RESUMO
Cranial operations are associated with a high risk of postoperative intracranial hemorrhage (pICH) and venous thromboembolic events, along with increased mortality and morbidity. With the use of acetylsalicylic acid (ASA) for prophylaxis becoming more prevalent, the risk of bleeding when ASA is administered preoperatively is unknown, as are the effects of discontinuation upon the occurrence of thromboembolic events, especially in societies with aging demographics. To address these questions, a retrospective analysis was performed using medical records and radiological images of 1862 patients subjected to brain tumor surgery over a decade in our department. The risk of pICH was compared in patients with metastases receiving ASA treatment versus patients not receiving ASA treatment. The occurrence of venous thromboembolic events after surgery was also evaluated. The study group consisted of 365 patients with different types of brain metastases. In total, 20 patients suffered pICH and 7 of these were associated with clinical neurological deterioration postoperatively. Of the 58 patients who took ASA preoperatively, 2 patients experienced pICH, compared with 5 patients in the non-ASA impact group (p = 0.120). Patients who took ASA were not at significantly higher risk of pICH and therefore a worse outcome compared to the group without ASA. Therefore, these data suggest that in patients at high cardiovascular risk, ASA can be safely continued during elective brain tumor surgery.
Assuntos
Aspirina , Neoplasias Encefálicas , Hemorragias Intracranianas , Tromboembolia Venosa , Humanos , Aspirina/uso terapêutico , Aspirina/efeitos adversos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Masculino , Feminino , Tromboembolia Venosa/etiologia , Pessoa de Meia-Idade , Idoso , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/etiologia , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Complicações Pós-OperatóriasRESUMO
Background: In routine medical practice, patients are increasingly using ASA for primary and secondary prevention. Although many of these patients discontinue ASA prior to elective intracranial surgery, there are limited data to support whether perioperative ASA use raises the risk of postoperative hemorrhage. This study aimed to investigate the implications of continuing or stopping ASA around the time of surgery in patients with intracranial meningiomas, focusing on postoperative hemorrhage and thromboembolic events. Methods: For this purpose, medical records and radiological images of 1862 patients who underwent cranial neurosurgical procedures for brain tumors over a decade at our neurosurgical institute were retrospectively analyzed. The risk of postoperative hemorrhage was evaluated by comparing meningioma patients who received ASA treatment with those who did not. Furthermore, we investigated other factors that influence postoperative hemorrhage and thromboembolic events, particularly in patients receiving ASA treatment. Results: A total of 422 patients diagnosed with meningiomas underwent surgical intervention. Among the patients who received ASA preoperatively, 4 out of 46 (8.69%) experienced postoperative hemorrhage requiring surgical intervention, whereas the same complication occurred in only 4 out of 376 patients (1.06%) in the non-ASA group (p = 0.007). There was no significant difference in the incidence of thromboembolic events between the two groups. Conclusions: Our analysis revealed an increased risk of postoperative hemorrhage in patients using ASA.
RESUMO
Postoperative wound infections are a prevalent concern among the hospital-associated infections in Europe, leading to prolonged hospital stays, increased morbidity and mortality, and substantial patient burdens. Addressing the root causes of this complication is crucial, especially given the rising number of spine surgeries due to aging populations. METHODS: A retrospective analysis was conducted on a cohort of 3019 patients who underwent lumbar spine surgery over a decade in our department. The study aimed to assess the predictors of wound healing disorders, focusing on laboratory values, particularly inflammatory parameters. RESULTS: Of the 3019 patients, 2.5% (N = 74) experienced deep or superficial wound healing disorders, showing the significant correlation between C-reactive protein (CRP) levels and these disorders (p = 0.004). A multivariate analysis identified several factors, including age, sex, hypertension, diabetes, cardiac comorbidity, surgical duration, dural injury, and blood loss, as being correlated with wound healing disorders. CONCLUSION: Demographic factors, pre-existing conditions, and perioperative variables play a role in the occurrence of adverse effects related to wound healing disorders. Elevated CRP levels serve as an indicator of increased infection risk, though they are not a definitive diagnostic tool for wound healing disorders.
