RESUMO
OBJECTIVES: Gastric cancer (GC) is a prevalent malignant tumor widely distributed globally, exhibiting elevated incidence and fatality rates. The gene LAMC2 encodes the laminin subunit gamma-2 chain and is found specifically in the basement membrane of epithelial cells. Its expression is aberrant in multiple types of malignant tumors. This research elucidated a link between LAMC2 and the clinical characteristics of GC and investigated the potential involvement of LAMC2 in GC proliferation and advancement. MATERIALS AND METHODS: LAMC2 expressions were detected in GC cell lines and normal gastric epithelial cell lines via qRT-PCR. Silencing and overexpression of the LAMC2 were conducted by lentiviral transfection. A xenograft mouse model was also developed for in vivo analysis. Cell functional assays were conducted to elucidate the involvement of LAMC2 in cell growth, migration, and penetration. Further, immunoblotting was conducted to investigate the impact of LAMC2 on the activation of signal pathways after lentiviral transfection. RESULTS: In the findings, LAMC2 expression was markedly upregulated in GC cell lines as opposed to normal gastric epithelial cells. In vitro analysis showed that sh-LAMC2 substantially inhibited GC cell growth, migration, and invasion, while oe-LAMC2 displayed a contrasting effect. Xenograft tumor models demonstrated that oe-LAMC2 accelerated tumor growth via high expression of Ki-67. Immunoblotting analysis revealed a substantial decrease in various signaling pathway proteins, PI3K, p-Akt, and Vimentin levels upon LAMC2 knockdown, followed by increased E-cadherin expression. Conversely, its overexpression exhibited contrasting effects. Besides, epithelial-mesenchymal transition (EMT) was accelerated by LAMC2. CONCLUSION: This study provides evidence indicating that LAMC2, by stimulating signaling pathways, facilitated EMT and stimulated the progression of GC cells in laboratory settings and mouse models. Research also explored that the abnormal LAMC2 expression acts as a biomarker for GC.
Assuntos
Proliferação de Células, Laminina, Invasividade Neoplásica, Fosfatidilinositol 3-Quinases, Proteínas Proto-Oncogênicas c-akt, Transdução de Sinais, Neoplasias Gástricas, Neoplasias Gástricas/patologia, Neoplasias Gástricas/genética, Neoplasias Gástricas/metabolismo, Humanos, Animais, Proteínas Proto-Oncogênicas c-akt/metabolismo, Fosfatidilinositol 3-Quinases/metabolismo, Camundongos, Laminina/metabolismo, Linhagem Celular Tumoral, Camundongos Nus, Transição Epitelial-Mesenquimal, Movimento Celular, Feminino, Masculino, Camundongos Endogâmicos BALB C, Metástase Neoplásica, Ensaios Antitumorais Modelo de Xenoenxerto, Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUNDS: Long nonconding RNAs (lncRNAs) have been found to be a vital regulatory factor in the development process of human cancer, and could regarded as diagnostic or prognostic biomarkers for human cancers. Here, we aim to confirm the expression and molecular mechanism of RP11-171K16.5 (lnc171) in hepatocellular carcinoma (HCC). METHODS: Screening of differentially expressed lncRNAs by RNA sequencing. Expression level of gene was studied by quantitative real-time PCR (qRT-PCR). The effects of lnc171, mir-873-5p, and ethanol on migration and invasion activity of cells were studied used transwell assay, and luciferase reporter assay was used to confirm the binding site. RESULTS: RNA sequencing showed that lnc171 was markedly up-regulated in HCC. siRNA-mediated knockdown of lnc171 repressed the migration and invasion ability of HCC cells. Bioinformatic analysis, dual luciferase reporter assay, and qRT-PCR indicated that lnc171 interacted with mir-873-5p in HCC cells, and Zin-finger E-box binding homeobox (ZEB1) was a downstream target gene of mir-873-5p. In addition, lnc171 could enhance migration and invasion ability of HCC cells by up-regulating ZEB1 via sponging mir-873-5p. More interestingly, ethanol stimulation could up-regulate the increase of lnc171, thereby regulating the expression of competing endogenous RNA (ceRNA) network factors which lnc171 participated in HCC cells. CONCLUSIONS: Our date demonstrates that lnc171 was a responsive factor of ethanol, and plays a vital role in development of HCC via binding of mir-873-5p.
