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The American Journal of Surgical... Apr 2024Glutamate decarboxylase 2 (GAD2) is the most important inhibitory neurotransmitter and plays a role in insulin-producing β cells of pancreatic islets. The limitation of...
Glutamate decarboxylase 2 (GAD2) is the most important inhibitory neurotransmitter and plays a role in insulin-producing β cells of pancreatic islets. The limitation of GAD2 expression to a few normal cell types makes GAD2 a potential immunohistochemical diagnostic marker. To evaluate the diagnostic utility of GAD2 immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, GAD2 staining was restricted to brain and pancreatic islet cells. GAD2 staining was seen in 20 (13.2%) of 152 tumor categories, including 5 (3.3%) tumor categories containing at least 1 strongly positive case. GAD2 immunostaining was most commonly seen in neuroendocrine carcinomas (58.3%) and neuroendocrine tumors (63.2%) of the pancreas, followed by granular cell tumors (37.0%) and neuroendocrine tumors of the lung (11.1%). GAD2 was only occasionally (<10% of cases) seen in 16 other tumor entities including paraganglioma, medullary thyroid carcinoma, and small cell neuroendocrine carcinoma of the urinary bladder. Data on GAD2 and progesterone receptor (PR) expression (from a previous study) were available for 95 pancreatic and 380 extrapancreatic neuroendocrine neoplasms. For determining a pancreatic origin of a neuroendocrine neoplasm, the sensitivity of GAD2 was 64.2% and specificity 96.3%, while the sensitivity of PR was 56.8% and specificity 92.6%. The combination of PR and GAD2 increased both sensitivity and specificity. GAD2 immunohistochemistry is a highly useful diagnostic tool for the identification of pancreatic origin in case of neuroendocrine neoplasms with unknown site of origin.
Topics: Humans; Pancreatic Neoplasms; Biomarkers, Tumor; Neuroendocrine Tumors; Pancreas; Carcinoma, Neuroendocrine; Glutamate Decarboxylase
PubMed: 38271200
DOI: 10.1097/PAS.0000000000002186 -
Cancer Letters Oct 2023Tumor antigens are crucial targets for T-cell-based therapy to induce tumor-specific rejection. However, identifying pancreatic ductal adenocarcinoma (PDAC)-specific...
Tumor antigens are crucial targets for T-cell-based therapy to induce tumor-specific rejection. However, identifying pancreatic ductal adenocarcinoma (PDAC)-specific T-cell epitopes has been challenging. Using advanced mass spectrometry (MS) analysis, we previously identified cancer-associated, class I MHC-bound epitopes shared by multiple PDAC patients with different HLA-A types. Here, we investigated one of these epitopes, LAMC2, a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2 peptide, we cloned T-cell receptors (TCRs) and transduced them into the Jurkat human T-cell line using a lentiviral vector. We found that Jurkat cells expressing LAMC2-specific TCRs resulted in potent, LAMC2 specific, in vitro cytotoxic effects on PDAC cells. Furthermore, in mice that harbored either subcutaneously or orthotopically implanted tumors originating from both HLA-A allele-matched and unmatched PDAC patients, tumor growth was suppressed in a LAMC2-dependent manner following the infusion of LAMC2-targeting T cells. We have therefore developed a LAMC2-specific TCR-based T-cell therapy strategy likely suitable for many PDAC patients. This is the first study to adopt MS analysis to identify natural CD8 T-cell epitopes in PDAC that could potentially serve as targets for PDAC immunotherapy.
Topics: Humans; Animals; Mice; Epitopes, T-Lymphocyte; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Receptors, Antigen, T-Cell; Mass Spectrometry; Cell- and Tissue-Based Therapy; HLA-A Antigens
PubMed: 37640197
DOI: 10.1016/j.canlet.2023.216366 -
Free Radical Biology & Medicine Feb 2024Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major...
Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major downstream effector of the Hippo-YAP pathway and plays a pivotal role in regulation of cell proliferation and organ regeneration and tumorigenesis. Activation of YAP signaling has been associated with PDAC progression and drug resistance. Verteporfin (VP) is a photosensitizer used for photodynamic therapy and previous work showed that it can function as a YAP inhibitor. The efficacy of VP on human cancer are being tested in several trials. In this study, we examined the effect of VP on reactive oxygen species (ROS) and lipid peroxidation in pancreatic cancer cells, by using fluorescent molecular probes and by measuring the levels of malondialdehyde, a metabolic byproduct and marker of lipid peroxidation. We found that VP causes rapid increase of both overall ROS and lipid peroxide levels, independent of light activation. These effects were not dependent on YAP, as knockdown of YAP did not cause ROS or lipid peroxidation or enhance VP-induced ROS production. Temoporfin, another photodynamic drug, did not show similar activities. In addition, VP treatment led to loss of cell membrane integrity and reduction of viability. Notably, the activity of VP to induce lipid peroxidation was neutralized by ferroptosis inhibitors ferrostatin-1 or liproxstatin-1. VP treatment also reduced the levels of glutathione peroxidase 4 (GPX4), an enzyme that protects against lipid peroxidation. These results indicate that VP can induce lipid peroxidation and ferroptosis in the absence of light activation. Our findings reveal a novel mechanism by which VP inhibits tumor growth and provide insights into development of new therapeutic strategies for the treatment of pancreatic cancer.
Topics: Humans; Verteporfin; Lipid Peroxidation; Reactive Oxygen Species; Ferroptosis; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal
PubMed: 38184120
DOI: 10.1016/j.freeradbiomed.2024.01.003 -
Journal of Controlled Release :... Aug 2023Owing to a lack of reliable markers and therapeutic targets, pancreatic ductal adenocarcinoma (PDAC) remains the most lethal malignant tumor despite numerous therapeutic...
Owing to a lack of reliable markers and therapeutic targets, pancreatic ductal adenocarcinoma (PDAC) remains the most lethal malignant tumor despite numerous therapeutic advances. In this study, we utilized cell-SELEX to isolate a DNA aptamer recognizing the natural conformation of the target on the cell surface. PAp7T8, an aptamer optimized by size and chemical modification, exhibited specific targeting to pancreatic cancer cells and orthotopic xenograft pancreatic tumors. To confer therapeutic functions to the aptamer, we adopted a drug-conjugated oligobody (DOligobody) strategy. Monomethyl auristatin E was used as a cytotoxic drug, digoxigenin acted as a hapten, and the humanized anti-digoxigenin antibody served as a universal carrier of the aptamer. The resulting PAp7T8-DOligobody showed extended in vivo half-life and markedly inhibited tumor growth in an orthotopic pancreatic cancer xenograft model without causing significant toxicity. Therefore, PAp7T8-DOligobody represents a promising novel therapeutic delivery platform for PDAC.
Topics: Humans; Pharmaceutical Preparations; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Antibodies; Oligonucleotides; Xenograft Model Antitumor Assays
PubMed: 37001565
DOI: 10.1016/j.jconrel.2023.03.048 -
Biomedicine & Pharmacotherapy =... Dec 2023Pancreatic cancer, including pancreatic ductal adenocarcinomas (PDACs), is a malignant tumor with characteristics of tumor-stroma interactions. Patients often have a... (Review)
Review
Pancreatic cancer, including pancreatic ductal adenocarcinomas (PDACs), is a malignant tumor with characteristics of tumor-stroma interactions. Patients often have a poor prognosis and a poor long-term survival rate. In recent years, rapidly-developing single-cell sequencing techniques have been used to analyze cell populations at a single-cell resolution, so that it is now possible to have a more in-depth and clearer understanding of the genetic composition of pancreatic cancer. In this review, we provide an overview of the current single-cell sequencing techniques and their applications in the exploration of intratumoral heterogeneity, the tumor microenvironment, therapy resistance, and novel treatments. Our hope is to provide new insight into the potential of precision therapy, which will perhaps one day lead to significant advances in PDAC treatment.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37837881
DOI: 10.1016/j.biopha.2023.115664 -
Journal of Investigative Surgery : the... Dec 2023Pancreatic carcinoma (PC) is a global health threat with a high death rate. miRNAs are implicated in tumor initiation and progression. This study explored the...
Pancreatic carcinoma (PC) is a global health threat with a high death rate. miRNAs are implicated in tumor initiation and progression. This study explored the expression of miR-425-5p in PC patients and its correlation with tumor immune microenvironment (TIME). miR-425-5p expression in cancer tissues and adjacent non-tumor tissues of PC patients was examined by RT-qPCR. The levels of immune cells and cytokines were measured by flow cytometry and ELISA. The correlation of miR-425-5p with TNM stage and TIME was assessed by Spearman method. The death of PC patients was recorded through 36-month follow-ups. The prognosis of patients was assessed by Kaplan-Meier curves. miR-425-5p expression was upregulated in PC tissues and elevated with increasing TNM stage. miR-425-5p expression was positively correlated with TNM stage. The PC tissues had decreased levels of CD3+, CD4+, CD8+, and natural killer (NK) cells, CD4+/CD8+ ratio, IL-2, and INF-γ, but increased levels of Tregs, IL-4, IL-10, and TGF-β. miR-425-5p level in cancer tissues was positively correlated with Tregs/IL-10/TGF-β, but negatively related to CD3+/CD4+/CD8+/NK cells and IL-2/INF-γ. Moreover, high miR-425-5p expression predicted a poor prognosis in PC patients. miR-425-5p is upregulated in PC patients and is prominently associated with the TIME, and high miR-425-5p predicts a poor prognosis in PC patients.
Topics: Humans; Interleukin-10; Interleukin-2; MicroRNAs; Pancreatic Neoplasms; Transforming Growth Factor beta; Cell Line, Tumor; Cell Proliferation; Tumor Microenvironment
PubMed: 37455016
DOI: 10.1080/08941939.2023.2216756 -
Acta Pharmacologica Sinica Aug 2023Autophagy-lysosome system plays a variety of roles in human cancers. In addition to being implicated in metabolism, it is also involved in tumor immunity, remodeling the... (Review)
Review
Autophagy-lysosome system plays a variety of roles in human cancers. In addition to being implicated in metabolism, it is also involved in tumor immunity, remodeling the tumor microenvironment, vascular proliferation, and promoting tumor progression and metastasis. Transcriptional factor EB (TFEB) is a major regulator of the autophagy-lysosomal system. With the in-depth studies on TFEB, researchers have found that it promotes various cancer phenotypes by regulating the autophagolysosomal system, and even in an autophagy-independent way. In this review, we summarize the recent findings about TFEB in various types of cancer (melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, colorectal cancer, breast cancer, prostate cancer, ovarian cancer and lung cancer), and shed some light on the mechanisms by which it may serve as a potential target for cancer treatment.
Topics: Male; Humans; Autophagy; Breast Neoplasms; Pancreatic Neoplasms; Lung Neoplasms; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37012494
DOI: 10.1038/s41401-023-01078-7 -
Annals of Surgical Oncology Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is most often metastatic at diagnosis. As systemic therapy continues to improve alongside advanced surgical techniques, the focus... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is most often metastatic at diagnosis. As systemic therapy continues to improve alongside advanced surgical techniques, the focus has shifted toward defining biologic, rather than technical, resectability. Several centers have reported metastasectomy for oligometastatic PDAC, yet the indications and potential benefits remain unclear. In this review, we attempt to define oligometastatic disease in PDAC and to explore the rationale for metastasectomy. We evaluate the existing evidence for metastasectomy in liver, peritoneum, and lung individually, assessing the safety and oncologic outcomes for each. Furthermore, we explore contemporary biomarkers of biological resectability in oligometastatic PDAC, including radiographic findings, biochemical markers (such as CA 19-9 and CEA), inflammatory markers (including neutrophil-to-lymphocyte ratio, C-reactive protein, and scoring indices), and liquid biopsy techniques. With careful consideration of existing data, we explore the concept of biologic resectability in guiding patient selection for metastasectomy in PDAC.
Topics: Humans; Pancreatic Neoplasms; Metastasectomy; Carcinoma, Pancreatic Ductal; Prognosis; Liver Neoplasms; Lung Neoplasms
PubMed: 38502293
DOI: 10.1245/s10434-024-15129-8 -
Frontiers in Immunology 2024Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and... (Review)
Review
Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.
Topics: Humans; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Signal Transduction; Immunomodulation
PubMed: 38361931
DOI: 10.3389/fimmu.2024.1287459 -
Advanced Science (Weinheim,... Mar 2024Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late-stage patient prognosis undergoing chemotherapy is challenging. This work shows...
Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late-stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes-rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles-rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early-stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late-stage PDAC patients undergoing chemotherapy, lower GPC1 tMV-mProtein and Exo-mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.
Topics: Humans; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Extracellular Vesicles; Glypicans; Pancreatic Neoplasms; Prognosis; RNA, Messenger
PubMed: 38204202
DOI: 10.1002/advs.202306373