RESUMO
Semaphorin-3F (SEMA3F), an axonal repulsant in nerve development, has been shown to inhibit the progression of human colorectal cancer (CRC); however, the underlying mechanism remains elusive. In this study we found a negative correlation between the levels of SEMA3F and CXCR4 in CRC specimens from 85 patients, confirmed by bioinformatics analysis of gene expression in 229 CRC samples from the Cancer Genome Atlas. SEMA3F(high) /CXCR4(low) patients showed the lowest frequency of lymph node and distant metastasis and the longest survival. Mechanistically, SEMA3F inhibited the invasion and metastasis of CRC cells through PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis. Specifically, ASCL2 enhanced the invasion and metastasis of CRC cells in vitro and expression of ASCL2 correlated with distant metastasis, tumour size and poor overall survival in CRC patients. Treatment of CRC cells with the CXCR4 antagonist AMD3100 attenuated SEMA3F knockdown-induced invasion and metastasis of CRC cells in vitro and in vivo. Our study thus demonstrates that SEMA3F functions as a suppressor of CRC metastasis via down-regulating the ASCL2-CXCR4 axis.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Movimento Celular , Neoplasias Colorretais/enzimologia , Neoplasias Hepáticas/enzimologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Células HCT116 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Proteínas de Membrana/genética , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas do Tecido Nervoso/genética , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Carga TumoralRESUMO
Invasion and metastasis are the major cause of deaths in patients with esophageal cancer. In this study, we isolated cancer stem-like cells from an esophageal squamous cell carcinoma cell line EC109 based on aldehyde dehydrogenase 1A1 (ALDH1A1), and found that ALDH1A1(high) cells possessed the capacities of self-renewal, differentiation and tumor initiation, indications of stem cell properties. To support their stemness, ALDH1A1(high) cells exhibited increased potential of invasion and metastasis as compared with ALDH1A1(low) cells. ALDH1A1(high) esophageal squamous cell carcinoma cells expressed increased levels of mRNA for vimentin, matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9), but decreased the level of E-cadherin mRNA, suggesting that epithelial-mesenchymal transition and secretary MMPs may be attributed to the high invasive and metastatic capabilities of ALDH1A1(high) cells. Furthermore, we examined esophageal squamous cell carcinoma specimens from 165 patients and found that ALDH1A1(high) cells were associated with esophageal squamous dysplasia and the grades, differentiation and invasion depth, lymph node metastasis and UICC stage of esophageal squamous cell carcinoma, as well as poor prognosis of patients. Our results provide the strong evidence that ALDH1A1(high) cancer stem-like cells contribute to the invasion, metastasis and poor outcome of human esophageal squamous cell carcinoma.
Assuntos
Aldeído Desidrogenase/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/metabolismo , Idoso , Família Aldeído Desidrogenase 1 , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Humanos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Prognóstico , Retinal DesidrogenaseRESUMO
BACKGROUND: Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) has been identified as a putative cancer stem cell (CSC) marker in breast cancer. However, the clinicopathological and prognostic significance of this protein in breast cancer patients remains controversial. METHODS: This meta-analysis was conducted to address the above issues using 15 publications covering 921 ALDH1A1(+) cases and 2353 controls. The overall and subcategory analyses were performed to detect the association between ALDH1A1 expression and clinicopathological/prognostic parameters in breast cancer patients. RESULTS: The overall analysis showed that higher expression of ALDH1A1 is associated with larger tumor size, higher histological grade, greater possibility of lymph node metastasis (LNM), higher level expression of epidermal growth factor receptor 2 (HER2), and lower level expression of estrogen receptor (ER)/progesterone receptor (PR). The prognosis of breast cancer patients with ALDH1A1(+) tumors was poorer than that of the ALDH1A1(-) patients. Although the relationships between ALDH1A1 expression and some clinicopathological parameters (tumor size, LNM, and the expression of HER2) was not definitive to some degree when we performed a subcategory analysis, the predictive values of ALDH1A1 expression for histological grade and survival of breast cancer patients were significant regardless of the different cutoff values of ALDH1A1 expression, the different districts where the patients were located, the different clinical stages of the patients, the difference in antibodies used in the studies, and the surgery status. CONCLUSIONS: Our results indicate that ALDH1A1 is a biomarker to predict tumor progression and poor survival of breast cancer patients. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for breast cancer.
