Gemcitabine (GEM)-based chemotherapy is commonly used to treat pancreatic cancer. However, acquired resistance to GEM remains a challenge in pancreatic cancer patients. Here we tested whether ...cancer-associated fibroblasts (CAFs) play vital roles in regulating drug resistance by transferring exosomal miRNA to cancer cells. CAFs were isolated from primary fibroblast of pancreatic cancer patients, and exosomes were collected and identified through transmission electron microscopy and western blotting analysis. The functions of CAFs-derived exosomal miRNA in regulating drug resistance were further investigated. We found that CAFs were innately resistant to GEM. The conditioned medium (CM) and the exosomes derived from CAFs contributed to GEM resistance, and GEM treatment further enhanced the effect of CAFs or CAFs-exosomes on pancreatic cancer cells proliferation. MiR-106b level was upregulated in CAFs and CAFs-exosomes following GEM treatment. MiR-106b was directly transferred from CAFs to pancreatic cancer cells through exosomes. Pretreatment of CAFs with miR-106b inhibitor suppressed miR-106b expression in CAFs-exosomes and resulted in a decreased resistance of cancer cells to GEM. MiR-106b promoted GEM resistance of cancer cells by directly targeting TP53INP1. Summarily, our data demonstrated that CAFs-derived exosomal miR-106b plays a vital role in causing GEM resistance of pancreatic cancer, thus offering a new target for sensitizing pancreatic cancer cells to GEM.
Programmed death‐ligand 1 (PD‐L1) blockade has revolutionized the prognosis of several cancers, but shows a weak effect on pancreatic cancer (PC) due to poor effective immune infiltration. Chemokine ...C‐C motif ligand 21 (CCL21), a chemokine promoting T cell immunity by recruiting and colocalizing dendritic cells (DCs) and T cells, serves as a potential antitumor agent in many cancers. However, its antitumor response and mechanism combined with PD‐L1 blockade in PC remain unclear. In our study, we found CCL21 played an important role in leukocyte chemotaxis, inflammatory response, and positive regulation of PI3K‐AKT signaling in PC using Metascape and gene set enrichment analysis. The CCL21 level was verified to be positively correlated with infiltration of CD8+ T cells by the CIBERSORT algorithm, but no significant difference in survival was observed in either The Cancer Genome Atlas or the International Cancer Genome Consortium cohort when stratified by CCL21 expression. Additionally, we found the growth rate of allograft tumors was reduced and T cell infiltration was increased, but tumor PD‐L1 abundance elevated simultaneously in the CCL21‐overexpressed tumors. Then, CCL21 was further verified to increase tumor PD‐L1 level through the AKT‐glycogen synthase kinase‐3β axis in human PC cells, which partly impaired the antitumor T cell immunity. Finally, the combination of CCL21 and PD‐L1 blockade showed superior synergistic tumor suppression in vitro and in vivo. Together, our findings suggested that CCL21 in combination with PD‐L1 blockade might be an efficient and promising option for the treatment of PC.
Chemokine C‐C motif ligand 21 (CCL21) in the tumor microenvironment can promote T cell infiltration and enhance their antitumor immune response. However, CCL21 also stabilizes and upregulates programmed death‐ligand 1 (PD‐L1) expression on pancreatic cancer cells through the AKT‐glycogen synthase kinase‐3β signaling pathway at the same time, which could partly impair the local immune response. Thus, PD‐L1 blockade was used in combination with CCL21, which showed a powerful synergism and promising therapeutic efficacy.
Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, ...its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.
As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass ...spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The Multiplexed Nanomaterial-Assisted LDI for Cancer Identification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis.
Pancreatic cancer with synchronous liver metastasis has an extremely poor prognosis, and surgery is not recommended for such patients by the current guidelines. However, an increasing body of studies ...have shown that concurrent resection of pancreatic cancer and liver metastasis is not only technically feasible but also beneficial to the survival in the selected patients. In this review, we aim to summarize the short- and long-term outcomes following synchronous liver metastasectomy for pancreatic cancer patients, and discuss the potential criteria in selecting appropriate surgical candidates, which might be helpful in clinical decision-making.
Pancreatic ductal adenocarcinoma (PDAC) remains a refractory disease. Programmed cell death protein-1 (PD-1) monotherapy has shown strong performance in targeting several malignancies. However, the ...effect and mechanism of intrinsic PD-1 in pancreatic cancer cells is still unknown. In this study, associations between clinicopathological characteristics and stained tissue microarrays of PDAC specimens were analyzed along with profiling and functional analyses. The results showed that cell-intrinsic PD-1 was significantly correlated with overall survival (OS). Independently of adaptive immunity, intrinsic PD-1 promoted tumor growth in PDAC. Concomitantly, the overexpression of intrinsic PD-1 enhanced cancer proliferation and inhibited cell apoptosis in vitro and in vivo. Mechanistically, PD-1 binds to the downstream MOB1, thereby inhibiting its phosphorylation. Moreover, greater synergistic tumor suppression in vitro resulted from combining Hippo inhibitors with anti-PD-1 treatment compared with the suppression achieved by either single agent alone. Additionally, Hippo downstream targets, CYR61 (CCN1) and CTGF (CCN2), were directly affected by PD-1 mediated Hippo signaling activation in concert with survival outcomes. Finally, the formulated nomogram showed superior predictive accuracy for OS in comparison with the TNM stage alone. Therefore, PD-1 immunotherapy in combination with Hippo pathway inhibitors may optimize the anti-tumor efficacy in PDAC patients via targeting cell-intrinsic PD-1.
•In pancreatic cancer tissues, cell-intrinsic PD-1 is significantly associated with unfavorable clinical outcomes.•Cell-intrinsic PD-1 promote cancer proliferation and growth through hippo signal pathway by targeting CYR61 and CTGF.•The effect of cell-intrinsic PD-1 depends on the PD-L1 and interacts with MOB1.•CYR6 and CTGF are dramatically associated with survival and the formulated nomogram showed superior predictive accuracy for survival.
Circular RNAs (circRNAs), the new stars of endogenous non-coding RNAs, are dysregulated in various tumors including pancreatic cancer. Here, we aimed to investigate the biological functions of ...hsa_circ_0071036 in the tumourigenesis and progression of pancreatic ductal adenocarcinoma (PDAC) and its clinical implications. The differential expression profile of circRNAs in 4 pairs of PDAC tissues was analyzed by microarray assay. Quantitative real-time PCR and fluorescence in situ hybridization (FISH) were utilized to determine the expression patterns and their clinical significance. Functional experiments in vitro and in vivo were performed to explore whether hsa_circ_0071036 functions as an oncogenic circRNA in PDAC. Mechanistically, RT-qPCR, dual luciferase reporter and RNA pull-down assays were conducted to identify the interaction between hsa_circ_0071036 and miR-489 in PDAC. Hsa_circ_0071036 was remarkably overexpressed in PDAC cell lines and tissue samples, which negatively correlated with miR-489 expression. Aberrant expression of hsa_circ_0071036 correlated with poor clinicopathological characteristics and prognoses of PDAC patients. Knockdown of hsa_circ_0071036 suppressed proliferation and invasion and induced apoptosis in vitro. Moreover, the in vivo xenograft model confirmed that silencing of hsa_circ_0071036 attenuated tumor growth. Mechanistic analyses indicated that hsa_circ_0071036 acted as an efficient miRNA sponge for miR-489 in PDAC. In summary, our study revealed that upregulated hsa_circ_0071036 promotes PDAC pathogenesis and progression by directly sponging miR-489, which implies an important role for this circRNA-miRNA functional network.
Background
Inflammatory factors and fasting blood glucose were verified to be associated with the prognosis of pancreatic ductal adenocarcinoma. The goal of this study is to confirm the prognostic ...role of preoperative blood glucose to lymphocyte ratio for patients with resected pancreatic ductal adenocarcinoma.
Methods
A total of 259 pancreatic ductal adenocarcinoma patients were enrolled and randomly divided into training cohort and validation cohort. The training cohort was used to generate an optimal cutoff value and the validation cohort was used to further validate the model.
Results
A total of 259 patients were incorporated in this study and randomly divided into the training cohort (
n
= 130, 1/2 of 259) and the validation cohort (129, 1/2 of 259). The optimal cutoff value of glucose to lymphocyte ratio was calculated to be 3.47 for overall survival. Cox regression analysis found that preoperative blood glucose to lymphocyte ratio was independent risk factor (
p
= 0.040) for overall survival. Prognostic values of glucose to lymphocyte ratio on overall survival were observed in younger male patients with pancreatic body and tail cancer, American Joint Committee on Cancer 8th N1 stage, without microvascular and peripancreatic fat invasion, and Carbohydrate antigen 19–9 higher than 200 U/ml. A prognostic prediction model of overall survival was designed and presented in nomogram.
Conclusion
Preoperative blood glucose to lymphocyte ratio is an independent biomarker to predict the overall survival for pancreatic ductal adenocarcinoma patients who underwent curative resection.
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