RESUMO
PURPOSE: Evaluation of extravascular, microscope integrated OCT (iOCT) as an in vivo imaging modality of cerebral blood vessels and as an intraoperative imaging method. METHODS: Microscope integrated optical coherence tomography of major cerebral arteries (n = 13) and superficial sylvian veins (n = 5) and one incidental cerebral vasospasm (n = 1) in (n = 10) patients. Post procedural analysis of OCT volume scans, microscopic images and videos during the time of scan as well as measurements of the diameter of vessel walls and its layers with an accuracy of 7.5 µm. RESULTS: iOCT was feasible during vascular microsurgical procedures. In all scanned arteries a clear delineation of the physiological three layered vessel wall composition could be achieved. Pathological arteriosclerotic alterations of cerebral artery walls could precisely be demonstrated. Major superficial cortical veins conversely presented a mono layered composition. First in vivo measurements of vascular mean diameters were possible. Cerebral artery walls showed a diameter of 296 µm, tunica externa 78 µm, media 134 µm and interna 84 µm. CONCLUSION: For the first time the microstructural composition of cerebral blood vessels could be illustrated in vivo. Due to an outstanding spatial resolution a clear definition of physiological and pathological characteristics was possible. Therefore, microscope integrated optical coherence tomography holds promise for basic research in the field of cerebrovascular arteriosclerotic diseases and for intraoperative guidance during microvascular surgery.
Assuntos
Veias Cerebrais , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Microscopia , ArtériasRESUMO
BACKGROUND: The conserved stem cell signaling network canonical Wingless (WNT) plays important roles in development and disease. Aberrant activation of this pathway has been linked to tumor progression and resistance to therapy. Industry and academia have substantially invested in developing substances, which can efficiently and specifically block the WNT signaling pathway. However, a clear clinical proof of the efficacy of this approach is still missing. Studies on the metabolomics dysregulation of cancer cells have led to innovations in oncological diagnostics. In addition, modulation of cancer cell metabolome is at the base of promising clinical oncology trials currently underway. While onco-protein activation can have profound metabolic outcomes, the involvement of stem cell signals, such as the WNT pathway, in tumor cell metabolomics is yet insufficiently characterized. MATERIAL AND METHODS: We determined live cell metabolism and bioenergetics in pathophysiological relevant, WNT-dependent glioblastoma stem cell (GSC) models. We quantified those parameters in cells with canonical WNT activity and in isogenic cells where WNT activity had been inhibited by short hairpin RNA against ß-catenin. Furthermore, we applied computational analysis of RNA sequencing to verify our functional findings in independent GSCs cohorts. RESULTS: The investigated collection of disease models allows the separation in tumors with low, moderate and high base line metabolic activity. Suppression of canonical WNT signaling led to significant reduction of total, mitochondrial, and glycolytic ATP production rates. Elevated canonical WNT transcription signature in GSCs positively correlated with transcription levels of mitochondrial ATP synthesis, whereas non-canonical WNT gene expression signature did not. CONCLUSION: The applied disease modeling technology allows the recapitulation of inter-tumoral heterogeneous metabolic properties of glioblastoma. Our data show for the first time that inhibition of canonical WNT signaling in alive GSCs functionally correlates with energy inhibition and glucose homeostasis. As this correlation occurs in GSCs from different transcriptional or epigenetic transcriptional subtypes, our results suggest that developing therapies directed against glycolysis/ATP-synthesis may be a promising strategy to overcome therapy resistance due to inter-tumoral heterogeneity and offers starting point to impair downstream signal WNT.
Assuntos
Glioblastoma , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Glioblastoma/patologia , Glicólise , Humanos , Células-Tronco Neoplásicas/patologia , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
AIMS: Brain invasion (BI) was firstly defined as a single criterion of atypia in otherwise benign meningiomas in the revised fourth edition of 2016 WHO classification of brain tumours after being previously inconsistently addressed. However, recent studies have raised doubts about the prognostic significance of BI in otherwise benign meningiomas. In our study, we investigate the reproducibility of such a prognostic effect. METHODS: We identified two cohorts one consisting of 483 patients with meningioma WHO grade I (M°I) or atypical meningioma WHO grade II (M°II) from Hannover Medical School and the other including atypical meningiomas defined according to the classical WHO criteria (M°IIb) from the University Hospital Heidelberg. Follow-up data with a median observation time of 38.2 months were available from 308 cases. These included 243 M°I and 65 M°II patients with the latter group consisting of 25 patients with otherwise benign meningiomas with BI (M°IIa) and 40 with M°IIb. RESULTS: A significant difference of progression-free interval (PFI) was found between patients with M°I and M°II, M°I and M°IIa and those with M°I and M°IIb of both cohorts and each separately. However, PFI of M°IIa and M°IIb patients showed no significant difference. In the multivariate regression analysis adjusted for M°I/M°IIa versus M°IIb, sex, age, extent of resection and tumour location, BI exhibited the strongest risk of relapse (Hazard ratio: 4.95) serving as an independent predictor of PFI (p = 0.002). CONCLUSIONS: Our results clearly support the definition of BI as a single criterion of atypia in WHO classification of 2016.
Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: Brain arteriovenous malformations (bAVM) are rare vascular lesions. Recent observations challenge the congenital nature of these lesions. The underlying cellular and molecular mechanisms associated with dynamic changes of bAVM still remain unclear. The objective of this study was to explore the potential role of COL4A2 (Collagen alpha-2(IV)) in the pathophysiology of bAVM. PATIENTS AND METHODS: Expression and localization of COL4A2 were analyzed on tissue microarrays from bAVM patients (n = 60) by immunohistochemistry. Correlations between COL4A2 levels and clinical parameters were examined with Pearson's test for normally- distibuted or Spearman's Rho for not normally distributed data. Comparison between different clinical parameters was performed using t-test, non-parametric Mann-Whitney U test or Kruskal- Wallis test. Fisher's exact test was used for categorical data. RESULTS: COL4A2 was mainly expressed beneath the endothelium of vessels in the tunica media of bAVM. This pattern of expression indicates the basement membrane of the vessel walls. High levels of COL4A2 expression correlated with the age at surgery of patients (p = 0.005; R = 0.393; Spearman's Rho). The age at surgery in young (17-25 years) and old patients (55-76 years) showed a linear correlation; a greater variance of COL4A2 expression was observed in the age group between 26-54 years. CONCLUSION: This study reports for the first time the expression of COL4A2 in bAVM and suggests a potential role of COL4A2 in bAVM pathophysiology. These findings contribute to a better understanding of the microenvironment of bAVM and may foster the development of improved therapeutic strategies for this disease.
Assuntos
Fístula Arteriovenosa/metabolismo , Vasos Sanguíneos/metabolismo , Colágeno Tipo IV/metabolismo , Matriz Extracelular/metabolismo , Malformações Arteriovenosas Intracranianas/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Fístula Arteriovenosa/cirurgia , Membrana Basal/metabolismo , Neoplasias Encefálicas/cirurgia , Estudos de Casos e Controles , Criança , Endotélio/metabolismo , Feminino , Glioma/cirurgia , Humanos , Imuno-Histoquímica , Malformações Arteriovenosas Intracranianas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Serial de Tecidos , Túnica Média/metabolismo , Adulto JovemRESUMO
Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection and radio-chemotherapy, more than 95% of GBM patients die within 5 years after diagnosis. Thus, there is still an urgent need to develop novel therapeutic strategies against this disease. Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM. This review article summarizes the latest findings on the molecular effects of cannabinoids on GBM, both in vitro and in (pre-) clinical studies in animal models and patients. The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors. Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment. Taken together these findings underline the importance of elucidating the full pharmacological effectiveness and the molecular mechanisms of the cannabinoid system in GBM pathophysiology.
RESUMO
In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date. By targeted sequencing, we identified novel ADAR and RNASEH2B variants, and a 3- to 17-fold frequency increase of the AGS mutations ADAR,c.577C>G;p.(P193A) and RNASEH2B,c.529G>A;p.(A177T) in the germline of familial glioma patients as well as in test and validation cohorts of glioblastomas and prostate carcinomas versus ethnicity-matched controls, whereby rare RNASEH2B variants were significantly more frequent in familial glioma patients. Tumors with ADAR or RNASEH2B variants recapitulated features of AGS, such as calcification and increased type I interferon expression. Patients carrying ADAR or RNASEH2B variants showed upregulation of interferon-stimulated gene (ISG) transcripts in peripheral blood as seen in AGS. An increased ISG expression was also induced by ADAR and RNASEH2B variants in tumor cells and was blocked by the JAK inhibitor Ruxolitinib. Our data implicate rare variants in the AGS genes ADAR and RNASEH2B and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis, consistent with a genetic basis underlying inflammation-driven malignant transformation in glioma and prostate carcinoma development.