Assuntos
Aldeído Desidrogenase/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Família Aldeído Desidrogenase 1 , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Feminino , Expressão Gênica , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Prognóstico , Viés de Publicação , Retinal Desidrogenase , Carga TumoralRESUMO
The invasion of malignant glioma cells into the surrounding normal brain tissues is crucial for causing the poor outcome of this tumor type. Recent studies suggest that glioma stem-like cells (GSLCs) mediate tumor invasion. However, it is not clear whether microenvironment factors, such as tumor-associated microglia/macrophages (TAM/Ms), also play important roles in promoting GSLC invasion. In this study, we found that in primary human gliomas and orthotopical transplanted syngeneic glioma, the number of TAM/Ms at the invasive front was correlated with the presence of CD133(+) GSLCs, and these TAM/Ms produced high levels of TGF-ß1. CD133(+) GSLCs isolated from murine transplanted gliomas exhibited higher invasive potential after being cocultured with TAM/Ms, and the invasiveness was inhibited by neutralization of TGF-ß1. We also found that human glioma-derived CD133(+) GSLCs became more invasive upon treatment with TGF-ß1. In addition, compared with CD133(-) committed tumor cells, CD133(+) GSLCs expressed higher levels of type II TGF-ß receptor (TGFBR2) mRNA and protein, and downregulation of TGFBR2 with short hairpin RNA inhibited the invasiveness of GSLCs. Mechanism studies revealed that TGF-ß1 released by TAM/Ms promoted the expression of MMP-9 by GSLCs, and TGFBR2 knockdown reduced the invasiveness of these cells in vivo. These results demonstrate that TAM/Ms enhance the invasiveness of CD133(+) GSLCs via the release of TGF-ß1, which increases the production of MMP-9 by GSLCs. Therefore, the TGF-ß1 signaling pathway is a potential therapeutic target for limiting the invasiveness of GSLCs.
Assuntos
Glioma/imunologia , Macrófagos/imunologia , Microglia/imunologia , Células-Tronco Neoplásicas/imunologia , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/fisiologia , Regulação para Cima/imunologia , Animais , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Glioma/metabolismo , Glioma/patologia , Humanos , Contagem de Leucócitos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Transplante de Neoplasias/imunologia , Transplante de Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/biossínteseRESUMO
Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.
Assuntos
Displasia Cortical Focal , Malformações do Desenvolvimento Cortical do Grupo I , Proteínas do Tecido Nervoso , Semaforinas , Esclerose Tuberosa , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia Resistente a Medicamentos/patologia , Epilepsia , Displasia Cortical Focal/metabolismo , Displasia Cortical Focal/patologia , Células Gigantes/metabolismo , Células Gigantes/patologia , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Neurônios/metabolismo , Neurônios/patologia , Semaforinas/metabolismo , Semaforinas/genética , Semaforinas/biossíntese , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologiaRESUMO
Malfunctioned gap junctional intercellular communication (GJIC) has been thought associated with malignant transformation of normal cells. However, the role of GJIC-related proteins such as connexins in sustaining the malignant behavior of cancer stem cells remains unclear. In this study, we obtained tumorspheres formed by glioma stem cells (GSCs) and adherent GSCs and then examined their GJIC. All GSCs showed reduced GJIC, and differentiated glioma cells had more gap junction-like structures than GSCs. GSCs expressed very low level of connexins, Cx43 in particular, which are key components of gap junction. We observed hypermethylation in the promoter of gap junction protein α1, which encodes Cx43 in GSCs. Reconstitution of Cx43 in GSCs inhibited their capacity of self-renewal, invasiveness, and tumorigenicity via influencing E-cadherin and its coding protein, which leads to changes in the expression of Wnt/ß-catenin targeting genes. Our results suggest that GSCs require the low expression of Cx43 for maintaining their malignant phenotype, and upregulation of Cx43 might be a potential strategy for treatment of malignant glioma.
