RESUMO
Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer that is prone to peritoneal dissemination, with poor patient prognosis. Although intercellular adhesion loss between cancer cells is a major characteristic of DGCs, the mechanism underlying the alteration in cell-to-extracellular matrix (ECM) adhesion is unclear. We investigated how DGCs progress and cause peritoneal dissemination through interactions between DGC cells and the tumour microenvironment (TME). P53 knockout and KRASG12V-expressing (GAN-KP) cells and Cdh1-deleted GAN-KP (GAN-KPC) cells were orthotopically transplanted into the gastric wall to mimic peritoneal dissemination. The GAN-KPC tumour morphology was similar to that of human DGCs containing abundant stroma. RNA sequencing revealed that pathways related to Rho GTPases and integrin-ECM interactions were specifically increased in GAN-KPC cells compared with GAN-KP cells. Notably, we found that Rac Family Small GTPase 1 (RAC1) induces Integrin Subunit Alpha 6 (ITGA6) trafficking, leading to its enrichment on the GC cell membrane. Fibroblasts activate the FAK/AKT pathway in GC cells by mediating extracellular matrix (ECM)-Itga6 interactions, exacerbating the malignant phenotype. In turn, GC cells induce abnormal expression of fibroblast collagen and its transformation into cancer-associated fibroblasts (CAFs), resulting in DGC-like subtypes. These findings indicate that Cdh1 gene loss leads to abnormal expression and changes in the subcellular localization of ITGA6 through RAC1 signalling. The latter, through interactions with CAFs, allows for peritoneal dissemination.
Assuntos
Caderinas , Integrina alfa6 , Neoplasias Peritoneais , Neoplasias Gástricas , Microambiente Tumoral , Proteínas rac1 de Ligação ao GTP , Animais , Humanos , Camundongos , Antígenos CD/metabolismo , Antígenos CD/genética , Caderinas/metabolismo , Caderinas/genética , Adesão Celular , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Transdução de Sinais , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Integrina alfa6/genética , Integrina alfa6/metabolismoRESUMO
Background & Aims: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined. Methods: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC. Results: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC. Conclusions: 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC. Impact and implications: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.
RESUMO
Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Fibroblastos Associados a Câncer/metabolismo , Ácido Láctico/metabolismo , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Glucose/metabolismo , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Extracellular vesicles (EVs), including exosomes, play a crucial role in intercellular communication and have emerged as important mediators in the development and progression of gastric cancer. This review discusses the current understanding of the role of EVs, particularly exosomal lncRNA and microRNA, in gastric cancer and their potential as diagnostic and therapeutic targets. Exosomes are small membrane-bound particles secreted by both cancer cells and stromal cells within the tumor microenvironment. They contain various ncRNA and biomolecules, which can be transferred to recipient cells to promote tumor growth and metastasis. In this review, we highlighted the importance of exosomal lncRNA and microRNA in gastric cancer. Exosomal lncRNAs have been shown to regulate gene expression by interacting with transcription factors or chromatin-modifying enzymes, which regulate gene expression by binding to target mRNAs. We also discuss the potential use of exosomal lncRNAs and microRNAs as diagnostic biomarkers for gastric cancer. Exosomes can be isolated from various bodily fluids, including blood, urine, and saliva. They contain specific molecules that reflect the molecular characteristics of the tumor, making them promising candidates for non-invasive diagnostic tests. Finally, the potential of targeting exosomal lncRNAs and microRNAs as a therapeutic strategy for gastric cancer were reviewed as wee. Inhibition of specific molecules within exosomes has been shown to suppress tumor growth and metastasis in preclinical models. In conclusion, this review article provides an overview of the current understanding of the role of exosomal lncRNA and microRNA in gastric cancer. We suggest that further research into these molecules could lead to new diagnostic tools and therapeutic strategies for this deadly disease.