Assuntos
Adenosina Desaminase/genética , Predisposição Genética para Doença , Interferon Tipo I/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Ligação a RNA/genética , Ribonuclease H/genética , Adenosina Desaminase/metabolismo , Adulto , Animais , Células Cultivadas , Estudos de Coortes , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Fibroblastos/metabolismo , Humanos , Isocitrato Desidrogenase/genética , Masculino , Camundongos Knockout , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Estabilidade Proteica , Proteínas de Ligação a RNA/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Mesenchymal stromal cells (MSC) are a major component of the tumor microenvironment in patients with head and neck squamous cell carcinoma (HNSCC). MSC display innate and regulatory immunologic functions, very similar to many hematopoietic 'classical' immune cells. Conversion of ATP to immunosuppressive adenosine is an immunosuppressive mechanism utilized by other hematopoietic immune cells. The present study explores the adenosine metabolism of tumor derived MSC in comparison to autologous MSC from non-malignant tissue. METHODS: From HNSCC patients (n=10), paired MSC were generated from tumor tissue (tMSC) and autologous healthy control tissue (cMSC). Differentiation properties and phenotype (CD105, CD73, CD39, CD90, CD26, CD29) were compared by flow cytometry. Production of immunosuppressive adenosine (ADO) by functionally active ectonucleotidases, CD39 and CD73, was determined by luminescence and mass spectrometry. Suppressive activity of ADO was tested in CFSE proliferation assays of isolated T-cells. Plasticity of cMSC was explored after incubation with tumor-cell conditioned media. RESULTS: Differentiation into osteogenic, chondrogenic and adipogenic directions was comparable in tMSC and cMSC. Expression of ectonucleotidases, CD39 and CD73, was decreased in tMSC as compared to corresponding cMSC, which correlated with decreased ATP metabolism in mass spectrometry. Proliferation of CD4+ T-cells was significantly suppressed by exogenous ADO. Tumor-conditioned medium was unable to down-regulate ADO production in cMSC. CONCLUSION: We identified MSC of the oropharyngeal mucosa as an important producer of exogenous ADO. In patients with HNSCC, reduced expression of ADO may contribute to excessive inflammation and tumor growth.
Assuntos
Adenosina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Células-Tronco Mesenquimais/metabolismo , Trifosfato de Adenosina/metabolismo , Idoso , Biomarcadores , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hidrólise , Imunofenotipagem , Masculino , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Brain arteriovenous malformations (bAVMs) are severe conditions which, upon rupture, cause debilitating neurological deficits and even death. The exact cellular and molecular mechanisms associated with bAVM rupture are currently unclear. The objective of this study was to explore the potential role of CEA-related cell adhesion molecule-1 (CEACAM1) in bAVM pathophysiology. Expression and localization of CEACAM1 were assessed immunohistochemically in tissue microarrays from bAVM patients (n = 60). The association of CEACAM1 with clinical parameters was analyzed with Spearman's rank correlation coefficient and chi-square test. The predictive value of CEACAM1 was tested using logistic regression analysis. CEACAM1 was highly expressed in tissue-infiltrating neutrophil granulocytes. High levels of CEACAM1-positive cells were associated with bAVM rupture (hemorrhage), but not with arteriovenous malformation (AVM) size, preoperative embolization, or seizure. This association was significant (p = 0.029, chi-square) in male but not in female patients, and high CEACAM1-positive immune infiltration showed predictive significance for hemorrhage in male bAVM patients only (OR = 6.50, 95 % CI 1.09-38.63, p = 0.040). Within the ruptured bAVM group, patients with a short hemorrhage to surgery (HTS) time interval had higher levels of CEACAM1 immune infiltration than patients with long HTS. This decrease in the levels of CEACAM1 immune infiltration between the HTS short and HTS long groups was, however, significant only in female patients (p = 0.022, chi-square). Our findings substantiate the role of inflammation in the pathophysiology of bAVM and suggest the presence of sexual dimorphism in this disease.
