RESUMEN
Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.
Asunto(s)
Neoplasias Pancreáticas , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Apoptosis/genética , Neoplasias Pancreáticas/genética , Muerte Celular , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMEN
BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Transición Epitelial-Mesenquimal/genética , Línea Celular Tumoral , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Pronóstico , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Neoplasias PancreáticasRESUMEN
BACKGROUND & AIMS: Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. METHODS: We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses. RESULTS: In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B-LYN-p85 complex, which increased PI3K-Akt-mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. CONCLUSIONS: Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.
Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Serotonina/metabolismo , Anciano , Animales , Apoptosis/efectos de los fármacos , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Silenciador del Gen , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Indoles/uso terapéutico , Ácido Láctico/biosíntesis , Masculino , Ratones , Persona de Mediana Edad , Monoaminooxidasa/análisis , Trasplante de Neoplasias , Páncreas/química , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor de Serotonina 5-HT2B/genética , Serotonina/análisis , Serotonina/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Transducción de Señal , Estrés Fisiológico , Serina-Treonina Quinasas TOR/metabolismo , Análisis de Matrices Tisulares , Transcriptoma , Triptófano Hidroxilasa/análisis , Urea/análogos & derivados , Urea/uso terapéutico , Familia-src Quinasas/metabolismoRESUMEN
Pancreatic Ductal Adenocarcinoma (PADC) metastasis is the leading cause of morality of this severe malignant tumor. Proteases are key players in the degradation of extracellular matrix which promotes the cascade of tumor metastasis. As a kind of serine proteases, the kallikrein family performs vital function on the cancer proteolysis scene, which have been proved in diverse malignant tumors. However, the specific member of kallikrein family and its function in PDAC remain unexplored. In this study, by data mining of GEO datasets, we have identified KLK10 is upregulated gene in PDAC. We found that KLK10 was significantly overexpressed in tissues of pancreatic intraepithelial neoplasia (PanIN) and PDAC from Pdx1-Cre; LSL-KrasG12D/+ mice (KC) and Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ mice (KPC) by immunohistochemical analysis. Moreover, KLK10 is extremely elevated in the PDAC tissues, especially that from the PDAC patients with lymphatic and distant metastasis. Aberrant KLK10 expression is significantly correlated with poor prognosis and shorter survival by univariable and multivariable analysis. Functionally, knockdown of KLK10 observably inhibits invasion and metastatic phenotype of PDAC cells in vitro and metastasis in vivo. In addition, blockade of KLK10 attenuates epithelial-mesenchymal transition and activation of FAK-SRC-ERK signaling, which explains the mechanism of KLK10 in promoting metastasis. Collectively, KLK10 should be considered as a promising biomarker for diagnosis and potential target for therapy in PDAC.
Asunto(s)
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Transición Epitelial-Mesenquimal/genética , Calicreínas/genética , Neoplasias Pancreáticas/genética , Regulación hacia Arriba/genética , Adenocarcinoma/patología , Animales , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Calicreínas/metabolismo , Ratones Endogámicos C57BL , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias Pancreáticas/patología , Fenotipo , Pronóstico , Transducción de Señal , Familia-src Quinasas/metabolismo , Neoplasias PancreáticasRESUMEN
To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Animales , Ratones , Carcinoma Ductal Pancreático/genética , Movimiento Celular , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal , Neoplasias PancreáticasRESUMEN
BACKGROUND: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism. METHODS: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms. RESULTS: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression. CONCLUSIONS: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/genética , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/farmacología , FN-kappa B/metabolismo , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Hot spot gene mutations in splicing factor 3b subunit 1 (SF3B1) are observed in many types of cancer and create abundant aberrant mRNA splicing, which is profoundly implicated in tumorigenesis. Here, we identified that the SF3B1 K700E (SF3B1K700E ) mutation is strongly associated with tumor growth in pancreatic ductal adenocarcinoma (PDAC). Knockdown of SF3B1 significantly retarded cell proliferation and tumor growth in a cell line (Panc05.04) with the SF3B1K700E mutation. However, SF3B1 knockdown had no notable effect on cell proliferation in two cell lines (BxPC3 and AsPC1) carrying wild-type SF3B1. Ectopic expression of SF3B1K700E but not SF3B1WT in SF3B1-knockout Panc05.04 cells largely restored the inhibitory role induced by SF3B1 knockdown. Introduction of the SF3B1K700E mutation in BxPC3 and AsPC1 cells also boosted cell proliferation. Gene set enrichment analysis demonstrated a close correlation between SF3B1 mutation and aerobic glycolysis. Functional analyses showed that the SF3B1K700E mutation promoted tumor glycolysis, as evidenced by glucose consumption, lactate release, and extracellular acidification rate. Mechanistically, the SF3B1 mutation promoted the aberrant splicing of PPP2R5A and led to the activation of the glycolytic regulator c-Myc via post-translational regulation. Pharmacological activation of PP2A with FTY-720 markedly compromised the growth advantage induced by the SF3B1K700E mutation in vitro and in vivo. Taken together, our data suggest a novel function for SF3B1 mutation in the Warburg effect, and this finding may offer a potential therapeutic strategy against PDAC with the SF3B1K700E mutation.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Glucólisis/genética , Humanos , Mutación/genética , Neoplasias Pancreáticas/patología , Fosfoproteínas/metabolismo , Empalme del ARN , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismoRESUMEN
Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC.