Assuntos
Caderinas/metabolismo , Conexina 43/metabolismo , Glioma/patologia , Células-Tronco Neoplásicas/metabolismo , Adulto , Animais , Caderinas/genética , Comunicação Celular , Proliferação de Células , Conexina 43/genética , Metilação de DNA , Feminino , Junções Comunicantes/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Fenótipo , Regiões Promotoras Genéticas , Ligação Proteica , Esferoides Celulares/metabolismo , Esferoides Celulares/ultraestrutura , Células Tumorais Cultivadas , Via de Sinalização WntRESUMO
BACKGROUND: The standard treatment for advanced T2 gastric cancer (GC) is laparoscopic or surgical gastrectomy (either partial or total) and D2 lymphadenectomy. A novel combined endoscopic and laparoscopic surgery (NCELS) has recently been proposed as a better option for T2 GC. Here we describe two case studies demonstrating the efficacy and safety of NCELS. CASE SUMMARY: Two T2 GC cases were both resected by endoscopic submucosal dissection and full-thickness resection and laparoscopic lymph nodes dissection. This method has the advantage of being more precise and minimally invasive compared to current methods. The treatment of these 2 patients was safe and effective with no complications. These cases were followed up for nearly 4 years without recurrence or metastasis. CONCLUSION: This novel method provides a minimally invasive treatment option for T2 GC, and its potential indications, effectiveness and safety needs to be further evaluated in controlled studies.
RESUMO
Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor-C (VEGF-C) and corresponding receptors VEGFR-2, VEGFR-3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF-C, VEGFR-2, and VEGFR-3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF-C, VEGFR-2 and VEGFR-3 was located in the micro-columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked-EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor- and AMPA receptor-mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X-ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF-C, however, could be antagonized by ki8751, the blocker of VEGFR-2. These results suggest that VEGF-C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor-mediated currents.
Assuntos
Malformações do Desenvolvimento Cortical , Fator C de Crescimento do Endotélio Vascular , Animais , Epilepsia , Humanos , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical do Grupo I , Ratos , Receptores de N-Metil-D-Aspartato , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.
Assuntos
Podossomos , Neoplasias Gástricas , Linhagem Celular Tumoral , Cortactina/genética , Cortactina/metabolismo , Humanos , Invasividade Neoplásica , Monoéster Fosfórico Hidrolases/metabolismo , Podossomos/metabolismo , Podossomos/patologia , Receptores de Superfície Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
AIMS: The aim of this study was to investigate the tumor microenvironment immune types (TMIT) based on tumor cell programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) distribution and whether distinct TMIT subtypes (TMIT I, PD-L1high /TILhigh ; TMIT II, PD-L1low /TILlow ; TMIT III, PD-L1high /TILlow ; and TMIT IV, PD-L1low /TILhigh ) differentially affect clinical outcomes of patients with lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). METHODS AND RESULTS: Immunohistochemistry (IHC) was applied to evaluate the expression of PD-L1 and the spatial distribution of programmed cell death 1 (PD-1) and CD8 TILs on the surgically resected specimens from 205 cases of LAC and 149 cases of SCC. PD-1 and CD8 TILs were more frequently distributed in SCC than those in LAC, regardless of their infiltrating in the tumor islets or stroma. The density of TILs was a poor prognostic factor in LAC but a favorable one in SCC. PD-L1 levels and its clinical prognostic significance differed in LAC vs SCC. LAC patients with TMIT III and SCC patients with TMIT I had the longest survival, respectively (P = .0197 and .0049). Moreover, TMIT stratification based on tumor cell PD-L1 expression and stromal CD8+ TILs could be considered as an independent prognostic factor of SCC patients' survival as determined by both univariate and multivariate analysis. CONCLUSION: Our study indicates that different type of TMIT provides its specific microenvironment with diverse impact on survival of LAC and SCC patients and highlights the importance of the integrative assessment of PD-L1 status and TILs' spatial distribution to predict patients' prognosis.