Assuntos
Antígenos CD/metabolismo , Encéfalo/cirurgia , Moléculas de Adesão Celular/metabolismo , Angiografia Cerebral , Malformações Arteriovenosas Intracranianas/cirurgia , Hemorragias Intracranianas/etiologia , Tomografia Computadorizada por Raios X/efeitos adversos , Encéfalo/fisiopatologia , Angiografia Cerebral/efeitos adversos , Embolização Terapêutica/efeitos adversos , Feminino , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Caracteres SexuaisRESUMO
BACKGROUND: The Wnt receptor Frizzled-7 (FZD7) promotes tumor progression and can be currently targeted by monoclonal antibody therapy. Here, we determined the prognostic value of FZD7 for the overall survival of glioblastoma (GBM) patients, both as individual marker and taken in combination with the previously-described markers MGMT and IDH1. Additionally, we tested whether these markers (alone or in combination) exhibited sex-specific differences. RESULTS: High levels of FZD7 (FZD7high) associated with shorter survival in GBM patients; however, FZD7high was a significant predictor of poor survival only in male patients. Mutation of IDH1 significantly associated with longer survival in male but not female patients. Methylated MGMT promoter significantly associated with longer survival only in female patients. Combination of FZD7 with MGMT enhanced the prognostic accuracy and abrogated the sex differences observed upon single marker analysis. Combination of FZD7 with IDH1 was a significant predictor of survival in male GBM patients only. MATERIALS AND METHODS: Three independent cohorts of patients with primary GBM (n=120, n=108 and n=105, respectively) were included in this study. FZD7 and IDH1 were assessed by immunohistochemistry in tissue microarrays. MGMT promoter methylation was determined by methylation-specific polymerase chain reaction. Survival analysis was performed by Kaplan-Meier estimate, log-rank test and Cox proportional hazard regression. CONCLUSIONS: Our study identifies novel individual and combination markers with prognostic and, possibly, therapeutic relevance in GBM. Furthermore, our findings substantiate the importance of sexual dimorphism in this type of cancer.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Receptores Frizzled/análise , Glioblastoma/patologia , Isocitrato Desidrogenase/análise , Proteínas Supressoras de Tumor/análise , Idoso , Neoplasias Encefálicas/mortalidade , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Caracteres Sexuais , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/genéticaRESUMO
INTRODUCTION: Mesenchymal stromal cells (MSC) are an integral cellular component of the tumor microenvironment. Nevertheless, very little is known about MSC originating from human malignant tissue and modulation of these cells by tumor-derived factors. The aim of this study was to isolate and characterize MSC from head and neck squamous cell carcinoma (HNSCC) and to investigate their interaction with tumor cells. METHODS: MSC were isolated from tumor tissues of HNSCC patients during routine oncological surgery. Immunophenotyping, immunofluorescence and in vitro differentiation were performed to determine whether the isolated cells met the consensus criteria for MSC. The cytokine profile of tumor-derived MSC was determined by enzyme-linked immunosorbent assay (ELISA). Activation of MSC by tumor-conditioned media was assessed by measuring cytokine release and expression of CD54. The impact of MSC on tumor growth in vivo was analyzed in a HNSCC xenograft model. RESULTS: Cells isolated from HNSCC tissue met the consensus criteria for MSC. Tumor-derived MSC constitutively produced high amounts of interleukin (IL)-6, IL-8 and stromal cell-derived factor (SDF)-1α. HNSCC-derived factors activated MSC and enhanced secretion of IL-8 and expression of CD54. Furthermore, MSC provided stromal support for human HNSCC cell lines in vivo and enhanced their growth in a murine xenograft model. CONCLUSIONS: This is the first study to isolate and characterize MSC from malignant tissues of patients with HNSCC. We observed cross-talk of stromal cells and tumor cells resulting in enhanced growth of HNSCC in vivo.
