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Pancreatic adenocarcinoma characterized by a mere 10% 5-year survival rate, poses a formidable challenge due to its specific anatomical location, making tumor tissue acquisition difficult. This limitation underscores the critical need for novel biomarkers to stratify this patient population. Accordingly, this study aimed to construct a prognosis prediction model centered on S100 family members. Leveraging six S100 genes and their corresponding coefficients, an S100 score was calculated to predict survival outcomes. The present study provided comprehensive internal and external validation along with power evaluation results, substantiating the efficacy of the proposed model. Additionally, the study explored the S100-driven potential mechanisms underlying malignant progression. By comparing immune cell infiltration proportions in distinct patient groups with varying prognoses, the research identified differences driven by S100 expression. Furthermore, the analysis explored significant ligand-receptor pairs between malignant cells and immune cells influenced by S100 genes, uncovering crucial insights. Notably, the study identified a novel biomarker capable of predicting the sensitivity of neoadjuvant chemotherapy, offering promising avenues for further research and clinical application.
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Adenocarcinoma , Biomarcadores Tumorais , Neoplasias Pancreáticas , Proteínas S100 , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Prognóstico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/genética , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
In recent years, the incidence of cancers is continuously increasing in young adults. Early-onset cancer (EOC) is usually defined as patients with cancers under the age of 50, and may represent a unique subgroup due to its special disease features. Overall, EOCs often initiate at a young age, present as a better physical performance but high degree of malignancy. EOCs also share common epidemiological and hereditary risk factors. In this review, we discuss several representative EOCs which were well studied previously. By revealing their clinical and molecular similarities and differences, we consider the group of EOCs as a unique subtype compared to ordinary cancers. In consideration of EOC as a rising threat to human health, more researches on molecular mechanisms, and large-scale, prospective clinical trials should be carried out to further translate into improved outcomes.
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Neoplasias , Adulto Jovem , Humanos , Estudos Prospectivos , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapia , Fatores de RiscoRESUMO
Pancreatic cancer (PC) is one of the most lethal malignancies, which is generally resistant to various treatments. Tumor angiogenesis is deemed to be a pivotal rate-determining step for tumor growth and metastasis. Therefore, anti-angiogenetic therapy is a rational strategy to treat various cancers. However, numerous clinical trials on anti-angiogenetic therapies for PC are overwhelmingly disappointing. The unique characteristics of tumor blood vessels in PC, which are desperately lacking and highly compressed by the dense desmoplastic stroma, are reconsidered to explore some optimized strategies. In this review, we mainly focus on its specific characteristics of tumor blood vessels, discuss the current dilemmas of anti-angiogenic therapy in PC and their underlying mechanisms. Furthermore, we point out the future directions, including remodeling the abnormal vasculature or even reshaping the whole tumor microenvironment in which they are embedded to improve tumor microcirculation, and then create therapeutic vulnerabilities to the current available therapeutic strategies.
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Neovascularização Patológica , Neoplasias Pancreáticas , Humanos , Neovascularização Patológica/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Imunoterapia , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer and has devastating consequences on affected families and society. Its dismal prognosis is attributed to poor specificity of symptoms during early stages. It is widely believed that PDAC patients with the wildtype (WT) KRAS gene benefit more from currently available treatments than those with KRAS mutations. The oncogenic genetic changes alternations generally found in KRAS wildtype PDAC are related to either the KRAS pathway or microsatellite instability/mismatch repair deficiency (MSI/dMMR), which enable the application of tailored treatments based on each patient's genetic characteristics. This review focuses on targeted therapies against alternative tumour mechanisms in KRAS WT PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias PancreáticasRESUMO
BACKGROUND: The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS: A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS: The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION: Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.