Assuntos
Carcinoma Hepatocelular, Movimento Celular, Etanol, Regulação Neoplásica da Expressão Gênica, Neoplasias Hepáticas, MicroRNAs, RNA Longo não Codificante, Homeobox 1 de Ligação a E-box em Dedo de Zinco, Humanos, MicroRNAs/genética, RNA Longo não Codificante/genética, Carcinoma Hepatocelular/genética, Carcinoma Hepatocelular/patologia, Carcinoma Hepatocelular/metabolismo, Neoplasias Hepáticas/genética, Neoplasias Hepáticas/patologia, Neoplasias Hepáticas/metabolismo, Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética, Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo, Movimento Celular/genética, Etanol/farmacologia, Linhagem Celular Tumoral, Invasividade Neoplásica/genéticaRESUMO
Conventional endoscopy is widely used in the diagnosis of early gastric cancers (EGCs), but the graphical features were loosely defined and dependent on endoscopists' experience. We aim to establish a more accurate predictive model for infiltration depth of early gastric cancer including a standardized colorimetric system, which demonstrates promising clinical implication. A retrospective study of 718 EGC cases was performed. Clinical and pathological characteristics were included, and Commission Internationale de l'Eclariage (CIE) standard colorimetric system was used to evaluate the chromaticity of lesions. The predicting models were established in the derivation set using multivariate backward stepwise logistic regression, decision tree model, and random forest model. Logistic regression shows location, macroscopic type, length, marked margin elevation, WLI color difference and histological type are factors significantly independently associated with infiltration depth. In the decision tree model, margin elevation, lesion located in the lower 1/3 part, WLI a*color value, b*color value, and abnormal thickness in enhanced CT were selected, which achieved an AUROC of 0.810. A random forest model was established presenting the importance of each feature with an accuracy of 0.80, and an AUROC of 0.844. Quantified color metrics can improve the diagnostic precision in the invasion depth of EGC. We have developed a nomogram model using logistic regression and machine learning algorithms were also explored, which turned out to be helpful in decision-making progress.
Assuntos
Aprendizado de Máquina, Invasividade Neoplásica, Neoplasias Gástricas, Neoplasias Gástricas/patologia, Neoplasias Gástricas/diagnóstico, Humanos, Masculino, Feminino, Pessoa de Meia-Idade, Estudos Retrospectivos, Idoso, Cor, Mucosa Gástrica/patologia, Mucosa Gástrica/diagnóstico por imagem, Detecção Precoce de Câncer/métodos, Modelos Logísticos, Gastroscopia/métodos, Árvores de DecisõesRESUMO
PURPOSE: In this study, we aimed to investigate the prognosis of invasive lung adenocarcinoma that manifests as pure ground glass nodules (pGGNs) and confirm the effectiveness of sublobectomy and lymph node sampling in patients with pGGN-featured invasive adenocarcinoma (IAC). MATERIALS AND METHODS: We retrospectively enrolled 139 patients with pGGN-featured IAC, who underwent complete resection in two medical institutions between January 2011 and May 2022. Stratification analysis was conducted to ensure balanced baseline characteristics among the patients. The 5-year overall survival (OS) and disease-free survival (DFS) rates were compared between the groups using Kaplan-Meier survival curves and log-rank test. RESULTS: The 5-year OS and DFS rates for patients with IAC presenting as pGGNs after surgery were 96.5% and 100%, respectively. No lymph node metastasis or recurrence was observed in any of the enrolled patients. There was no statistically significant difference in the 5-year OS between patients who underwent lobectomy or sublobectomy, along with lymph node resection or sampling. CONCLUSION: IAC presented as pGGNs exhibited low-grade malignancy and had a relatively good prognosis. Therefore, these patients may be treated with sublobectomy and lymph node sampling.