Assuntos
Carcinoma de Células Escamosas/patologia , Citocinas/metabolismo , Progressão da Doença , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Mesenquimais/patologia , Microambiente Tumoral , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Quimiocina CXCL12/metabolismo , Meios de Cultivo Condicionados , Citometria de Fluxo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Camundongos Nus , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Mesenchymal stem/stromal cells (MSCs) are emerging as important regulators of innate and adaptive immunity. In this context, both proinflammatory and anti-inflammatory effects have been described for MSCs. The mechanisms mediating this functional plasticity are poorly characterized at present. Here, we investigated the inflammatory responses of MSCs isolated from human nasal mucosa (nmMSCs) upon challenge with different Toll-like receptor (TLR) ligands. We found that TLR3 ligands induced the strongest release of both proinflammatory cytokines [interleukin (IL)-6 and IL-8] and type I interferon by nmMSCs compared with other TLR ligands. Notably, TLR3 ligands triggered a biphasic cytokine response, with an early peak of type I interferon at 4 h poststimulation and a late release of proinflammatory cytokines at 24 h poststimulation. While the early interferon response was subject to direct stimulation, the proinflammatory response was regulated by factors released during the early cytokine response, which subsequently enhanced sensitivity to TLR3 ligation and amplified the production of IL-6 and IL-8 but not that of interferon. Taken together, our findings indicate that TLR3 ligands polarize the inflammatory phenotype of MSCs in a time-dependent manner. Thus, our study proposes a novel model that helps to explain the strikingly dichotomous functionality of MSCs in inflammation and immunoregulation.
Assuntos
Comunicação Autócrina , Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Células-Tronco Mesenquimais/metabolismo , Mucosa Nasal/metabolismo , Receptor 3 Toll-Like/metabolismo , Adulto , Idoso , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Imunofluorescência , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/genéticaRESUMO
Expression of the forkhead transcription factor (FoxP3)--an established marker of regulatory T cells--has been found in other cell types as well, including tumour cells. Recent studies indicated that high tumour FoxP3 expression might be associated with a poor outcome of patients with several types of solid cancers. Here, we investigated the role of FoxP3 expressed by the tumour cells in the prognosis of larynx and oro-hypopharynx squamous cell carcinoma (LSCC and OHSCC)--two major subtypes of head and neck cancer. To this end, we analysed by immunohistochemistry the expression of tumour FoxP3 in tissues from 83 LSCC and 89 OHSCC patients in relation to overall survival. In multivariate analysis we found that high tumour FoxP3 expression significantly associated with poor survival in OHSCC but not in LSCC patients. In further studies, we combined the prognostic value of FoxP3 with selected markers of inflammation (cyclooxygenase-2; COX2) or with markers of enhanced tumour migration/invasion (AHNAK and CORTACTIN). Interestingly, we found that the combination of FoxP3 and AHNAK (in LSCC) or FoxP3 and CORTACTIN (in OHSCC) had significantly stronger prognostic values than either marker analysed individually. Combination of FoxP3 and COX2 enhanced the prognostic accuracy only in OHSCC. Thus, our study identifies novel individual and combination markers that might have enhanced and distinct prognostic relevance in different subtypes of head and neck cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Laríngeas/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Adulto , Carcinoma de Células Escamosas/metabolismo , Cortactina/metabolismo , Ciclo-Oxigenase 2/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Laríngeas/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Neoplasias Orofaríngeas/metabolismo , Prognóstico , Análise de SobrevidaRESUMO
Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge. Increased numbers of neutrophil granulocytes have been observed both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Importantly, these studies linked neutrophils to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting activities. Indeed, a number of functional in vitro and in vivo studies demonstrated that tumors stimulated neutrophils to promote angiogenesis and immunosuppression, as well as migration, invasion and metastasis of the tumor cells. Therefore, it became necessary to understand the mechanisms modulating the changes in the biology and functions of neutrophils in the context of the tumor microenvironment. In this review we will discuss several functions of neutrophils that might contribute to tumor progression. Furthermore, we will address in detail the cellular and molecular mechanisms that control modulation of neutrophils in the tumor microenvironment, such as recruitment to the tumor site (chemotaxis), prolonged survival and enhanced release of protumoral mediators.
