scholarly journals CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 952 ◽  
Author(s):  
Andrea Resovi ◽  
Patrizia Borsotti ◽  
Tommaso Ceruti ◽  
Alice Passoni ◽  
Massimo Zucchetti ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Active Regions ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Pharmacokinetic Analysis ◽  
Matricellular Protein ◽  
Major Barrier ◽  
Promising Therapeutic Target ◽  
Combination Regimens

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC.

scholarly journals Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

2021 ◽  
Vol 8 ◽  
Author(s):  
Sen Yang ◽  
Qiaofei Liu ◽  
Quan Liao
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Immune Escape ◽  
Early Stage ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Tumor Associated Macrophages ◽  
Polarization Functions ◽  
High Possibility

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. PDAC is only cured by surgical resection in its early stage, but there remains a relatively high possibility of recurrence. The development of PDAC is closely associated with the tumor microenvironment. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in the pancreatic tumor stroma. TAMs are inclined to M2 deviation in the tumor microenvironment, which promotes and supports tumor behaviors, including tumorigenesis, immune escape, metastasis, and chemotherapeutic resistance. Herein, we comprehensively reviewed the latest researches on the origin, polarization, functions, and reprogramming of TAMs in PDAC.

scholarly journals The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment

2020 ◽  
Vol 19 ◽  
pp. 153303382092096
Author(s):  
Hongzhi Sun ◽  
Bo Zhang ◽  
Haijun Li
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stromal Cells ◽  
Genomic Analysis ◽  
Ductal Adenocarcinoma ◽  
Genetic Mutations ◽  
Cellular Processes ◽  
Dismal Prognosis ◽  
Mutant Genes

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

scholarly journals Mast Cells in Tumor Microenvironment Promotes the In Vivo Growth of Pancreatic Ductal Adenocarcinoma

2011 ◽  
Vol 17 (22) ◽  
pp. 7015-7023 ◽  
Author(s):  
David Z. Chang ◽  
Ying Ma ◽  
Baoan Ji ◽  
Huamin Wang ◽  
Defeng Deng ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
In Vivo Growth

scholarly journals Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

2020 ◽  
Author(s):  
S. Mahnaz ◽  
L. Das Roy ◽  
M. Bose ◽  
C. De ◽  
S. Nath ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

Abstract PO-115: Effects of mesothelin exert on tumor microenvironment in pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Dongliang Liu ◽  
Ethan Poteet ◽  
Zhengdong Liang ◽  
Emily Laplante ◽  
Lisa Brubaker ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

scholarly journals A generalizable data-driven multicellular model of pancreatic ductal adenocarcinoma

GigaScience ◽  
2020 ◽  
Vol 9 (7) ◽  
Author(s):  
Boris Aguilar ◽  
David L Gibbs ◽  
David J Reiss ◽  
Mark McConnell ◽  
Samuel A Danziger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Interactions ◽  
Positive Impact ◽  
Stellate Cells ◽  
The Cancer Genome Atlas ◽  
Data Driven ◽  
Ductal Adenocarcinoma ◽  
Modeling Framework ◽  
Pertinent Data

Abstract Background Mechanistic models, when combined with pertinent data, can improve our knowledge regarding important molecular and cellular mechanisms found in cancer. These models make the prediction of tissue-level response to drug treatment possible, which can lead to new therapies and improved patient outcomes. Here we present a data-driven multiscale modeling framework to study molecular interactions between cancer, stromal, and immune cells found in the tumor microenvironment. We also develop methods to use molecular data available in The Cancer Genome Atlas to generate sample-specific models of cancer. Results By combining published models of different cells relevant to pancreatic ductal adenocarcinoma (PDAC), we built an agent-based model of the multicellular pancreatic tumor microenvironment, formally describing cell type–specific molecular interactions and cytokine-mediated cell-cell communications. We used an ensemble-based modeling approach to systematically explore how variations in the tumor microenvironment affect the viability of cancer cells. The results suggest that the autocrine loop involving EGF signaling is a key interaction modulator between pancreatic cancer and stellate cells. EGF is also found to be associated with previously described subtypes of PDAC. Moreover, the model allows a systematic exploration of the effect of possible therapeutic perturbations; our simulations suggest that reducing bFGF secretion by stellate cells will have, on average, a positive impact on cancer apoptosis. Conclusions The developed framework allows model-driven hypotheses to be generated regarding therapeutically relevant PDAC states with potential molecular and cellular drivers indicating specific intervention strategies.

Abstract PO-047: Lorazepam modifies the pancreatic ductal adenocarcinoma tumor microenvironment

2020 ◽  
Author(s):  
Abigail C. Cornwell ◽  
Abdulrahman A. Alahmari ◽  
Arwen A. Tisdale ◽  
Michael E. Feigin
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma
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