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1.
Sci Rep ; 14(1): 15200, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956290

RESUMO

Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expression data were obtained from the Genotype-Tissue Expression (GTEx) project. The R package was used to construct anoikis-related PC prognostic models, which were later validated with the ICGC-PACA database. Survival analyses demonstrated a poorer prognosis for patients in the high-risk group, consistent across both TCGA-PAAD and ICGC-PACA datasets. A nomogram was designed as a predictive tool to estimate patient mortality. The study also analyzed tumor mutations and immune infiltration across various risk groups, uncovering notable differences in tumor mutation patterns and immune landscapes between high- and low-risk groups. In conclusion, this research successfully developed a prognostic model centered on anoikis-related genes, offering a novel tool for predicting the clinical trajectory of PC patients.


Assuntos
Anoikis , Neoplasias Pancreáticas , Anoikis/genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Regulação Neoplásica da Expressão Gênica , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Nomogramas , Biomarcadores Tumorais/genética , Mutação , Feminino , Masculino , Análise de Sobrevida , Perfilação da Expressão Gênica
2.
BMC Microbiol ; 24(1): 235, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38956452

RESUMO

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited. METHODS: Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16  S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm. RESULTS: PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification. CONCLUSION: PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.


Assuntos
Bile , Carcinoma Ductal Pancreático , Microbiota , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/microbiologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Bile/microbiologia , Masculino , Feminino , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Microbiota/genética , Pessoa de Meia-Idade , Idoso , Disbiose/microbiologia , Intervalo Livre de Progressão , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Estudos Prospectivos , RNA Ribossômico 16S/genética
3.
Sci Adv ; 10(27): eadl1197, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38959305

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (Pdx1-Cre, LSL-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPflC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.


Assuntos
Carcinoma Ductal Pancreático , Fibrose , Neoplasias Pancreáticas , Proteômica , Animais , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Proteômica/métodos , Camundongos , Humanos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Modelos Animais de Doenças , Linhagem Celular Tumoral , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Moléculas de Adesão Celular
4.
J Cancer Res Clin Oncol ; 150(7): 332, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951245

RESUMO

PURPOSE: In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy. PATIENTS AND METHODS: The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11. RESULTS: The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed. CONCLUSION: The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Irinotecano , Leucovorina , Oxaliplatina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Feminino , Pessoa de Meia-Idade , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Idoso , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Adulto , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Intervalo Livre de Progressão , Estudos Cross-Over
5.
Sci Rep ; 14(1): 15037, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951569

RESUMO

The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This study aimed to explore the relationship between NK cell marker genes and prognosis, immune response of PDAC patients. By scRNA-seq data, we found the proportion of NK cells were significantly downregulated in PDAC and 373 NK cell marker genes were screened out. By TCGA database, we enrolled 7 NK cell marker genes to construct the signature for predicting prognosis in PDAC patients. Cox analysis identified the signature as an independent factor for pancreatic cancer. Subsequently, the predictive power of signature was validated by 6 GEO datasets and had an excellent evaluation. Our analysis of relationship between the signature and patients' immune status revealed that the signature has a strong correlation with immunocyte infiltration, inflammatory reaction, immune checkpoint inhibitors (ICIs) response. The NK cell marker genes are closely related to the prognosis and immune capacity of PDAC patients, and they have potential value as a therapeutic target.


Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Células Matadoras Naturais , Neoplasias Pancreáticas , Análise de Célula Única , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Células Matadoras Naturais/imunologia , Prognóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Biomarcadores Tumorais/genética , Análise de Célula Única/métodos , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Análise de Sequência de RNA , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Pessoa de Meia-Idade , Idoso , Perfilação da Expressão Gênica
6.
J Cancer Res Clin Oncol ; 150(7): 347, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38990367

RESUMO

BACKGROUND: Therapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC). CASE PRESENTATION: We report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response. CONCLUSIONS: Treatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.


Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células Acinares , Neoplasias Pancreáticas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Carcinoma de Células Acinares/tratamento farmacológico , Carcinoma de Células Acinares/patologia , Masculino , Antineoplásicos Imunológicos/uso terapêutico , Pessoa de Meia-Idade , Idoso
7.
Dis Model Mech ; 17(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38979684

RESUMO

Pancreatic ductal adenocarcinoma is an aggressive malignancy with limited treatment options. Chemotherapy offers little benefit and, although there is some evidence that radiotherapy may improve response, its use in the clinical management of pancreatic cancer remains controversial due to conflicting reports on its survival benefit. There has also been a lack of clinical trials that directly investigate the efficacy of radiotherapy in pancreatic cancer. The limited progress in the development of radiotherapeutic strategies in pancreatic cancer can be attributed, at least in part, to a dearth of preclinical research and our limited understanding of the effects of radiation on the pancreatic tumour microenvironment. In this Perspective, we discuss how insight into the immunosuppressive tumour microenvironment and the complex signalling between tumour and stromal cells following radiation is needed to develop effective radiosensitising strategies for pancreatic cancer. We also highlight that to have the best chance for successful clinical translation, more preclinical research is required in appropriately complex models.


Assuntos
Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Humanos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Microambiente Tumoral/efeitos da radiação
8.
Nat Commun ; 15(1): 5763, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982051

RESUMO

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.


Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , DNA Tumoral Circulante , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Feminino , Masculino , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mutação , Intervalo Livre de Progressão , Metástase Neoplásica
9.
Sci Rep ; 14(1): 15782, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982134

RESUMO

This study aims to assess the predictive capability of cylindrical Tumor Growth Rate (cTGR) in the prediction of early progression of well-differentiated gastro-entero-pancreatic tumours after Radio Ligand Therapy (RLT), compared to the conventional TGR. Fifty-eight patients were included and three CT scans per patient were collected at baseline, during RLT, and follow-up. RLT response, evaluated at follow-up according to RECIST 1.1, was calculated as a percentage variation of lesion diameters over time (continuous values) and as four different RECIST classes. TGR between baseline and interim CT was computed using both conventional (approximating lesion volume to a sphere) and cylindrical (called cTGR, approximating lesion volume to an elliptical cylinder) formulations. Receiver Operating Characteristic (ROC) curves were employed for Progressive Disease class prediction, revealing that cTGR outperformed conventional TGR (area under the ROC equal to 1.00 and 0.92, respectively). Multivariate analysis confirmed the superiority of cTGR in predicting continuous RLT response, with a higher coefficient for cTGR (1.56) compared to the conventional one (1.45). This study serves as a proof of concept, paving the way for future clinical trials to incorporate cTGR as a valuable tool for assessing RLT response.


Assuntos
Progressão da Doença , Neoplasias Pancreáticas , Neoplasias Gástricas , Tomografia Computadorizada por Raios X , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Idoso , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Tomografia Computadorizada por Raios X/métodos , Adulto , Curva ROC , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/patologia , Estudo de Prova de Conceito , Carga Tumoral
10.
Vascul Pharmacol ; 155: 107311, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38985614

RESUMO

Purinergic signaling plays a crucial role in vascular endothelium functions. In particular, ionotropic P2X receptors (P2XRs) are engaged in various intracellular pathways through which endothelial cells (ECs) adapt to external stimuli. However, very little is known about the impact of P2XRs on vascular remodeling during carcinogenesis. We previously demonstrated that high purinergic stimulation impairs the migratory phenotype of tumor-derived endothelial cells (TECs) but not of normal ECs. Since P2XRs are sensitive to different physical and chemical factors, we investigated the impact of tumor microenvironment (TME) on healthy ECs to verify the ability of cancer cells to affect endothelial migratory phenotype through purinergic signaling tuning. More specifically, we focused on P2XR modulation by two different types of TME, mimicking breast and pancreas cancer milieux, which show very different features in terms of vascularization and composition. ECs conditioning with both cancer cell types induced a significant upregulation of some of the most represented P2XR. However, only conditioning with MCF-7 cells and not that with PANC-1 cells was able to alter the migratory phenotype of normal ECs supporting a P2XR-mediated inhibition of cell migration. The differences observed between the two cancer cells could be due to their different proliferative potential and the subsequent different extracellular pH. In addition, in agreement with some of our previous data, the P2XR-induced inhibition of EC migration seems to be independent of calcium signals, as conditioned ECs didn't reveal any changes in the long-lasting responses evoked by purinergic agonists. Collectively, highlighting a significant P2RX modulation by TME, our data strengthen the hypothesis that purinergic signaling may play a central role in vascular remodeling during carcinogenesis. However, the molecular routes upstream and downstream of this modulation remain to be elucidated.