Assuntos
Imunomodulação , Neoplasias/imunologia , Neutrófilos/imunologia , Microambiente Tumoral/imunologia , Animais , Sobrevivência Celular/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Progressão da Doença , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Transdução de SinaisRESUMO
CORTACTIN is an actin-binding protein critically involved in cellular migration and invasion. Here, we investigated the role of CORTACTIN in the pathophysiology of orohypopharynx carcinoma - one of the major subtypes of head and neck cancer. To this end, we analyzed CORTACTIN expression in tumor tissues from 89 orohypopharynx carcinoma patients in relation to clinical parameters. We found that high tumoral CORTACTIN expression associated with poor survival, higher T-stage, and higher lymph node metastasis (N-stage) in these patients. Next, we combined the prognostic values of tumoral and stromal cell biological parameters in our patient cohort. We determined the potential interaction of tumoral CORTACTIN with tumor-infiltrating neutrophils, which have been previously linked to poor clinical outcome in orohypopharynx carcinoma patients with advanced disease. Interestingly, we found that patients with both high tumoral CORTACTIN expression and high neutrophilic infiltration had significantly worse clinical outcome than all other patients in our cohort. These findings suggest that tumoral CORTACTIN and tumor-infiltrating neutrophils might be functionally linked during progression of orohypopharynx carcinoma. In vitro, we showed that neutrophils released soluble factors which phosphorylated CORTACTIN in the tumor cells and promoted their migration. Furthermore, we demonstrated that strong CORTACTIN phosphorylation significantly correlated with strong neutrophilic infiltration in tumor tissues from orohypopharynx carcinoma patients. Taken together, our findings unravel a novel mechanism of tumor-stroma interaction, which might be relevant for a more accurate prognosis and improved therapeutic strategies in this tumor entity.
RESUMO
AHNAK/Desmoyokin is a giant protein which has been recently linked to reorganization of the actin cytoskeleton, cellular migration and invasion. Here, we investigated the role of AHNAK in the pathophysiology of larynx carcinoma-one of the major subtypes of head and neck cancer. To this end, we analysed AHNAK expression in tumor tissues from 83 larynx carcinoma patients in relation to overall survival. We found that tumoral AHNAK overexpression significantly associated with poor survival of these patients both in univariate and multivariate analysis. In further studies, we combined the prognostic value of AHNAK with selected markers of inflammation, such as macrophage migration inhibitory factor (MIF) and tumor-infiltrating neutrophils (CD66b-positive cells). Both MIF and neutrophils have been linked to enhanced tumoral migration and poor clinical outcome in patients with orohypopharynx carcinoma-another major subtype of head and neck cancer. Interestingly, we found that synchronous high levels of AHNAK and MIF or AHNAK and neutrophils, respectively, were stronger predictors of poor survival than AHNAK alone. Synchronous high levels of all three markers were the strongest predictors of poor survival in our patient cohort. Taken together, our findings propose novel strategies for an accurate prognosis in larynx carcinoma and suggest potential mechanisms of inflammation-mediated tumor progression.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Progressão da Doença , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Análise Multivariada , Prognóstico , Análise de SobrevidaRESUMO
Neutrophils are primary inflammatory cells and absolutely essential to protect the host during the early phases of microbial infection. Their role in cancer is less clear. Current evidence suggests that neutrophils show high functional plasticity and can adopt protumor and antitumor activity. Protumor neutrophils are functionally related to the recently described granulocytic myeloid-derived suppressor cells. We propose a model in which homeostatic chronic recruitment and activation of neutrophils result in mainly protumor activity. In contrast, therapeutic interventions in many cases elicit acute activation, enhance direct effector functions as well as indirect regulatory functions of neutrophils with potent antitumor activity. Conversion of protumor activity of neutrophils into antitumor activity by means of appropriate stimulation or modulation may offer new possibilities in biologic therapy of cancer.
Assuntos
Modelos Imunológicos , Neoplasias/imunologia , Neutrófilos/imunologia , Animais , Homeostase/imunologia , Humanos , Neoplasias/patologia , Neoplasias/terapia , Neutrófilos/patologiaRESUMO
Accumulating evidence indicates that myeloid cells are critically involved in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages, the significance of granulocytes in cancer has only recently begun to emerge. A number of studies found increased numbers of neutrophil granulocytes and granulocytic myeloid-derived suppressor cells (GrMDSCs) both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Most importantly, granulocytes have been linked to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting effects. In this review, we will address in detail the following major topics: (1) neutrophils and GrMDSCs in the peripheral blood of cancer patients-phenotype and functional changes; (2) neutrophils and GrMDSCs in the tumor tissue-potential mechanisms of tumor progression and (3) relevance of neutrophils and GrMDSCs for the clinical outcome of cancer patients. Furthermore, we will discuss the advantages and disadvantages of the current strategies used for identification and monitoring of human MDSCs. We propose a six-color immunophenotyping protocol that discriminates between monocytic MDSCs (MoMDSCs), two subsets of GrMDSCs and two subsets of immature myeloid cells in human cancer patients, thus, allowing for an improved characterization and understanding of these multifaceted cells.