Assuntos
Adenocarcinoma de Pulmão, Neoplasias Pulmonares, Linfonodos, Metástase Linfática, Pneumonectomia, Humanos, Masculino, Feminino, Estudos Retrospectivos, Pessoa de Meia-Idade, Neoplasias Pulmonares/patologia, Neoplasias Pulmonares/cirurgia, Neoplasias Pulmonares/mortalidade, Adenocarcinoma de Pulmão/cirurgia, Adenocarcinoma de Pulmão/patologia, Adenocarcinoma de Pulmão/mortalidade, Idoso, Prognóstico, Pneumonectomia/métodos, Linfonodos/patologia, Linfonodos/cirurgia, Invasividade Neoplásica, Excisão de Linfonodo/métodos, Taxa de Sobrevida/tendências, Intervalo Livre de Doença, AdultoRESUMO
BACKGROUND: Renal cell carcinoma (RCC), a common and highly invasive malignant tumour, presents clinical challenges due to its propensity for easy metastasis. Inferior vena cava tumour thrombus is a common RCC complication significantly impacting patient prognosis. This study investigates C-X-C chemokine receptor type 2 (CXCR2)/Snail-1-induced epithelial-mesenchymal transition (EMT) in RCC with inferior vena cava tumour thrombus. METHODS: Tissues from 51 RCC patients were analysed for CXCR2 and Snail-1 Messenger Ribonucleic Acid (mRNA) levels using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Elevated levels of both were observed in tumour and inferior vena cava tumour thrombus tissues. Using Short Hairpin RNA (shRNA) technology, we inhibited CXCR2 and Snail-1 expression to investigate their impact on EMT, invasiveness, and metastatic potential in RCC cells. RESULTS: Compared with that in the Short Hairpin RNA-Negative Control (ShNC) group, inhibition of CXCR2 and Snail-1 suppressed the degree of EMT, invasiveness, and metastatic ability of RCC cells (p < 0.01). Further mechanistic studies showed that CXCR2/Snail-1 participated in the formation and progression of RCC by regulating the extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathways. Additionally, compared with that in the ShNC group, knockdown of CXCR2 and Snail-1 significantly inhibited the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9; p < 0.01), thereby regulating the metastasis of RCC. CONCLUSIONS: Our findings suggest that CXCR2/Snail-1-induced EMT plays an important role in the formation and progression of RCC with inferior vena cava tumour thrombus. CXCR2/Snail-1 participates in the invasion and metastasis of RCC by regulating the expression of multiple signalling pathways and related genes. These results provide new insights and directions for the treatment of RCC.
Assuntos
Carcinoma de Células Renais, Progressão da Doença, Transição Epitelial-Mesenquimal, Neoplasias Renais, Fatores de Transcrição da Família Snail, Veia Cava Inferior, Idoso, Feminino, Humanos, Masculino, Pessoa de Meia-Idade, Carcinoma de Células Renais/metabolismo, Carcinoma de Células Renais/patologia, Carcinoma de Células Renais/secundário, Neoplasias Renais/patologia, Neoplasias Renais/metabolismo, Invasividade Neoplásica, Fatores de Transcrição da Família Snail/metabolismo, Células Tumorais Cultivadas, Veia Cava Inferior/patologiaRESUMO
BACKGROUND: To investigate the correlation between microinvasion and various features of hepatocellular carcinoma (HCC), and to clarify the microinvasion distance from visible HCC lesions to subclinical lesions, so as to provide clinical basis for the expandable boundary of clinical target volume (CTV) from gross tumor volume (GTV) in the radiotherapy of HCC. METHODS: HCC patients underwent hepatectomy of liver cancer in our hospital between July 2019 and November 2021 were enrolled. Data on various features and tumor microinvasion distance were collected. The distribution characteristics of microinvasion distance were analyzed to investigate its potential correlation with various features. Tumor size compared between radiographic and pathologic samples was analyzed to clarify the application of pathologic microinvasion to identify subclinical lesions of radiographic imaging. RESULTS: The average microinvasion distance was 0.6 mm, with 95% patients exhibiting microinvasion distance less than 3.0 mm, and the maximum microinvasion distance was 4.0 mm. A significant correlation was found between microinvasion and liver cirrhosis (P = 0.036), serum albumin level (P = 0.049). Multivariate logistic regression analysis revealed that HCC patients with cirrhosis had a significantly lower risk of microinvasion (OR = 0.09, 95%CI = 0.02 ~ 0.50, P = 0.006). Tumor size was overestimated by 1.6 mm (95%CI=-12.8 ~ 16.0 mm) on radiographic size compared to pathologic size, with a mean %Δsize of 2.96% (95%CI=-0.57%~6.50%). The %Δsize ranged from - 29.03% to 34.78%. CONCLUSIONS: CTV expanding by 5.4 mm from radiographic GTV could include all pathologic microinvasive lesions in the radiotherapy of HCC. Liver cirrhosis was correlated with microinvasion and were independent predictive factor of microinvasion in HCC.
