scholarly journals Semiconducting Polymer Nano-Radiopharmaceutical For Combined Radio-Photothermal Therapy of Pancreatic Tumor

2021 ◽  
Author(s):  
Xiumin Shi ◽  
Qing Li ◽  
Chuan Zhang ◽  
Hailong Pei ◽  
Guanglin Wang ◽  
...  
Keyword(s):  
Side Effects ◽  
Photothermal Therapy ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Cell Uptake ◽  
Ductal Adenocarcinoma ◽  
Tumor Stem Cells ◽  
Semiconducting Polymer ◽  
Mesenchymal Transition ◽  
Therapeutic Outcomes

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastatingly malignant tumor with a high mortality. However, current strategies to treat PDAC generally have low efficacy and high side-effects, therefore, effective treatment against PDAC remains an urgent need. Results: We report a semiconducting polymer nano-radiopharmaceutical with intrinsic photothermal capability and labeling with therapeutic radioisotope 177Lu (177Lu-SPN-GIP) for combined radio- and photothermal therapy of pancreatic tumor. 177Lu-SPN-GIP endowed good stability at physiological conditions, high cell uptake, and long retention time in tumor site. By virtue of combined radiotherapy (RT) and photothermal therapy (PTT), 177Lu-SPN-GIP exhibited enhanced therapeutic capability to kill cancer cells and xenograft tumor in living mice compared with RT or PTT alone. More importantly, 177Lu-SPN-GIP could suppress the growth of the tumor stem cells and reverse epithelial mesenchymal transition (EMT), which may greatly reduce the occurrence of metastasis. Conclusion: Such strategy we developed could improve therapeutic outcomes over traditional RT as it is able to ablate tumor with relatively lower doses of radiopharmaceuticals to reduce its side effects.

scholarly journals Semiconducting polymer nano-radiopharmaceutical for combined radio-photothermal therapy of pancreatic tumor

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiumin Shi ◽  
Qing Li ◽  
Chuan Zhang ◽  
Hailong Pei ◽  
Guanglin Wang ◽  
...  
Keyword(s):  
Side Effects ◽  
Photothermal Therapy ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Cell Uptake ◽  
Ductal Adenocarcinoma ◽  
Tumor Stem Cells ◽  
Semiconducting Polymer ◽  
Mesenchymal Transition ◽  
Therapeutic Outcomes

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a devastatingly malignant tumor with a high mortality. However, current strategies to treat PDAC generally have low efficacy and high side-effects, therefore, effective treatment against PDAC remains an urgent need. Results We report a semiconducting polymer nano-radiopharmaceutical with intrinsic photothermal capability and labeling with therapeutic radioisotope 177Lu (177Lu-SPN-GIP) for combined radio- and photothermal therapy of pancreatic tumor. 177Lu-SPN-GIP endowed good stability at physiological conditions, high cell uptake, and long retention time in tumor site. By virtue of combined radiotherapy (RT) and photothermal therapy (PTT), 177Lu-SPN-GIP exhibited enhanced therapeutic capability to kill cancer cells and xenograft tumor in living mice compared with RT or PTT alone. More importantly, 177Lu-SPN-GIP could suppress the growth of the tumor stem cells and reverse epithelial mesenchymal transition (EMT), which may greatly reduce the occurrence of metastasis. Conclusion Such strategy we developed could improve therapeutic outcomes over traditional RT as it is able to ablate tumor with relatively lower doses of radiopharmaceuticals to reduce its side effects. Graphical abstract

scholarly journals Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽  
2021 ◽  
Vol 40 (17) ◽  
pp. 3164-3179
Author(s):  
Yang Liu ◽  
Tianchi Tang ◽  
Xiaosheng Yang ◽  
Peng Qin ◽  
Pusen Wang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Noncoding Rna ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Noncoding Rnas ◽  
Ductal Adenocarcinoma ◽  
Overall Survival Rate ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

scholarly journals Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. E. Anselmino ◽  
M. V. Baglioni ◽  
F. Malizia ◽  
N. Cesatti Laluce ◽  
C. Borini Etichetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Drug Repositioning ◽  
Combined Treatment ◽  
Alternative Therapy ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tumor Types

AbstractDrug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

scholarly journals Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1090
Author(s):  
Hassan Sadozai ◽  
Animesh Acharjee ◽  
Thomas Gruber ◽  
Beat Gloor ◽  
Eva Karamitopoulou
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Disease Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Budding ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

scholarly journals HNF1A recruits UTX to activate a differentiation program that suppresses pancreatic cancer

2019 ◽  
Author(s):  
Mark Kalisz ◽  
Edgar Bernardo ◽  
Anthony Beucher ◽  
Miguel Angel Maestro ◽  
Natalia del Pozo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Pancreatic Acinar Cells ◽  
Ductal Adenocarcinoma ◽  
Molecular Phenotype ◽  
Mesenchymal Transition ◽  
A Cell ◽  
Pancreatic Exocrine ◽  
Direct Genetic Evidence

AbstractDefects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding the histone demethylase UTX, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutations phenocopy Utx deficient mutations, and both synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic and biochemical studies to show that HNF1A recruits UTX to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates a differentiation program, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. Finally, we identify a subset of non-classical PDAC samples that exhibit the HNF1A/UTX-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A-deficiency promotes PDAC. They also connect the tumor suppressive role of UTX deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

scholarly journals Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

Gut ◽  
2020 ◽  
pp. gutjnl-2019-319970 ◽  
Author(s):  
Johann Gout ◽  
Lukas Perkhofer ◽  
Mareen Morawe ◽  
Frank Arnold ◽  
Michaela Ihle ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Mesenchymal Transition ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Copy Number Variations ◽  
Ductal Adenocarcinoma ◽  
Parp Inhibition ◽  
Independent Manner ◽  
Mesenchymal Transition ◽  
Fork Stalling

ObjectiveATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).DesignCombinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.ResultsSynergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance.ConclusionAnalysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition.

scholarly journals ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas

Gut ◽  
2018 ◽  
Vol 68 (7) ◽  
pp. 1245-1258 ◽  
Author(s):  
Wenjia Wang ◽  
Scott C Friedland ◽  
Bing Guo ◽  
Michael R O’Dell ◽  
William B Alexander ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Lines ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Ductal Adenocarcinoma ◽  
Interaction Domain ◽  
Mesenchymal Transition ◽  
Poorly Differentiated

ObjectiveHere, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.DesignMice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.ResultsArid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.ConclusionsARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.

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