RESUMO
Introduction: As neoadjuvant chemotherapy (NCT) has been successfully introduced in gastric cancer (GC), more biomarkers are needed to evaluate the efficacy. Cancer-associated fibroblasts (CAFs) is associated with chemoresistance and prognosis. Three biomarkers, CD10, fibroblast activation protein-α (FAP) and G-protein-coupled receptor 77 (GPR77), have been proved to express in CAFs. However, their predictive values for efficacy of NCT and prognosis in gastric cancer is unknown. Methods: Totally, specimens of 171 locally advanced gastric cancer patients who underwent NCT and D2 radical gastrectomy and matched preoperative biopsy specimens were retrospectively analyzed. Tumor regression grade (TRG) is reevaluated according to Mandard TRG. Expressions of CD10, FAP and GPR77 in CAFs before NCT (pre-) and after NCT (post-) were evaluated by immunohistochemistry. Survival curves on overall survival (OS) were obtained by Kaplan-Meier method, and differences were analyzed by log-rank test. Associations between categorical variables were explored by chi-square test or Fisher's exact method. Univariable and multivariate analyses were performed by logistic regression model and Cox proportional hazard regression model. Results: High expressions of post-CD10, post-FAP, post-GPR77 and pre-CD10 were related to worse TRG (all p<0.05). In multivariable analysis, post- and pre-FAP were independent predictive factors to TRG (p<0.010). Post-CD10 (p=0.032) and post-FAP (p=0.013) were related to OS in univariable analysis, but none of biomarkers were independent prognostic factors in multivariable analysis. Conclusions: Expressions of CD10, FAP and GPR77 in CAFs were related to chemoresistance and overall survival, and these biomarkers have predictive values for tumor regression and prognosis in locally advanced gastric cancer patients.
RESUMO
Purpose: Pretreatment neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios are markers of systemic inflammation. In patients with locally advanced gastric cancer (GC), the utility of these ratios in predicting tumor regression grade (TRG) after neoadjuvant chemotherapy (NCT) remains unclear. Methods: This retrospective study examined 283 locally advanced GC patients who underwent NCT and radical surgery. The receiver operating characteristic (ROC) curve analysis and the Youden index were applied to identify optimal NLR/PLR cutpoints. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival (DFS). Univariate/multivariate analyses were conducted by the logistic regression method. Results: TRG grade proved significantly worse in patients with high values of both NLR and PLR whether in univariate (OR = 3.457; p = 0.044) or multivariate (OR = 6.876; p = 0.028) analysis. The degree of tumor differentiation was an independent predictive factor for TRG (OR = 2.874; p = 0.037) in multivariate analysis. In the subgroup analyses, NLR predicted OS (p = 0.04) and DFS (p = 0.03) in female patients, whereas PLR was predictive of both OS (p = 0.026) and DFS (p = 0.018) in patients with clinical TNM stage 3 disease and dissected lymph node counts <28. PLR similarly predicted OS in patients <65 years old (p = 0.049), those with positive lymph nodes (p = 0.021), or those with moderate or poorly differentiated tumors (p = 0.049). Conclusion: Pretreatment NLR and PLR together serve to independently predict TRG after NCT and surgery in patients with locally advanced GC. Screening for patients with high NLR and PLR values may allow them to benefit upfront from alternatives to NCT.
RESUMO
Purpose: Tumor regression grade (TRG) is widely used to evaluate the efficacy of neoadjuvant chemotherapy (NCT) and it is related to many clinicopathological factors. However, whether TRG can be predicted by clinical characteristics is unknown. Methods: 141 locally advanced gastric cancer (GC) patients who underwent NCT and curative operation were retrospectively analyzed. TRG is reevaluated according to the CAP guideline. The values of CA199, CA125 and CA724 before NCT (pre-) and after NCT (post-) were extracted from our database. Survival curves on overall survival (OS) were obtained by Kaplan-Meier method, and differences were analyzed by log-rank test. Associations between categorical variables were explored by chi-square test or Fisher's exact method. Univariable and multivariate analyses were performed by logistic regression model or Cox proportional hazard regression model. Results: TRG was related to OS (P < 0.001), especially when divided into responders (TRG 0-1) and non-responders (TRG 2-3). Pre-CA724 (p = 0.029) and post-CA199 (p = 0.038) were related to OS. In multivariable analysis, pre-CA724 (p = 0.015) and post-CA199 (p = 0.007) were independent prognostic factors for OS, respectively. The changes (diff-) of all tumor markers were not related to OS. Among the clinical characteristics, pre-CA724 (P = 0.047) and tumor size (P = 0.012) were related to TRG, while pre-CA199 (P = 0.377) and pre-CA125 (P = 0.856) were not. In logistics analysis, pre-CA724 (P = 0.032), tumor size (P = 0.011) and tumor location (P = 0.047) were independent risk factors to pathological response. Conclusion: CA724 was an independent prognostic factor for OS and could be used to predict pathological response.