Assuntos
Carcinoma Hepatocelular, Hepatectomia, Neoplasias Hepáticas, Invasividade Neoplásica, Carga Tumoral, Humanos, Carcinoma Hepatocelular/patologia, Carcinoma Hepatocelular/radioterapia, Carcinoma Hepatocelular/diagnóstico por imagem, Carcinoma Hepatocelular/cirurgia, Neoplasias Hepáticas/patologia, Neoplasias Hepáticas/radioterapia, Neoplasias Hepáticas/diagnóstico por imagem, Masculino, Feminino, Pessoa de Meia-Idade, Prognóstico, Hepatectomia/métodos, Idoso, Seguimentos, Estudos Retrospectivos, Adulto, Planejamento da Radioterapia Assistida por Computador/métodos, Cirrose Hepática/patologiaAssuntos
MicroRNAs, Tumor Trofoblástico de Localização Placentária, Proteína Wnt-5a, Humanos, Feminino, MicroRNAs/genética, MicroRNAs/metabolismo, Gravidez, Tumor Trofoblástico de Localização Placentária/metabolismo, Tumor Trofoblástico de Localização Placentária/genética, Tumor Trofoblástico de Localização Placentária/patologia, Proteína Wnt-5a/metabolismo, Proteína Wnt-5a/genética, Invasividade Neoplásica, Neoplasias Uterinas/genética, Neoplasias Uterinas/metabolismo, Neoplasias Uterinas/patologia, Regulação Neoplásica da Expressão GênicaRESUMO
Several studies have shown an association between prostate carcinoma (PCa) and Epstein-Barr virus (EBV); however, none of the studies so far have identified the histopathological and genetic markers of cancer aggressiveness associated with EBV in PCa tissues. In this study, we used previously characterized EBV-PCR-positive (n = 39) and EBV-negative (n = 60) PCa tissues to perform an IHC-based assessment of key histopathological and molecular markers of PCa aggressiveness (EMT markers, AR expression, perineural invasion, and lymphocytic infiltration characterization). Additionally, we investigated the differential expression of key oncogenes, EMT-associated genes, and PCa-specific oncomiRs, in EBV-positive and -negative tissues, using the qPCR array. Finally, survival benefit analysis was also performed in EBV-positive and EBV-negative PCa patients. The EBV-positive PCa exhibited a higher percentage (80%) of perineural invasion (PNI) compared to EBV-negative PCa (67.3%) samples. Similarly, a higher lymphocytic infiltration was observed in EBV-LMP1-positive PCa samples. The subset characterization of T and B cell lymphocytic infiltration showed a trend of higher intratumoral and tumor stromal lymphocytic infiltration in EBV-negative tissues compared with EBV-positive tissues. The logistic regression analysis showed that EBV-positive status was associated with decreased odds (OR = 0.07; p-value < 0.019) of CD3 intratumoral lymphocytic infiltration in PCa tissues. The analysis of IHC-based expression patterns of EMT markers showed comparable expression of all EMT markers, except vimentin, which showed higher expression in EBV-positive PCa tissues compared to EBV-negative PCa tissues. Furthermore, gene expression analysis showed a statistically significant difference (p < 0.05) in the expression of CDH1, AR, CHEK-2, CDKN-1B, and CDC-20 and oncomiRs miR-126, miR-152-3p, miR-452, miR-145-3p, miR-196a, miR-183-3p, and miR-146b in EBV-positive PCa tissues compared to EBV-negative PCa tissues. Overall, the survival proportion was comparable in both groups. The presence of EBV in the PCa tissues results in an increased expression of certain oncogenes, oncomiRs, and EMT marker (vimentin) and a decrease in CD3 ITL, which may be associated with the aggressive forms of PCa.