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Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Neoplasias Pancreáticas , Tetraspanina 29 , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
Pancreatic cancer is the seventh leading cause of cancer death worldwide, with a low 5-year survival rate. Novel agents are urgently necessary to treat the main pathological type, known as pancreatic ductal carcinoma (PDAC). The dysregulation of histone deacetylases (HDACs) has been identified in association with PDAC, which can be more easily targeted by small molecular inhibitors than gene mutations and may represent a therapeutic breakthrough for PDAC. However, the contributions of HDACs to PDAC remain controversial, and pharmacokinetic challenges have limited the application of HDAC inhibitors (HDACis) in PDAC. This review summarizes the mechanisms associated with success and failure of HDACis in PDAC and discusses the recent progress made in HDACi development and application, such as combination therapies designed to enhance efficacy. More precise strategies involving HDACis might eventually improve the outcomes of PDAC treatment.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Histona Desacetilases/uso terapêutico , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
Background: Pancreatic adenocarcinoma, the deadliest malignant cancer, has gradually become the third leading cause of cancer-related death. Multidisciplinary therapy has been difficult to implement because of the particularity of pancreatic adenocarcinoma. Research has increasingly indicated the significance of metabolic adaption in pancreatic adenocarcinoma. The difference in metabolism may influence immune cell infiltration in pancreatic adenocarcinoma. Novel immune-related metabolism biomarkers are needed to improve the therapeutic outcomes of existing targeted therapies. Methods: We enrolled whole-genome sequencing data and clinical information about 168 pancreatic adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database, other pancreatic adenocarcinoma samples, and clinical information from other cohorts. We used the gene set variation analysis (GSVA) package to calculate feature score, the weighted gene co-expression network analysis (WGCNA) and randomSurvivalForest package to screen hub genes, the ConsenClusterPlus package to classify subtypes, the pRRopthetic package to evaluate drug sensibility, the maftools package to analyze mutation information and the Seurat package to analyze single cell sequencing data. Results: We revealed the prognosis significance of Th2 cell infiltration, classified two subtypes based on hub genes, compared immune cell infiltration, substance metabolism, cellular processes, gene mutation, and copy number variation (CNV) between subtypes and explored the clinical and biological features of Th2 cell infiltration. Conclusions: We displayed the poor prognosis significance of Th2 cell infiltration and the significant difference of simple nucleotide polymorphism, CNV, natural killer (NK) CD56 bright cell infiltration, substance metabolism, autophagy and necroptosis between subtypes. Additionally, we discovered the sensitivity difference of chemotherapy drug and the Th2 cell infiltration changes after chimeric antigen receptor T cells (CAR-T) cell therapy and radiotherapy and explored the differences between normal liver and metastatic liver tissues of pancreatic adenocarcinoma patients.
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Background: Extracellular traps (ETs) and tumor-infiltrating immune cells can contribute to disease progression. The clinical significance of tumor-infiltrating neutrophils and macrophages and related extracellular traps in pancreatic neuroendocrine tumors (pNETs) has not been fully elucidated. This study aimed to explore the prognostic value of tumor infiltration and ET formation by neutrophils and macrophages in pNETs. Methods: A total of 135 patients with radical resection of nonfunctional pNETs were analyzed retrospectively. Immunohistochemistry and immunofluorescence were utilized to stain tumor tissue sections. The recurrence-free survival (RFS) of subgroups determined by Kaplan-Meier analysis was compared with the log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was established to predict 3-year RFS. Results: Patients with high tumor-infiltrating neutrophils or macrophages or positive expression of neutrophils ETs or macrophage ETs displayed worse RFS (all p<0.05). Moreover, univariate and multivariate Cox regression analyses showed that neutrophil and macrophage infiltration and ETs were independent prognostic factors for RFS (all p<0.05). A combined parameter including WHO grade, TNM stage, tumor-infiltrating neutrophils and macrophages, and neutrophil and macrophage ETs had the highest C-index (0.866) and lowest Akaike information criteria (326.557). The calibration plot of nomogram composed of the combined parameter exhibited excellent prognostic values for 3-year RFS. Conclusions: Infiltration and ETs by neutrophils and macrophages can be used as biological indicators of patient prognosis, suggesting the treatment potential for targeting those in nonfunctional pNETs.
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Armadilhas Extracelulares/imunologia , Macrófagos/imunologia , Tumores Neuroendócrinos/imunologia , Infiltração de Neutrófilos/imunologia , Neoplasias Pancreáticas/imunologia , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Nomogramas , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. METHODS: We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. RESULTS: PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P < 0.001, and P < 0.001, respectively). Using these factors, we established a novel risk factor panel (R-panel), which predicted early recurrence (P < 0.001, HR = 15.02, 95% CI 5.76-39.19). Predictive accuracy of this R-panel was favorable, with a C-index of 0.853, higher than AJCC TNM staging (0.713). We further built an integrated staging system combining R-panel scoring and TNM staging, which improved predictive probability of TNM staging. Finally, we showed that adjuvant therapy with long-acting somatostatin analogs (SSAs) significantly reduced postoperative recurrence (P < 0.001) and prolonged long-term survival (P = 0.021) in patients with the above risk factors. CONCLUSION: We identified a novel risk factor panel, which includes PanNET G3, pancreatic duct dilatation, and perineural invasion; this panel predicted early recurrence of PanNETs after curative resection. Patients with these risk factors can benefit from adjuvant therapy with SSAs.
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Antígeno Ki-67/análise , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Valor Preditivo dos Testes , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Feminino , Humanos , Antígeno Ki-67/sangue , Masculino , Pessoa de Meia-Idade , Pancreatectomia/normas , Pancreatectomia/estatística & dados numéricos , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
Pancreatic ductal adenocarcinoma is one of the most lethal malignancies and is known for its high resistance and low response to treatment. Cancer treatments can reshape the microbiota and in turn, the microbiota influences the therapeutic efficacy by regulating immune response and metabolism. This crosstalk is bidirectional, heterogeneous, and dynamic. In this review, we elaborated on the interactions between the microbiota and therapeutic resistance in pancreatic ductal adenocarcinoma. Regulating the microbiota in pancreatic tumor microenvironment may not only generate direct anti-cancer but also synergistic effects with other treatments, providing new directions in cancer therapy.
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Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Microbioma Gastrointestinal/genética , Adenocarcinoma/imunologia , Adenocarcinoma/microbiologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/microbiologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade/efeitos dos fármacos , Imunidade/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour-bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19-9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3-ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.
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Carcinoma Ductal Pancreático/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Neoplasias Pancreáticas/metabolismo , Baço/citologia , Baço/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estudos de Coortes , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Metástase Linfática , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Pancreatectomia , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Recombinantes , Baço/patologia , EsplenectomiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.
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OBJECTIVES: Numerous studies have suggested that an increase in neutrophil-to-lymphocyte ratio (NLR) before treatment is associated with worse survival in pancreatic adenocarcinoma (PAC). The aim of this study was to investigate the prognostic value of treatment-induced NLR change among PAC patients so as to better identify the characteristics of those who can benefit more from treatment. METHODS: This meta-analysis was undertaken using the PRISMA statement. Previously published studies between the correlation of NLR change and patients' survival were searched in Pubmed, Embase, and Web of Science databases. RevMan 5.3 was used to conduct statistical analysis. RESULTS: A total of 1213 patients with PAC from 6 retrospective studies were included in this meta-analysis. Four studies investigated the HR of pre-treatment NLR, demonstrating its prognostic impact on overall survival (OS) (HR = 2.21, 95%CI: 1.45-3.36). One study reported that an elevated post-treatment NLR was associated with poorer OS (HR = 1.28, 95%CI = 1.08-1.52). Pooled analysis indicated that NLR reduction might predict favorable survival in both the overall population (HR = 1.52, 95% CI: 1.34-1.73) and the subgroup treated with chemotherapy (HR = 1.50, 95% CI: 1.32-1.70). CONCLUSION: Treatment-induced NLR change can act as an early predictor for PAC. Patients with reduced NLR after chemotherapy are expected to have better survival.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Linfócitos/metabolismo , Neutrófilos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Antineoplásicos/farmacologia , Feminino , Humanos , Linfócitos/patologia , Neutrófilos/patologia , Neoplasias Pancreáticas/mortalidade , Análise de Sobrevida , Neoplasias PancreáticasRESUMO
Pancreatic cancer is one of the most common causes of cancer-related deaths worldwide. The two major histological subtypes of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all cases, and pancreatic neuroendocrine neoplasm (PanNEN), which makes up 3-5% of all cases. PanNEN is classified into well-differentiated pancreatic neuroendocrine tumor and poorly-differentiated pancreatic neuroendocrine carcinoma (PanNEC). Although PDAC and PanNEN are commonly thought to be different diseases with distinct biology, cell of origin, and genomic abnormalities, the idea that PDAC and PanNEC share common cells of origin has been gaining support. This is substantiated by evidence that the molecular profiling of PanNEC is genetically and phenotypically related to PDAC. In the current review, we summarize published studies pointing to common potential cells of origin and speculate about how the distinct paths of differentiation are determined by the genomic patterns of each disease. We also discuss the overlap between PDAC and PanNEC, which has been noted in clinical observations.