Assuntos
Neoplasias da Mama , Movimento Celular , Células Endoteliais , Receptores Purinérgicos P2X , Transdução de Sinais , Microambiente Tumoral , Humanos , Movimento Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Receptores Purinérgicos P2X/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Células MCF-7 , Feminino , Fenótipo
11.
Pancreas ; 53(7): e560-e565, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38986077

RESUMO

OBJECTIVE: We investigated metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on pre-treatment FDG-PET as prognostic markers for survival in patients with metastatic neuroendocrine neoplasms (NENs) receiving peptide receptor radionuclide therapy (PRRT). METHODS: A retrospective review of patients with metastatic NENs receiving PRRT was undertaken. Pre-treatment FDG-PET images were analyzed and variables collected included MTV and TLG (dichotomized by median into high vs low). Main Outcomes were overall survival (OS) and progression-free survival (PFS) by MTV and TLG (high vs low). RESULTS: One hundred five patients were included. Median age was 64 years (50% male). Main primary NEN sites were small bowel (43.8%) and pancreas (40.0%). Median MTV was 3.8 mL and median TLG was 19.9. Dichotomization formed identical cohorts regardless of whether MTV or TLG were used. Median OS was 72 months; OS did not differ based on MTV/TLG high versus low (47.4 months vs not reached; hazard ratio, 0.43; 95% confidence interval [CI], 0.18-1.04; P = 0.0594). Median PFS was 30.4 months; PFS differed based on MTV/TLG high versus low (21.6 months vs 45.7 months; hazard ratio, 0.35; 95% CI, 0.19-0.64; P = 0.007). CONCLUSIONS: Low MTV/TLG on pre-treatment FDG-PET was associated with longer PFS in metastatic NEN patients receiving PRRT.


Assuntos
Fluordesoxiglucose F18 , Tumores Neuroendócrinos , Octreotida , Compostos Organometálicos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Carga Tumoral , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Estudos Retrospectivos , Idoso , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Compostos Organometálicos/uso terapêutico , Adulto , Receptores de Peptídeos/metabolismo , Glicólise , Idoso de 80 Anos ou mais , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Intervalo Livre de Progressão , Resultado do Tratamento
12.
Pancreas ; 53(7): e603-e610, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38986080

RESUMO

OBJECTIVES: Pancreatic cancer (PC) is one of the most aggressive malignancies due to the high rate of metastasis. The mechanisms underlying metastasis need to be elucidated. Small extracellular vesicles (sEVs) mediate cell-to-cell communication, and cancer-derived sEVs contribute to the formation of premetastatic niches. The present study examined changes in adhesiveness by the internalization of PC-derived sEVs into vascular endothelial cells, and investigated the molecular mechanisms underlying metastasis. MATERIALS AND METHODS: Pancreatic cancer-derived sEVs were internalized into vascular endothelial cells, and changes in adhesiveness were evaluated. We evaluated the effects of sEVs on the formation of liver metastasis in vivo. We also assessed molecular changes in vascular endothelial cells by the internalization of PC-derived sEVs. RESULTS: The internalization of PC-derived sEVs into vascular endothelial cells promoted the adhesiveness of vascular endothelial cells and PC cells. Pancreatic cancer-derived sEVs contained high levels of transforming growth factor ß1 mRNA and acted as its transporter. Once PC-derived sEVs were internalized into vascular endothelial cells, the expression of fibronectin 1 increased on the cell surface, and the adhesiveness of vascular endothelial cells was enhanced. CONCLUSIONS: We investigated association between PC-derived sEVs and adhesiveness. Regulation of PC-derived sEVs has potential as a therapeutic modality to suppress the metastasis of PC.