Assuntos
Biomarcadores Tumorais, Infecções por Vírus Epstein-Barr, Herpesvirus Humano 4, Neoplasias da Próstata, Humanos, Masculino, Neoplasias da Próstata/genética, Neoplasias da Próstata/patologia, Neoplasias da Próstata/virologia, Neoplasias da Próstata/mortalidade, Neoplasias da Próstata/metabolismo, Herpesvirus Humano 4/genética, Infecções por Vírus Epstein-Barr/virologia, Infecções por Vírus Epstein-Barr/genética, Infecções por Vírus Epstein-Barr/patologia, Infecções por Vírus Epstein-Barr/complicações, Biomarcadores Tumorais/genética, Idoso, Regulação Neoplásica da Expressão Gênica, Marcadores Genéticos, Pessoa de Meia-Idade, Linfócitos do Interstício Tumoral/imunologia, Transição Epitelial-Mesenquimal/genética, Invasividade NeoplásicaRESUMO
BACKGROUND: As per AJCC 8th edition TNM staging system, bone invasion is a poor prognostic marker that upstages oral cavity squamous carcinoma (OSCC) to pT4a. Cortical erosion alone of bone or tooth socket by a gingival primary is not sufficient to upstage a tumour. The differentiation of cortical erosion from invasion through the cortical bone into the medulla is often challenging, limiting accurate staging. This review aims to assess the difficulties in differentiating cortical erosion from medullary invasion and evaluate the prognostic significance of different patterns of bone involvement. METHODS: A retrospective review of OSCC with primary curative surgery and bone resection treated at a single-center over 10 years, was performed to assess the prognostic significance of bone invasion. Hematoxylin-eosin stained slides of a subset of cases were re-reviewed in a planned manner to assess difficulties in precise categorization (no invasion/erosion/cortical invasion and medullary invasion), evaluate interobserver agreement, and correlate with clinical outcome. RESULTS: Five hundred and ninety patients were included, with a median follow-up of 28 months. On univariate analysis, the 3-year local, nodal and distant metastasis control were not significantly different in the 3 groups of no invasion, erosion, and invasion (p = 0.43, 0.47, and 0.47, respectively). Overall survival (OS) at 3 years was 78.1% and disease-free-survival(DFS) was 63.7% in the entire cohort. On univariate analysis, there was significant difference in OS and DFS based on these groups. This did not translate into independent prognostic benefit on multivariable analysis (p = 0.75 and 0.19, respectively). The independent prognostic factors were margin positivity, tumor differentiation, perineural invasion and pathological nodal involvement. Planned re-review of a subset of 202 cases resulted in a change in bone involvement category in 26/202 cases, which was mainly due to difficulty in assessing cortico-medullary junction near the tooth socket and bone fragmentation. The assessment showed moderate to near complete agreement (kappa 0.59-0.82) between 2 observers. CONCLUSION: Our study shows that bone involvement is not an independent prognostic marker and there is no specific correlation of medullary invasion with outcome over those that showed cortical erosion. Several factors contribute to difficulties and interobserver variability in assessing bone involvement.
Assuntos
Neoplasias Bucais, Invasividade Neoplásica, Humanos, Estudos Retrospectivos, Masculino, Feminino, Pessoa de Meia-Idade, Prognóstico, Neoplasias Bucais/patologia, Neoplasias Bucais/mortalidade, Idoso, Adulto, Idoso de 80 Anos ou mais, Neoplasias Ósseas/patologia, Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia, Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade, Carcinoma de Células Escamosas/patologiaRESUMO
BACKGROUND: Perineural invasion (PNI) has been used as an important pathological indicator and independent prognostic factor for patients with rectal cancer (RC). Preoperative prediction of PNI status is helpful for individualized treatment of RC. Recently, several radiomics studies have been used to predict the PNI status in RC, demonstrating a good predictive effect, but the results lacked generalizability. The preoperative prediction of PNI status is still challenging and needs further study. AIM: To establish and validate an optimal radiomics model for predicting PNI status preoperatively in RC patients. METHODS: This retrospective study enrolled 244 postoperative patients with pathologically confirmed RC from two independent centers. The patients underwent pre-operative high-resolution magnetic resonance imaging (MRI) between May 2019 and August 2022. Quantitative radiomics features were extracted and selected from oblique axial T2-weighted imaging (T2WI) and contrast-enhanced T1WI (T1CE) sequences. The radiomics signatures were constructed using logistic regression analysis and the predictive potential of various sequences was compared (T2WI, T1CE and T2WI + T1CE fusion sequences). A clinical-radiomics (CR) model was established by combining the radiomics features and clinical risk factors. The internal and external validation groups were used to validate the proposed models. The area under the receiver operating characteristic curve (AUC), DeLong test, net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) were used to evaluate the model performance. RESULTS: Among the radiomics models, the T2WI + T1CE fusion sequences model showed the best predictive performance, in the training and internal validation groups, the AUCs of the fusion sequence model were 0.839 [95% confidence interval (CI): 0.757-0.921] and 0.787 (95%CI: 0.650-0.923), which were higher than those of the T2WI and T1CE sequence models. The CR model constructed by combining clinical risk factors had the best predictive performance. In the training and internal and external validation groups, the AUCs of the CR model were 0.889 (95%CI: 0.824-0.954), 0.889 (95%CI: 0.803-0.976) and 0.894 (95%CI: 0.814-0.974). Delong test, NRI, and IDI showed that the CR model had significant differences from other models (P < 0.05). Calibration curves demonstrated good agreement, and DCA revealed significant benefits of the CR model. CONCLUSION: The CR model based on preoperative MRI radiomics features and clinical risk factors can preoperatively predict the PNI status of RC noninvasively, which facilitates individualized treatment of RC patients.