RESUMO
BACKGROUND Gastric cancer is the most common gastrointestinal tumor, and the rates of recurrence and metastasis are high. Research results on molecular biomarkers used for prognosis of gastric cancer remain inconclusive. This study aimed to explore the gene expression module of gastric cancer and to determine potential prognostic biomarkers. MATERIAL AND METHODS Three microarray datasets (GSE13911, GSE79973, and GSE29272) from Gene Expression Omnibus (GEO), including 206 pairs of gastric tumors and adjacent normal samples, were used for analysis of differentially expressed genes (DEGs). The 3 microarray datasets yielded 144 genes associated with the progression and prognosis of gastric cancer. After this, a risk score model was developed for result validation using an independent dataset from The Cancer Genome Atlas. RESULTS The validation of the independent dataset showed significantly increased NID2, SPARC, and MFAP2 expression in gastric tumor tissues, which were associated with poor outcomes in gastric cancer patients. Moreover, the high risk score obtained was associated with poor overall survival (HR: 1.787; 1.069-2.986; P=0.027). Subgroup analyses revealed that these significant prognostic values were detected in patients aged <65.0 years, tumors in the antrum/distal colon, grade 3 tumors, or TNM-M0 stages of cancer. CONCLUSIONS The findings of this study show that NID2, SPARC, and MFAP2 are upregulated in gastric tumor tissues and are significantly associated with poor overall survival. Therefore, the predictive values of the risk score model employed for the prognosis of gastric cancer could be improved by using these 3 upregulated DEGs.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Moléculas de Adesão Celular/genética , Osteonectina/genética , Fatores de Processamento de RNA/genética , Neoplasias Gástricas/genética , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Bases de Dados Genéticas , Progressão da Doença , Mucosa Gástrica/metabolismo , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes , Humanos , Análise em Microsséries , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Osteonectina/metabolismo , Prognóstico , Fatores de Processamento de RNA/metabolismo , Neoplasias Gástricas/mortalidade , Análise de SobrevidaRESUMO
BACKGROUND: Serum tumor markers including AFU, AFP, CEA, CA199, CA125 and CA724, are of great importance in the diagnosis, prognostic prediction and recurrence monitoring of gastrointestinal malignancies. However, their significance in gastric cancer (GC) patients with neoadjuvant therapy (NCT) is still uncertain. The aim of this study was to evaluate the predictive value of these six tumor markers in locally advanced GC patients who underwent NCT and curative surgery. METHODS: In total, 290 locally advanced GC patients who underwent NCT and D2 radical gastrectomy were retrospectively analyzed. Data on their tumor markers before (pre-) and after (post-) NCT and pathological characteristics were extracted from the database of our hospital. The optimal cutoff values of the six tumor markers were calculated by the ROC curve and Youden index. Their predictive significance was analyzed and survival curves for overall survival (OS) were obtained by the Kaplan-Meier method. Associations between categorical variables were explored by the chi-square test or Fisher's exact test. Multivariate analyses were performed by the Cox regression model. RESULTS: Pre- and post-CA199, -CA125 and -CA724 could predict overall survival (all P < 0.05), but only the change (diff-) of CA199 was related to prognosis (P = 0.05). In the multivariable analysis, pre- (P = 0.014) and post-CA724 (P = 0.036) remained significant, though diff-CA724 was not an independent prognostic factor (P = 0.581). In addition, pre- and post-CA199, -CA125 and -CA724 were associated with lymph node metastasis (N- vs N+) and pathological stage (I-II vs III) (all P < 0.05). Moreover, post-CA724 was related to the vascular or lymphatic invasion (P = 0.019), while pre-CA724 was not (P = 0.082). However, AFU, AFP and CEA showed no association with survival (P > 0.05). CONCLUSIONS: CA724 is an independent factor for prognosis and could be used to predict ypN and ypTNM stage in locally advanced GC patients undergoing NCT and curative resection.
Assuntos
Adenocarcinoma/mortalidade , Antígenos Glicosídicos Associados a Tumores/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Gástricas/mortalidade , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
PURPOSE: Tumor regression grade (TRG) has been widely used in gastrointestinal carcinoma to assess pathological responses to neoadjuvant chemotherapy (NCT). There are various standards without a consensus, and it is still unclear which kind of system has better predictive value. This study aims to investigate and compare the predictive ability of the Mandard and Becker TRGs in patients with locally advanced gastric cancer. MATERIALS AND METHODS: A total of 290 patients with locally advanced gastric adenocarcinoma who underwent NCT and curative surgery were studied. Survival analysis for overall survival (OS) and disease-free survival (DFS) were based on the Kaplan-Meier method and Cox proportional hazards method. Predictive values of TRGs and models were assessed by time-dependent receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), nomogram, and calibration curve. RESULTS: In multivariable analysis, the Mandard TRG was associated with OS (hazard ratio [HR], 1.806; p=0.026) and DFS (HR, 1.792; p=0.017). The Becker TRG was also related to OS (HR, 1.880; p=0.014) and DFS (HR, 1.919; p=0.006). The Mandard and Becker TRG AUCs for 5-year survival were 0.72 and 0.71, respectively. The whole models showed an increased predictive value, with AUCs of 0.85 and 0.86, respectively. There was no significant difference between the two TRGs and two models. CONCLUSION: TRG was an independent predictor for survival, and there was no significant difference between these two systems.
Assuntos
Adenocarcinoma/genética , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidade , Idoso , Feminino , Humanos , Masculino , Gradação de Tumores , Valor Preditivo dos Testes , Prognóstico , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: As the neoadjuvant therapy has been successfully introduced in the treatment of gastrointestinal malignancies, the evaluation of therapeutic effectiveness is becoming increasingly important. Tumor-node-metastasis system has been widely applied. However, this system is mainly based on the location of residual tumor, but does not consider the amount of residual tumor. Tumor regression grading system, a quantitative method to assess the reaction of tumor to neoadjuvant treatment, could be used as a supplement to tumor-node-metastasis system and provide additional information on prognosis. To date, numerous gastrointestinal grading systems have been used in esophageal/esophagogastric junction carcinoma, gastric adenocarcinoma, colorectal cancer, and most of them were considered to associate with clinical outcomes. MATERIALS AND METHODS: In this review, firstly, we expounded the importance of tumor regression grading systems, and summarized the histopathological changes after neoadjuvant therapy. Secondly, we introduced some commonly used gastrointestinal systems, as well as the relationships and nuance. Finally, we discussed pivotal issues about these systems. In this part, we explained the calculation methods based on grid points and square measures, discussed several factors leading to observer bias, containing the slice number and the grading tier number, and analyzed the factors that might affect clinical significance, covering anatomical location, the selection of survival index, and the tumor type. RESULTS: Tumor regression grade systems could be divided into two main classifications, the relative amount of fibrosis and residual tumor, and the proportion of residual tumor in the tumor bed. However, the definitions of these systems were still need to be improved. CONCLUSIONS: The tumor regression grading system is useful in evaluating tumor response to neoadjuvant therapy, but more work is needed to refine and unify the system.
Assuntos
Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Gradação de Tumores , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Neoplasias Esofágicas/patologia , Humanos , Terapia Neoadjuvante/métodosRESUMO
BACKGROUND: Tumor regression grade (TRG) is widely used in gastrointestinal carcinoma to evaluate pathological responses to neoadjuvant chemotherapy (NCT), but whether it is an independent prognostic factor is still controversial. The aim of this study is to investigate the value of TRG in locally advanced gastric adenocarcinoma patients who underwent NCT and curative resection. METHODS: Pathological regression was reevaluated according to the Mandard TRG. Survival curves were obtained by the Kaplan-Meier method, and differences in overall survival (OS) and disease-free survival (DFS) were compared using the log-rank test. Univariate and multivariate analyses for survival were based on the Cox proportional hazards method. RESULTS: In total, 290 patients were identified in our electronic database. In univariable analysis, TRG was associated with OS (HR = 3.822, P ≤ 0.001) and DFS (HR = 3.374, P ≤ 0.001). However, in multivariable analysis, TRG was not an independent factor for OS (P = 0.231) or DFS (P = 0.191). In the stratified analysis, TRG retrieved prognostic significance in patients with the metastasis of lymph node (HR = 2.034, P = 0.035 for OS; HR = 2.220, P = 0.016 for DFS), while not in patients with negative lymph node (P = 0.296 for OS; P = 0.172 for DFS). CONCLUSIONS: TRG was not an independent predictor for survival, but the system regained its predicting significance in patients with lymph node metastasis.