Assuntos
Adesão Celular , Células Endoteliais , Vesículas Extracelulares , Fibronectinas , Neoplasias Pancreáticas , Fator de Crescimento Transformador beta1 , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Vesículas Extracelulares/metabolismo , Humanos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Animais , Fibronectinas/metabolismo , Linhagem Celular Tumoral , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Camundongos Nus , Comunicação Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Masculino
13.
PLoS One ; 19(7): e0305413, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38976715

RESUMO

Pancreatic ductal adenocarcinoma is the most prevalent pancreatic cancer, which is considered a significant global health concern. Chemotherapy and surgery are the mainstays of current pancreatic cancer treatments; however, a few cases are suitable for surgery, and most of the cases will experience recurrent episodes. Compared to DNA or peptide vaccines, mRNA vaccines for pancreatic cancer have more promise because of their delivery, enhanced immune responses, and lower proneness to mutation. We constructed an mRNA vaccine by analyzing S100 family proteins, which are all major activators of receptors for advanced glycation end products. We applied immunoinformatic approaches, including physicochemical properties analysis, structural prediction and validation, molecular docking study, in silico cloning, and immune simulations. The designed mRNA vaccine was estimated to have a molecular weight of 165023.50 Da and was highly soluble (grand average of hydropathicity of -0.440). In the structural assessment, the vaccine seemed to be a well-stable and functioning protein (Z score of -8.94). Also, the docking analysis suggested that the vaccine had a high affinity for TLR-2 and TLR-4 receptors. Additionally, the molecular mechanics with generalized Born and surface area solvation analysis of the "Vaccine-TLR-2" (-141.07 kcal/mol) and "Vaccine-TLR-4" (-271.72 kcal/mol) complexes also suggests a strong binding affinity for the receptors. Codon optimization also provided a high expression level with a GC content of 47.04% and a codon adaptation index score 1.0. The appearance of memory B-cells and T-cells was also observed over a while, with an increased level of helper T-cells and immunoglobulins (IgM and IgG). Moreover, the minimum free energy of the mRNA vaccine was predicted at -1760.00 kcal/mol, indicating the stability of the vaccine following its entry, transcription, and expression. This hypothetical vaccine offers a groundbreaking tool for future research and therapeutic development of pancreatic cancer.


Assuntos
Vacinas Anticâncer , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas , Neoplasias Pancreáticas/imunologia , Humanos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas de mRNA/imunologia , Biologia Computacional/métodos , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Vacinologia/métodos , Receptor 2 Toll-Like/imunologia , Simulação por Computador , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Imunoinformática
14.
Sci Rep ; 14(1): 15744, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977725

RESUMO

Detection of circulating tumor DNA (ctDNA) from plasma cell free DNA (cfDNA) has shown promise for diagnosis, therapeutic targeting, and prognosis. This study explores ctDNA detection by next generation sequencing (NGS) and associated clinicopathologic factors in patients with pancreatic adenocarcinoma (PDAC). Patients undergoing surgical exploration or resection of pancreatic lesions were enrolled with informed consent. Plasma samples (4-6 ml) were collected prior to surgery and cfDNA was recovered from 95 plasma samples. Adequate cfDNA for NGS (20 ng) was obtained from 81 patients. NGS was performed using the Oncomine Lung cfDNA assay on the Ion Torrent S5 sequencing platform. Twenty-five patients (30.9%) had detectable mutations in KRAS and/or TP53 with allele frequencies ranging from 0.05 to 8.5%, while mutations in other genes were detected less frequently and always along with KRAS or TP53. Detectable ctDNA mutations were more frequent in patients with poorly differentiated tumors, and patients without detectable ctDNA mutations showed longer survival (medians of 10.5 months vs. 18 months, p = 0.019). The detection of circulating tumor DNA in pancreatic adenocarcinomas is correlated with worse survival outcomes.


Assuntos
Adenocarcinoma , DNA Tumoral Circulante , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/sangue , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Adulto , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/sangue
15.
J Transl Med ; 22(1): 633, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978106

RESUMO

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS: In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS: We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS: In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.


Assuntos
Antígenos B7 , Imunoterapia Adotiva , Neoplasias Pancreáticas , Receptores de Antígenos Quiméricos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Imunoterapia Adotiva/métodos , Antígenos B7/metabolismo , Antígenos B7/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos , Proliferação de Células , Linfócitos T/imunologia
16.
J Exp Clin Cancer Res ; 43(1): 189, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978141

RESUMO

BACKGROUND: Distinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease. METHODS: Plasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma). RESULTS: Small RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC. CONCLUSIONS: This is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence.