Assuntos
Imageamento por Ressonância Magnética, Invasividade Neoplásica, Neoplasias Retais, Humanos, Neoplasias Retais/diagnóstico por imagem, Neoplasias Retais/patologia, Neoplasias Retais/cirurgia, Imageamento por Ressonância Magnética/métodos, Masculino, Estudos Retrospectivos, Feminino, Pessoa de Meia-Idade, Idoso, Valor Preditivo dos Testes, Prognóstico, Período Pré-Operatório, Nervos Periféricos/diagnóstico por imagem, Nervos Periféricos/patologia, Adulto, Fatores de Risco, Reto/diagnóstico por imagem, Reto/patologia, Reto/cirurgia, Curva ROC, RadiômicaRESUMO
Breast cancer is the most common invasive neoplasm and the leading cause of cancer death in women worldwide. The main cause of mortality in cancer patients is invasion and metastasis, where the epithelial-mesenchymal transition (EMT) is a crucial player in these processes. Pharmacological therapy has plants as its primary source, including isoflavonoids. Brazilin is an isoflavonoid isolated from Haematoxilum brasiletto that has shown antiproliferative activity in several cancer cell lines. In this study, we evaluated the effect of Brazilin on canonical markers of EMT such as E-cadherin, vimentin, Twist, and matrix metalloproteases (MMPs). By Western blot, we evaluated E-cadherin, vimentin, and Twist expression and the subcellular localization by immunofluorescence. Using gelatin zymography, we determined the levels of secretion of MMPs. We used Transwell chambers coated with matrigel to determine the in vitro invasion of breast cancer cells treated with Brazilin. Interestingly, our results show that Brazilin increases 50% in E-cadherin expression and decreases 50% in vimentin and Twist expression, MMPs, and cell invasion in triple-negative breast cancer (TNBC) MDA-MB-231 and to a lesser extend in MCF7 ER+ breast cancer cells. Together, these findings position Brazilin as a new molecule with great potential for use as complementary or alternative treatment in breast cancer therapy in the future.
Assuntos
Benzopiranos, Neoplasias da Mama, Caderinas, Transição Epitelial-Mesenquimal, Proteína 1 Relacionada a Twist, Vimentina, Humanos, Transição Epitelial-Mesenquimal/efeitos dos fármacos, Feminino, Caderinas/metabolismo, Vimentina/metabolismo, Vimentina/genética, Linhagem Celular Tumoral, Proteína 1 Relacionada a Twist/metabolismo, Proteína 1 Relacionada a Twist/genética, Benzopiranos/farmacologia, Neoplasias da Mama/patologia, Neoplasias da Mama/tratamento farmacológico, Neoplasias da Mama/metabolismo, Neoplasias da Mama/genética, Neoplasias de Mama Triplo Negativas/patologia, Neoplasias de Mama Triplo Negativas/tratamento farmacológico, Neoplasias de Mama Triplo Negativas/metabolismo, Neoplasias de Mama Triplo Negativas/genética, Células MCF-7, Biomarcadores Tumorais/metabolismo, Biomarcadores Tumorais/genética, Invasividade Neoplásica/genética, Metaloproteinases da Matriz/metabolismo, Metaloproteinases da Matriz/genética, Proteínas NuclearesRESUMO
AIM: To estimate the diagnostic value of magnetic resonance imaging (MRI)-based radiomic models in detecting the extramural venous invasion (EMVI) of rectal cancer. MATERIALS AND METHODS: Appropriate studies in multiple electronic databases were systematically retrieved. The Quality Assessment of Diagnostic Accuracy Studies 2 and Radiomics Quality Score (RQS) were used to evaluate the eligible studies' methodology quality. Summary accuracy metrics were calculated, and the publication bias was detected using Deek's funnel plot. The sensitivity and meta-regression analysis were performed to investigate the causes of heterogeneity. RESULTS: For the seven eligible studies, which included 1175 patients, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.80 (95 % CI, 0.70-0.88), 0.89 (95 % CI, 0.84-0.92), 7.0 (95 % CI, 4.7, 10.4), 0.22 (95 % CI, 0.14, 0.34), and 32 (95 % CI, 16, 65), respectively. The area under the receiver operating characteristic curve (AUC) was 0.91 (95 % CI, 0.88, 0.93). Moderate heterogeneity was found due to I2 values of 38.63 % and 32.29 % in sensitivity and specificity, respectively. Meta-regression analysis suggested that the patient enrollment, number of patients, segmentation method, and RQS score were the source of the heterogeneity. The head-to-head analysis suggested that radiomics model had a higher sensitivity for detection of EMVI than subjective evaluation by radiologist (0.47 vs. 0.73, p ≤ 0.001). CONCLUSION: Our study suggests that MRI-based radiomic models have good diagnostic value in detecting EMVI for rectal cancer patients. Nevertheless, more prospective and high-quality studies with larger sample sizes are needed in the future to validate these results.
Assuntos
Imageamento por Ressonância Magnética, Invasividade Neoplásica, Neoplasias Retais, Humanos, Neoplasias Retais/diagnóstico por imagem, Neoplasias Retais/patologia, Imageamento por Ressonância Magnética/métodos, Sensibilidade e Especificidade, Valor Preditivo dos Testes, RadiômicaRESUMO
BACKGROUND: Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain. METHODS: We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures. RESULTS: PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease. CONCLUSIONS: Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present.
Assuntos
Neoplasias do Colo, Invasividade Neoplásica, Estadiamento de Neoplasias, Nervos Periféricos, Pontuação de Propensão, Humanos, Feminino, Masculino, Neoplasias do Colo/patologia, Neoplasias do Colo/mortalidade, Neoplasias do Colo/tratamento farmacológico, Neoplasias do Colo/cirurgia, Pessoa de Meia-Idade, Prognóstico, Idoso, Estudos Prospectivos, Taxa de Sobrevida, Nervos Periféricos/patologia, Quimioterapia Adjuvante/métodos, Seguimentos, Metástase Linfática, Adulto, Taiwan/epidemiologiaRESUMO
The transition from collective to single-cell invasion in metastatic tumors has been regarded as the consequence of oncogenic drivers in concert with extracellular triggers received from the tumor microenvironment. In this issue, Yoon and colleagues (https://doi.org/10.1083/jcb.202308080) have identified an epigenetic program by which collective niches release laminin-332 and thereby cause the detachment and invasion of fully individualized tumor cells.
Assuntos
Neoplasias, Microambiente Tumoral, Humanos, Neoplasias/patologia, Neoplasias/genética, Neoplasias/metabolismo, Invasividade Neoplásica, Animais, Epigênese GenéticaRESUMO
Metastasis is the most dreaded outcome after a breast cancer diagnosis, and little is known regarding what triggers or promotes breast cancer to spread distally, or how to prevent or eradicate metastasis effectively. Bilateral breast cancers are an uncommon form of breast cancers. In our study, a percentage of bilateral breast cancers were clonally related based on copy number variation profiling. Whole exome sequencing and comparative sequence analysis revealed that a limited number of somatic mutations were acquired in this "breast-to-breast" metastasis that might promote breast cancer distant spread. One somatic mutation acquired was SIVA-D160N that displayed pro-metastatic phenotypes in vivo and in vitro. Over-expression of SIVA-D160N promoted migration and invasion of human MB-MDA-231 breast cancer cells in vitro, consistent with a dominant negative interfering function. When introduced via tail vein injection, 231 cells over-expressing SIVA-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA-D160N promoted invasion and anchorage independent growth of mouse 4T1 breast cancer cells in vitro. When introduced orthotopically via mammary fat pad injection in syngeneic Balb/c mice, over-expression of SIVA-D160N in 4T1 cells increased orthotopically implanted mammary gland tumor growth as well as liver metastasis. Clonally related bilateral breast cancers represented a novel system to investigate metastasis and revealed a role of SIVA-D160N in breast cancer metastasis. Further characterization and understanding of SIVA function, and that of its interacting proteins, may elucidate mechanisms of breast cancer metastasis, providing clinically useful biomarkers and therapeutic targets.
Assuntos
Neoplasias da Mama, Metástase Neoplásica, Feminino, Humanos, Neoplasias da Mama/genética, Neoplasias da Mama/patologia, Animais, Camundongos, Linhagem Celular Tumoral, Invasividade Neoplásica, Mutação, Movimento Celular/genética, Camundongos Endogâmicos BALB C, Variações do Número de Cópias de DNARESUMO
We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodeling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through the activation of a RhoA-ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by the binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here, we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analyzed the levels of the EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express the EGFR and found that EGFR-expressing cells responded to the EGF ligand by increasing ODZ1 at the mRNA and protein levels. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway, or Additionally, the siRNA-mediated knockdown of MAPK11 (p38ß MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signaling pathway through p38ß MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF-EGFR pathway for novel therapeutic approaches.