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BACKGROUND: Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs. METHODS: Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry. RESULTS: TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p<0.001) and overall survival (OS, p=0.001), but the number of TLS had no prognostic significance. Multivariate Cox-regression analyses demonstrated that the presence of TLS, WHO classification, and 8th edition American Joint Committee on Cancer (AJCC8th) tumor-node-metastasis (TNM) stage were independent prognostic factors for RFS (p=0.004, p=0.001, and p<0.001, respectively) and OS (p=0.009, p=0.008, and p=0.019, respectively). These results were confirmed using an external validation set. Finally, a nomogram incorporating the presence of TLS was constructed to predict the probability of 5-year RFS of resected G1/G2 NF-PanNETs, which improved on the current WHO classification and AJCC8th TNM stage. CONCLUSIONS: The presence of TLS is an independent and favorable predictor of resected G1/G2 NF-PanNETs, which may play a role in cancer immunobiology.
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Biomarcadores Tumorais/metabolismo , Imunoterapia/métodos , Neoplasias Pancreáticas/complicações , Estruturas Linfoides Terciárias/fisiopatologia , Microambiente Tumoral/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estruturas Linfoides Terciárias/mortalidadeRESUMO
Pancreatic cancer is highly lethal, and the most effective treatment is curative resection followed by chemotherapy. Unfortunately, chemoresistance is an extremely common occurrence, and novel treatment modalities, such as immunotherapy and molecular targeted therapy, have shown limited success in clinical practice. Pancreatic cancer is characterized by an abundant stromal compartment. Cancer-associated fibroblasts (CAFs) and the extracellular matrix they deposit account for a large portion of the pancreatic tumor stroma. CAFs interact directly and indirectly with pancreatic cancer cells and can compromise the effects of, and even promote tumorigenic responses to, various treatment approaches. To eliminate these adverse effects, CAFs depletion strategies were developed. Instead of the anticipated antitumor effects of CAFs depletion, more aggressive tumor phenotypes were occasionally observed. The failure of universal stromal depletion led to the investigation of CAFs heterogeneity that forms the foundation for stromal remodeling and normalization. This review analyzes the role of CAFs in therapeutic resistance of pancreatic cancer and discusses potential CAFs-targeting strategies basing on the diverse biological functions of CAFs, thus to improve the outcome of pancreatic cancer treatment.
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Carcinoma Ductal Pancreático/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Movimento Celular , Proliferação de Células , Matriz Extracelular/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de SinaisRESUMO
BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous and indolent; systemic therapy is not essential for every patient with metastatic PanNET. The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis, if the patient has stable disease. However, specific factors that influence surveillance were not mentioned. In addition, data regarding the period of active surveillance in patients with metastatic PanNET are lacking. AIM: To specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs (NF-PanNETs). METHODS: Seventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled. Time to disease progression (TTP) and time to initiation of systemic therapy were determined. RESULTS: Thirty-one (40.8%) patients had recurrent liver disease after R0 resection; 45 (59.2%) were diagnosed with liver metastasis. The median follow-up period was 42 mo and 90.7% patients were observed to have disease progression. The median TTP (mTTP) was 10 mo. Multivariate analysis showed that the largest axis of the liver metastasis > 5 mm (P = 0.04), non-resection of the primary tumor (P = 0.024), and T3-4 stage (P = 0.028) were associated with a shorter TTP. The mTTP in patients with no risk factors was 24 mo, which was significantly longer than that in patients with one (10 mo) or more (6 mo) risk factors (P < 0.001). A nomogram with three risk factors showed reasonable calibration, with a C-index of 0.603 (95% confidence interval: 0.47-0.74). CONCLUSION: Active surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors, and other patients progressed rapidly without treatment. Further studies with a larger sample size and a control group are needed.
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Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.