Assuntos
Carcinoma Ductal Pancreático , Vesículas Extracelulares , MicroRNAs , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , MicroRNAs/sangue , MicroRNAs/genética , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Idoso , Biomarcadores Tumorais/sangue , Estudos Prospectivos
17.
J Coll Physicians Surg Pak ; 34(7): 832-837, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38978250

RESUMO

OBJECTIVE: To assess both solid and cystic pancreatic lesions using endoscopic ultrasound (EUS), and the effect of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in patient management. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Gastroenterology, Division of Internal Diseases, Sivas Cumhuriyet University Hospital, Sivas, Turkiye, from January 2018 to 2022. METHODOLOGY: Patients with pancreatic mass, who underwent EUS-FNA were inducted in the study. EUS-FNA was performed using a 22-gauge needle via both transgastric and transduodenal routes. The size of the pancreatic lesion, its location, and whether there was SMA or CA invasion were evaluated on CT and EUS scans. Biopsy results of 64 patients who received EUS-FNA due to pancreatic lesions were considered. The results were divided into malignancy or benign pathology. RESULTS: A total of 64 cases were compared. Crosstable Chi-square analysis showed a statistically significant difference between CT and EUS (p <0.001). EUS-FNA results revealed that out of the 64 patients with pancreatic mass detected in EUS, 46 had adenocarcinoma, 7 were negative for malignancy, 4 had intraductal papillary mucinous neoplasia (IPMN), 3 had neuroendocrine tumour (NET), 2 had lymphoma, and 2 had solid pseudopapillary neoplasia (SPN). In the 2-year follow-up of the seven patients who were negative for malignancy in EUS-FNA, there were no clinical, laboratory or imaging findings indicating pancreatic malignancy or distant metastasis. CONCLUSION: Tissue sampling through EUS-FNA has minimal side effects and remains useful in managing preoperative patients with resectable or suspicious pancreatic masses. KEY WORDS: Pancreatic cancer, Abdominal CT, Endoscopic ultrasound (EUS), Ultrasound-guided fine-needle aspiration (EUS-FNA).


Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pancreáticas , Humanos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Pâncreas/patologia , Endossonografia/métodos , Tomografia Computadorizada por Raios X
18.
Proc Natl Acad Sci U S A ; 121(29): e2403917121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38980903

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.


Assuntos
Carcinoma Ductal Pancreático , Células T Matadoras Naturais , Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Camundongos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Células T Matadoras Naturais/imunologia , Microambiente Tumoral/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Humanos , Células Supressoras Mieloides/imunologia
19.
Cancer Med ; 13(13): e7453, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38986683

RESUMO

OBJECTIVE: The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy. METHODS: This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut-off value. The Kaplan-Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA). RESULTS: The best cut-off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional-hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA. CONCLUSION: We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.


Assuntos
Inflamação , Nomogramas , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/imunologia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Inflamação/imunologia , Idoso , Prognóstico , Neutrófilos/imunologia , Curva ROC , Estimativa de Kaplan-Meier , Linfócitos/imunologia , Monócitos/imunologia , Metástase Neoplásica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Modelos de Riscos Proporcionais
20.
Biosci Trends ; 18(3): 224-232, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38987162

RESUMO

Pancreatic cancer (PC) has the poorest prognosis among digestive cancers; only 15-20% of cases are resectable at diagnosis. This review explores multidisciplinary treatments for advanced PC, emphasizing resectability classification and treatment strategies. For locally advanced unresectable PC, systemic chemotherapy using modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel is standard, while the role of chemoradiation is debated. Induction chemotherapy followed by chemoradiation may be a promising therapy. Conversion surgery after initial chemotherapy or chemoradiotherapy offers favorable survival, however criteria for conversion need further refinements. For metastatic PC, clinical trials using immune checkpoint inhibitors and molecular targeted therapies are ongoing. Multidisciplinary approaches and further research are crucial for optimizing treatment and improving outcomes for advanced PC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Quimiorradioterapia/tendências , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Irinotecano/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Fluoruracila/uso terapêutico , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Leucovorina/uso terapêutico
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