Assuntos
Fator de Crescimento Epidérmico, Receptores ErbB, Glioblastoma, Regulação para Cima, Humanos, Glioblastoma/patologia, Glioblastoma/metabolismo, Glioblastoma/genética, Receptores ErbB/metabolismo, Regulação para Cima/efeitos dos fármacos, Regulação para Cima/genética, Fator de Crescimento Epidérmico/farmacologia, Fator de Crescimento Epidérmico/metabolismo, Linhagem Celular Tumoral, Transdução de Sinais/efeitos dos fármacos, Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos, Invasividade NeoplásicaRESUMO
Aspartate ß-hydroxylase (ASPH) is a protein associated with malignancy in a wide range of tumors. We hypothesize that inhibition of ASPH activity could have anti-tumor properties in patients with head and neck cancer. In this study, we screened tumor tissues of 155 head and neck squamous cell carcinoma (HNSCC) patients for the expression of ASPH using immunohistochemistry. We used an ASPH inhibitor, MO-I-1151, known to inhibit the catalytic activity of ASPH in the endoplasmic reticulum, to show its inhibitory effect on the migration of SCC35 head and neck cancer cells in cell monolayers and in matrix-embedded spheroid co-cultures with primary cancer-associated fibroblast (CAF) CAF 61137 of head and neck origin. We also studied a combined effect of MO-I-1151 and HfFucCS, an inhibitor of invasion-blocking heparan 6-O-endosulfatase activity. We found ASPH was upregulated in HNSCC tumors compared to the adjacent normal tissues. ASPH was uniformly high in expression, irrespective of tumor stage. High expression of ASPH in tumors led us to consider it as a therapeutic target in cell line models. ASPH inhibitor MO-I-1151 had significant effects on reducing migration and invasion of head and neck cancer cells, both in monolayers and matrix-embedded spheroids. The combination of the two enzyme inhibitors showed an additive effect on restricting invasion in the HNSCC cell monolayers and in the CAF-containing co-culture spheroids. We identify ASPH as an abundant protein in HNSCC tumors. Targeting ASPH with inhibitor MO-I-1151 effectively reduces CAF-mediated cellular invasion in cancer cell models. We propose that the additive effect of MO-I-1151 with HfFucCS, an inhibitor of heparan 6-O-endosulfatases, on HNSCC cells could improve interventions and needs to be further explored.
Assuntos
Movimento Celular, Neoplasias de Cabeça e Pescoço, Invasividade Neoplásica, Carcinoma de Células Escamosas de Cabeça e Pescoço, Humanos, Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia, Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo, Neoplasias de Cabeça e Pescoço/patologia, Neoplasias de Cabeça e Pescoço/metabolismo, Linhagem Celular Tumoral, Movimento Celular/efeitos dos fármacos, Regulação para Cima/efeitos dos fármacos, Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos, Feminino, Pessoa de Meia-Idade, Oxigenases de Função Mista/metabolismo, Masculino, Técnicas de Cocultura, Idoso, Proteínas de Ligação ao Cálcio, Proteínas de Membrana, Proteínas MuscularesRESUMO
Dysregulated Wnt/ß-catenin signaling is a common feature of colorectal cancer (CRC). The T-cell factor/lymphoid enhancer factor (TCF/LEF; hereafter, TCF) family of transcription factors are critical regulators of Wnt/ß-catenin target gene expression. Of the four TCF family members, TCF7L1 predominantly functions as a transcriptional repressor. Although TCF7L1 has been ascribed an oncogenic role in CRC, only a few target genes whose expression it regulates have been characterized in this cancer. Through transcriptome analyses of TCF7L1 regulated genes, we noted enrichment for those associated with cellular migration. By silencing and overexpressing TCF7L1 in CRC cell lines, we demonstrated that TCF7L1 promoted migration, invasion, and adhesion. We localized TCF7L1 binding across the CRC genome and overlapped enriched regions with transcriptome data to identify candidate target genes. The growth arrest-specific 1 (GAS1) gene was among these and we demonstrated that GAS1 is a critical mediator of TCF7L1-dependent CRC cell migratory phenotypes. Together, these findings uncover a novel role for TCF7L1 in repressing GAS1 expression to enhance migration and invasion of CRC cells.