Asunto(s)
Antígenos CD/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Plasticidad Neuronal , Neuronas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Sialiltransferasas/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Humanos , Invasividad Neoplásica , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective treatment strategies. There is an urgent need for the development of new strategies for PDAC therapy. The genetic and phenotypic heterogeneity of PDAC cancer cell populations poses further challenges in the clinical management of PDAC. In this study, we performed single-cell RNA sequencing to characterize PDAC tumors from KPC mice. Functional studies and clinical analysis showed that PDAC cluster 2 cells with highly Hsp90 expression is much more aggressive than the other clusters. Genetic and pharmacologic inhibition of Hsp90 impaired tumor cell growth both in vitro and in vivo. Further mechanistic study revealed that HSP90 inhibition disrupted the interaction between HSP90 and OPA1, leading to a reduction in mitochondrial cristae amount and mitochondrial energy production. Collectively, our study reveals that HSP90 might be a potential therapeutic target for PDAC.
RESUMEN
The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.
Asunto(s)
Inmunosupresores/farmacología , Neoplasias Hepáticas/inmunología , Neutrófilos/metabolismo , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Páncreas/inmunología , Páncreas/patología , Neoplasias Pancreáticas/patología , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/inmunología , Receptores Purinérgicos P2X/metabolismoRESUMEN
Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.
Asunto(s)
Acetilcolina/metabolismo , Carcinoma Ductal Pancreático/patología , Invasividad Neoplásica/inmunología , Neoplasias Pancreáticas/patología , Microambiente Tumoral/inmunología , Animales , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Invasividad Neoplásica/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with no effective treatment. Cancer cells, especially cancer stem cells (CSCs), redirect immune cells to evade immune surveillance and even coopt these immune cells to support their growth and metastasis. However, the identification of CSCs and how CSCs interact with immune cells in PDAC remain uncharacterized. Here, we report that CD90 is expressed on both stromal and tumor cells and that high expression of CD90 is related to a poor prognosis in patients with PDAC. The CD90 highly expressed (CD90hi) population in PDAC cells harbors high stemness features and tumorigenicity. Notably, CD90 acts as an anchor for monocyte/macrophage adhesion, providing a physical interaction between CD90hi cells and monocytes/macrophages. In response, the crosstalk between CD90hi cells and monocytes/macrophages promotes immunosuppressive features of immune cells, which enhance the stemness and epithelial-mesenchymal transition (EMT) of PDAC cells. Moreover, PD-L1 is dominantly expressed in the CD90hi population, providing another strategy for these cells to evade immune surveillance. These findings provide an understanding of the biological significance of CD90 expression in PDAC cells and uncover a novel mechanism for how "stem-like" PDAC cells evade immune surveillance.
Asunto(s)
Carcinoma Ductal Pancreático/inmunología , Células Madre Neoplásicas/inmunología , Neoplasias Pancreáticas/inmunología , Antígenos Thy-1/inmunología , Animales , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Xenoinjertos , Humanos , Tolerancia Inmunológica , Macrófagos/inmunología , Ratones , Ratones Desnudos , Monitorización Inmunológica , Monocitos/inmunología , Neoplasias Pancreáticas/patología , Células del Estroma/inmunología , Células del Estroma/patología , Antígenos Thy-1/biosíntesisRESUMEN
Secreted Frizzled-Related Protein 4 (SFRP4), a member of secreted frizzled-related protein family, has been found as a vital modulator in cell proliferation, cell self-renew and apoptosis through Wnt signaling transduction pathway. In the present study, we re-analyzed the expression pattern of SFRPs in Gene Expression Omnibus (GEO) datasets and evaluated the expression of SFRP4 at protein level in both KrasG12D/+; Trp53R172H/+; Pdx1-Cre; (KPC) mice and human pancreatic ductal adenocarcinoma (PDAC) tissue. We found that the expression of SFRP4 increased gradually in PanINs and PDAC lesions in KPC mice and high expression of SFRP4 was much more common in tumor lesions compared to the adjacent non-tumor tissues. Then we performed Kaplan-Meier survival and Cox regression analysis and found that high expression of SFRP4 in the serum and tumor lesions predicted poor prognosis for pancreatic cancer patients. Furthermore, we demonstrated that SFRP4 positively correlated with FOXP3+ Treg cells infiltration while the down-regulation of SFRP4 in tumor cells impaired the production of cytokines and the recruitments of T cells. This study suggested that SFRP4 can be a novel prognostic biomarker and potential therapeutic target for pancreatic cancer.
