentos Neurocirúrgicos/efeitos adversos , Radioterapia Adjuvante , Reoperação , Neoplasias da Medula Espinal/líquido cefalorraquidiano , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/secundário , Doenças da Coluna Vertebral/etiologiaRESUMO
Chronic graft-vs.-host disease (cGVHD) occurs in 20-50% of patients who survive for at least 100 d after allogeneic stem cell transplantation (SCT). cGVHD includes scleroderma-like skin changes, chronic cholangitis, obstructive lung disease and general wasting syndrome. Polymyositis or myopathy are rare manifestations of cGVHD with approximately 40 reported cases. Polymyositis accompanied by hemosiderin deposits in cGVHD has been reported only once, and there are no reports on lipofuscin deposits in skeletal muscle cells in cGVHD. We report here on a 56-yr-old male who underwent allogeneic SCT in 1999 for osteomyelofibrosis and progressive hematopoietic insufficiency. In February 2004, the patient was hospitalized for progressive muscular weakness with loss of the ability to walk. Laboratory tests demonstrated normal values for serum creatine kinase, aldolase and lactic dehydrogenase; the ferritin level was highly elevated. The femoral muscle biopsy showed mostly perifascicular atrophy as well as numerous subsarcolemmal hemosiderin and lipofuscin deposits. Intravenous administration of the chelating agent deferoxamine was ineffective. Three weeks later the patient died of aspiration pneumonia. Interestingly, autopsy disclosed moderate hemosiderin deposits in the liver, the organ usually involved in hemosiderosis.
Assuntos
Doença Enxerto-Hospedeiro/metabolismo , Hemossiderina/metabolismo , Polimiosite/metabolismo , Mielofibrose Primária/terapia , Transplante de Células-Tronco , Biópsia , Doença Crônica , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Hemossiderose/metabolismo , Hemossiderose/patologia , Humanos , Lipofuscina/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Polimiosite/etiologia , Polimiosite/patologia , Mielofibrose Primária/complicações , Mielofibrose Primária/patologia , Sarcolema/metabolismo , Sarcolema/patologia , Transplante de Células-Tronco/métodos , Transplante HomólogoRESUMO
OBJECTIVE: The major tensile strength of fetal membranes is provided by their extracellular matrix (ECM) components. The transcription factor Ets-1 is a critical mediator of ECM remodelling. The purpose of this study was to examine whether Ets-1 is expressed in human fetal membranes and whether it is implicated in premature membrane rupture. STUDY DESIGN: Amniochorionic membranes from 52 women in the following categories were analyzed for Ets-1 expression: preterm and term premature rupture of membranes, preterm and term labor and delivery, and preterm and term cesarean sections without previous onset of labor. Ets-1 protein was localized with the use of immunohistochemistry. Ets-1 levels were determined with a histoscore. RESULTS: Ets-1 protein was localized to the trophoblast as well as to the stromal layers. Ets-1 protein expression was up-regulated in the stroma of term and preterm prematurely ruptured membranes. CONCLUSION: Ets-1 is expressed in human fetal membranes and its expression is up-regulated with premature rupture of membranes, suggesting a role for Ets-1 in ECM remodelling of the membranes.
Assuntos
Âmnio/metabolismo , Córion/metabolismo , Ruptura Prematura de Membranas Fetais/metabolismo , Trabalho de Parto Prematuro/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Fatores de Transcrição/biossíntese , Feminino , Feto , Humanos , Imuno-Histoquímica , Gravidez , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets , Estudos Retrospectivos , Fatores de Transcrição/genética , Regulação para CimaRESUMO
Prostate cancer is among the most frequent tumours in industrialized nations and many questions remain open concerning the molecular events underlying its development and progression. In the present study we have combined cDNA array hybridization to laser-assisted microdissection (LAM) in order to investigate differences in gene expression between epithelial and stromal cells of prostate cancer and normal peripheral prostate tissue. Results have been verified for selected candidate genes by quantitative real-time RT-PCR. Using this approach and immunohistochemistry we could demonstrate a down-regulation of cellular retinoic acid binding protein 2 (CRABP2) mRNA and protein in carcinoma cells compared to normal glandular cells. CRABP2 is a main regulator of anti-carcinogenic activities of retinoic acid and may become a novel diagnostic marker and experimental therapeutic tool for prostate cancer. In addition, results of cDNA array hybridization suggest an up-regulation of 34 further genes and a down-regulation of 6 genes in cancer tissues compared to normal peripheral prostate tissues. Several of these genes have already been reported to be associated with carcinogenesis in organs such as the prostate.
Assuntos
Neoplasias da Próstata/genética , Receptores do Ácido Retinoico/biossíntese , Idoso , Biomarcadores Tumorais/análise , Transformação Celular Neoplásica , Regulação para Baixo , Células Epiteliais/fisiologia , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias da Próstata/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/fisiologiaRESUMO
Ets-1 is the prototype of the family of ETS transcription factors. In human tumors, Ets-1 is expressed in endothelial cells and fibroblasts of the tumor stroma and is proposed to play a role in tumor vascularization and invasion by upregulating expression of matrix-degrading proteases. In human carcinomas, Ets-1 is also expressed by neoplastic cells, but little is known about the functional implications of this observation. We have addressed the role of Ets-1 in epithelial HeLa tumor cells by selecting stably Ets-1 over and underexpressing HeLa cells. Ets-1 expression increases the transformed phenotype of HeLa cells, by promoting cell migration, invasion and anchorage-independent growth, while Ets-1 downregulation reduces cell attachment. In correlation with these results, Ets-1 upregulation increases integrinbeta2 expression but not that of other integrins. These results suggest that, in addition to its role in the tumor stroma, Ets-1 may also promote tumor development and progression by increasing neoplastic transformation.
Assuntos
Transformação Celular Neoplásica , Células Epiteliais/fisiologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/fisiologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/fisiologia , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células , Transformação Celular Neoplásica/genética , Progressão da Doença , Células HeLa , Humanos , Invasividade Neoplásica , Fenótipo , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas c-etsRESUMO
Malignant gliomas represent the most aggressive tumours of the central nervous system and are characterised by both extensive proliferation and invasive growth. Matrix degrading proteases called matrix metalloproteinases (MMPs), particularly MMP-9, play a crucial role in glioma infiltration. The activity of these enzymes is regulated at different levels. In this regard, the control of transcriptional activity by specific transcription factors is believed to be very important. In the present study, we examined whether rat C6 glioma cells express the Ets 1 transcription factor and whether inhibition of Ets 1 by a specific decoy strategy affects C6 glioma cell proliferation and mmp-9 expression. We found that C6 glioma cells express Ets 1 and can efficiently be transfected with an Ets 1-specific decoy oligodesoxynucleotide (ODN). This ODN significantly reduces cell proliferation and mmp-9 expression, the latter in a dose-dependent manner. We conclude that inhibition of transcription factors, which play a role for glioma development and progression such as Ets 1 by specific decoy approaches, might represent useful tools for experimental therapeutic strategies against malignant gliomas.