Assuntos
Adenocarcinoma de Pulmão/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Pulmonares/imunologia , Microambiente Tumoral/imunologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pulmão/imunologia , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Pneumonectomia , Prognóstico , Estudos Retrospectivos , Análise EspacialRESUMO
The original and corrected figures are shown in the accompanying Author Correction.
RESUMO
Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133+Notch1+, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.
Assuntos
Neoplasias Encefálicas/metabolismo , Retroalimentação Fisiológica/fisiologia , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Substância Branca/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Imagem de Tensor de Difusão , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Proteína Jagged-1/metabolismo , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/patologia , Substância Branca/patologiaRESUMO
Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer.Significance: Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation-independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer. Cancer Res; 78(11); 3041-53. ©2018 AACR.
Assuntos
MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteínas Serina-Treonina Quinases/genética , Neoplasias Gástricas/genética , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Humanos , MAP Quinase Quinase Quinase 2 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genéticaRESUMO
OBJECTIVE: To investigate the expression and significance of MGMT in different molecular subtypes of glioblastoma (GBM), and to evaluate the important role of MGMT and P53 in predicting the prognosis of GBM patients. METHODS: MGMT expression was detected by immunohistochemical staining in 72 cases of GBM which had been classified as three molecular subtypes. The relationship between MGMT and P53, an important molecule for identification of proneural-like GBM, were further analyzed. The association between MGMT and patients' prognosis was analyzed with Kaplan-Meier method, which was further validated by the data from 513 cases of GBM in the TCGA database. RESULTS: MGMT expression was lower in proneural-like subtype in 72 GBM cases (p < 0.001), and was negatively correlated with P53 (r=-0. 6203, p < 0.001). This results was also verified by a validation group of 87 GBM cases (r=-0. 2950, p < 0.001). Interestingly, low expression of MGMT predicted a better outcome in proneurallike subtype or P53 high-expression group (p < 0.05) but not in non-proneural-like subtype and P53 low-expression group. All of these results were verified by the data from TCGA database. CONCLUSION: MGMT can be used as an independent prognostic factor and plays an important role in molecular typing and diagnosis of GBM by combination with proneural-like subtype marker P53.
RESUMO
Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1(+) tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the "classical-like" (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients' outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1(+) cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1(-) cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1(+) cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma.
RESUMO
Tumor cell stemness has been recognized as a key contributor to tumor initiation, progression and recurrence. Our previous studies have found that semaphorin-3F (SEMA3F), an axon guidance molecule in the development of central nervous system, inhibited the growth and metastasis of colorectal cancer (CRC). However, a possible role for SEMA3F in regulating cancer cell stemness remains unknown. Here, we report a novel mechanism of the acquirement of stemness of CRC cells regulated by SEMA3F. Knockdown of SEMA3F significantly promoted the self-renewal and tumorigenicity of CRC cells, and increased the expression of stemness-associated genes, while overexpressing SEMA3F reduced the stemness of CRC cells. Mechanistically, GTP-Rac1 was involved in SEMA3F mediated regulation of CRC cell stemness by targeting the Wnt/ß-catenin pathway. Clinically, GTP-Rac1 expression was inversely correlated with SEMA3F levels in CRC samples and patients with SEMA3F(low)/GTP-Rac1(high) CRC showed poorer prognosis. Our findings demonstrate the ability of SEMA3F to inhibit the stemness of human CRC cells by suppressing Rac1 activation, which suggests a novel therapeutic approach for CRC.
Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Proteínas de Membrana/genética , Recidiva Local de Neoplasia/genética , Proteínas do Tecido Nervoso/genética , Proteínas rac1 de Ligação ao GTP/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Membrana/biossíntese , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Proteínas do Tecido Nervoso/biossíntese , Transdução de Sinais/genética , Via de Sinalização Wnt/genética , Proteínas rac1 de Ligação ao GTP/biossínteseRESUMO
Infiltration of inflammatory cells and production of pro-angiogenic factors are important in lung cancer immunity. The distributions of those cells and their contributions to the production of pro-angiogenic factors and the activation phenotype of macrophages in bronchoalveolar lavage fluid (BALF) from lung cancer patients remain unclear. We analyzed the presence of distinct inflammatory cells and the macrophage activation phenotype together with the levels of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8) within BALF from 54 smoking lung cancer patients including 36 squamous cell carcinoma (SCC), 9 adenocarcinoma (AC), and 9 small cell lung cancer (SCLC) in comparison with those from 13 non-smoking and 7 smoking patients with nonspecific chronic inflammation and 8 non-smoking normal controls. We found a significantly lower percentage of total macrophages and a much higher percentage of neutrophils among all inflammatory cells in BALF from lung cancer and non-specific chronic inflammation patients. BALF from AC patients had a significantly higher percentage of lymphocytes. CD163(+)) macrophages predominantly existed in BALF from SCLC patients. BALF of lung cancer patients had markedly higher levels of IL-8 and VEGF. Interestingly, IL-8 level was positively correlated to the numbers of neutrophils and lymphocytes. VEGF level was inversely correlated to the number of lymphocytes but positively to cancer cells in SCC cases, whereas no correlation existed between CD163(+)) macrophages and the levels of IL-8 and VEGF. Our results suggest that the detection of infiltrating inflammatory cells and pro-angiogenic factors in BALF will be helpful for diagnosis of cancerous inflammation in lungs.
Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Interleucina-8/imunologia , Neoplasias Pulmonares/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/imunologiaRESUMO
Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer.
Assuntos
Neoplasias da Mama/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Células-Tronco Neoplásicas/imunologia , Evasão Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células K562 , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Interferência de RNA , Adulto JovemRESUMO
PURPOSE: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC. METHODS AND RESULTS: In this study, we examined ALDH1A1 expression by immunohistochemistry including 406 cases of primary CRC with corresponding adjacent mucosa, with confirmation of real-time PCR and Western blotting. We found that the expression patterns of ALDH1A1 were heterogeneous in the CRC and corresponding adjacent tissues. We defined the ratio of ALDH1A1 level in adjacent mucosa to that in tumor tissues as RA/C and found that the capabilities of tumor invasion and metastasis in the tumors with RA/C < 1 were significantly higher than those with RA/C ≥ 1. Follow-up data showed the worse prognoses in the CRC patients with RA/C < 1. For understanding the underlying mechanism, the localization of ß-catenin was detected in the CRC tissues with different patterns of ALDH1A1 expression from 221 patients and ß-catenin was found preferentially expressed in cell nuclei of the tumors with RA/C < 1 and ALDH1A1(high) expression of HT29 cell line, indicating that nuclear translocation of ß-catenin might contribute to the increased potentials of invasion and metastasis. CONCLUSION: Our results indicate that RA/C is a novel biomarker to reflect the distinct expression patterns of ALDH1A1 for predicting metastasis and prognosis of CRC.
Assuntos
Aldeído Desidrogenase/biossíntese , Biomarcadores Tumorais/análise , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Aldeído Desidrogenase/análise , Família Aldeído Desidrogenase 1 , Animais , Western Blotting , Neoplasias Colorretais/mortalidade , Citometria de Fluxo , Xenoenxertos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica/patologia , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Retinal DesidrogenaseRESUMO
Cancer stem cells (CSCs) constitute a subpopulation of cancer cells that have the potential for self-renewal, multipotent differentiation, and tumorigenicity. Studies on CSC biology and CSC-targeted therapies depend on CSC isolation and/or enrichment methodologies. Scientists have conducted extensive research in this field since John Dick's group successfully isolated CSCs based on the expression of the CD34 and CD38 surface markers. Progress in CSC research has been greatly facilitated by the enrichment and isolation of these cells. In this review, we summarize the current strategies used in our and other laboratories for CSC isolation and enrichment, including methods based on stem cell surface markers, intracellular enzyme activity, the concentration of reactive oxygen species, the mitochondrial membrane potential, promoter-driven fluorescent protein expression, autofluorescence, suspension/adherent culture, cell division, the identification of side population cells, resistance to cytotoxic compounds or hypoxia, invasiveness/adhesion, immunoselection, and physical property. Although many challenges remain to be overcome, it is reasonable to believe that more reliable, efficient, and convenient methods will be developed in the near future.