RESUMEN
BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.
Asunto(s)
Antígeno B7-H1/metabolismo , Carcinoma Neuroendocrino/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/inmunología , Neoplasias Gástricas/inmunología , Anciano , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/patología , Variaciones en el Número de Copia de ADN , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Inmunoterapia/métodos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/efectos de los fármacos , Estómago/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Escape del Tumor/inmunologíaRESUMEN
Due to the therapy resistance and frequent metastasis, pancreatic ductal adenocarcinoma(PDAC) remains one of the most malignant carcinoma. WNT7A, an important ligand of Wnt/ß-catenin signaling pathways, has a controversial role in tumor development. The role of WNT7A in PDAC remains unclear. In this study, we analyzed the expression pattern of WNT7A at mRNA and protein levels. We found pancreatic cancer tissue demonstrated a significant high WNT7A expression compared with the adjacent non-tumor tissue and the expression of WNT7A positively correlates with poor prognosis and lymph node metastasis. Then, we performed transwell assays and wound healing assays in vitro and found that WNT7A promotes the migration capacity of cancer cells. Furthermore, we explored the underlying mechanism of the WNT7A inducing cell migration. Results showed that up-regulated WNT7A expression inducing higher expression of N-cadherin and lower expression of E-cadherin while the contrast result was shown in the WNT7A knock-down group, which suggested that WNT7A might contribute to an epithelial-mesenchymal transition. Finally, we found that the hypoxia culture condition remarkably increased the WNT7A expression. In conclusion, our work demonstrated that hypoxia induced high expression of WNT7A might promote the cell migration via enhancing the epithelial-mesenchymal transition in PDAC.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Regulación Neoplásica de la Expresión Génica , Proteínas Wnt/genética , Hipoxia de la Célula/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba/genética , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/genéticaRESUMEN
Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293-305. ©2018 AACR.
Asunto(s)
Carcinoma Ductal Pancreático/patología , Interleucinas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/patología , Receptores de Interleucina/metabolismo , Factor de Transcripción STAT3/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Carcinogénesis , Carcinoma Ductal Pancreático/mortalidad , Autorrenovación de las Células , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Páncreas/patología , Neoplasias Pancreáticas/mortalidad , Cultivo Primario de Células , Pronóstico , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Interleucina-22RESUMEN
Dickkopf-1(DKK-1), the downstream target of ß-catenin/T-cell factor, participates in a negative feedback loop in the Wnt signaling and reported as an important biomarker in many tumors. In this study, we analyzed the expression of DKK-1 in pancreatic ductal adenocarcinoma (PDAC) patients at both mRNA and protein levels. We used real-time PCR to detect the expression of DKK-1 in 32 PDAC and paired adjacent non-tumor tissues, results suggested that the expression of DKK-1 was increased in PDAC tissues. We found the similar results in the analysis of 3 independent microarray data sets. Immunohistochemical staining of 311 pairs of PDAC tissues suggested that DKK-1 expression was significantly associated with T classification (P = 0.039) and lymph node metastasis (P = 0.035). Furthermore, Kaplan-Meier analysis for DKK-1 expression demonstrated that patients with higher DKK-1 level had shorter overall survival (OS) and relapse-free survival (RFS) time in Ren Ji cohort and online PDAC database at both mRNA and protein levels. Univariable and multivariable Cox regression analysis confirmed that DKK-1 as well as lymph node metastasis and histology were independent predictors of OS in patients with PDAC. This study demonstrated that DKK-1 may be a predictor for prognosis in PDAC patients.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Supervivencia , Regulación hacia Arriba/genéticaRESUMEN
We have conducted a meta-analysis and systematic review to determine the overall survival, mortality rate, and complete resection rate of neo-adjuvant chemoradiotherapy (CRT) compared with pancreaticoduodenectomy alone in patients with pancreatic adenocarcinoma. Whether neo-adjuvant CRT is beneficial in the treatment of resectable pancreatic cancer or not, it is still a controversial issue. Medline and Cochrane were searched with relevant terms. Eight studies with a total of 833 participants were selected. The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The analysis revealed neo-adjuvant group may have a benefit in the overall survival, as compared with the resection group, although it did not reach statistical significance (pooled hazard ratioâ=â0.87, 95% confidence interval [CI]â=â0.75-1.00, Pâ=â0.051). We found no difference in the in-hospital mortality rate (pooled odds ratio [OR]â=â1.27, 95% CIâ=â0.35-4.58, Pâ=â0.710). The complete resection rate was significantly higher in the neo-adjuvant group than in the resection group (pooled ORâ=â2.39, 95% CIâ=â1.21-4.74, Pâ=â0.012). This meta-analysis found that there was no significant difference in the overall survival between patients treated with neo-adjuvant CRT or pancreaticduodenectomy.
Asunto(s)
Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Quimioradioterapia Adyuvante/métodos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomía/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica , Mortalidad Hospitalaria , Humanos , Análisis de SupervivenciaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC.