scholarly journals Hypoxia-driven oncometabolite L-2HG maintains “stemness”-differentiation balance and facilitates immune suppression in pancreatic cancer

2020 ◽  
Author(s):  
Vineet K Gupta ◽  
Nikita S Sharma ◽  
Brittany Durden ◽  
Vanessa T Garrido ◽  
Kousik Kesh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell Activation ◽  
Immune Suppression ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Isomeric Form ◽  
Spectrometric Analysis ◽  
Self Renewal ◽  
Pancreatic Cancer Cells ◽  
First Time

Abstract2-hydroxyglutarate (2-HG) has gained considerable importance in glioma and blood cancers that have mutations in the IDH1/2 gene. In the current study we show for the first time that pancreatic tumors produce 2HG in the absence of IDH1/2 mutation. Our study shows that hypoxic pancreatic tumors that have activated lactate dehydrogenase (LDH) activity, produce the L-isoform of 2HG.Metabolic mass spectrometric analysis along with chiral derivatization showed that pancreatic cancer cells as well as stromal cells secrete the L-isomeric form of 2-hydroxyglutarate (L-2HG) when exposed to hypoxic environment. Serum analysis of human pancreatic cancer patients also showed similar accumulation of L-2HG. Our results showed that this abnormally accumulated L-2HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (Pdx-1, HB9, NKX6.1). Further analysis showed that secreted L-2HG mediates cross talk with immune T-cells and hampers their proliferation and migration thereby suppressing the anti-tumor immunity. In vivo targeting of LDH enzyme with inhibitor (GSK2837808A) showed decrease in L-2HG as well as subsequent tumor regression and sensitization to immune-checkpoint therapy.Present study shows for the first time that hypoxia mediated accumulation of L-2HG drives self-renewal in pancreatic cancer by shifting critical balance of gene expression towards stemness and promotes immune suppression by impairing T cell activation in this disease. Additionally, it indicates that targeting LDH can sensitize pancreatic tumors to anti-PD1 therapy by decreasing L-2HG and reverting their immune evasive function.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

Relationship between tissue factor expression by human pancreatic cancer cells and activation of coagulation and thrombosis in a mouse model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Julia E. Geddings ◽  
Jian-guo Wang ◽  
Jessica C Cardenas ◽  
Pichika Chantrathammachart ◽  
Julie C Williams ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tissue Factor ◽  
Saphenous Vein ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Increased Risk ◽  
Patients At Risk

e14505 Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF expression in 4 different human pancreatic cancer cell lines. We also measured TF microparticle (MP) release from these tumors in vivo by flow cytometry and TF activity assay. We then used these lines in a mouse model of pancreatic cancer to evaluate the sources of TF that activate coagulation and contribute to thrombosis using a saphenous vein model. Results: We found that mice bearing orthotopic pancreatic tumors which express higher levels of TF (HPAC and HPAF) show increased activation of coagulation (measured by thrombin-antithrombin complex) as compared to mice bearing TF negative tumors (MIA-PaCa-2 and PANC-1). This activation of coagulation could be reduced by treatment with a human TF antibody. Further, mice bearing tumors derived from TF high cell line HPAC demonstrated an activation of coagulation despite a lack of circulating TF-positive MPs. Mice bearing TF expressing pancreatic tumors also demonstrated increased thrombosis by a saphenous vein model. Treatment of tumor-free mice with TF MPs did not result in an activation of coagulation or increased thrombosis unless mice were given 40-100 fold higher levels of TF bearing MPs than are found in the circulation of tumor bearing mice. Conclusions: The data suggest that TF on the tumor itself is involved in the activation of coagulation whereas circulating TF-positive MPs is likely to contribute to thrombosis. Elevated levels of TF-positive MPs may be used as a biomarker to identify cancer patients at risk for thrombosis.

Use of high-resolution fluorescence laparoscopy with fluorophore-conjugated tumor-specific antibodies for the detection of pancreatic cancer metastasis invisible with standard laparoscopy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 212-212
Author(s):  
Cristiina A. Metildi ◽  
Sharmeela Kaushal ◽  
Hop S. Tran Cao ◽  
Cynthia S. Snyder ◽  
Mark A. Talamini ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Light Source ◽  
Cancer Metastasis ◽  
False Negative ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Primary Tumors ◽  
Led Light ◽  
Pancreatic Cancer Cells ◽  
Standard Laparoscopy

212 Background: Standard laparoscopy for pancreatic cancer often leads to false negative results, causing understaging of the disease. Improved sensitivity and resolution are necessary. Methods: Orthotopic and carcinomatosis mouse models of human pancreatic cancer were established with red fluorescent protein (RFP)-expressing or non-fluorescent BxPC-3 human pancreatic cancer cells. The mice with orthotopic unlabeled pancreatic cancer were administered Alexa 488- or 555-conjugated anti-CEA by tail-vein injection 2-4 weeks after tumor implantation. Diagnostic laparoscopy was performed with a Stryker L9000 LED light source or X8000 xenon light source 24 hours later. Pancreatic tumors were detected and localized under each light mode. After laparoscopy, intravital images were obtained with the OV-100 and Maestro CRI Small Animal Imaging Systems as positive controls. Tumors were collected for histologic analysis. Results: Fluorescence laparoscopy (FL) with the use of 495-nm excitation filter and an LED light source enabled more rapid and accurate identification and localization of primary tumors and metastases than bright light laparoscopy (BL). The use of fluorescent conjugates antibody-labeled tumors improved the accuracy of staging laparoscopy, increasing the sensitivity from 40% in BL to 96% in FL (p<0.001). FL was sufficiently sensitive to detect sub-millimeter tumor deposits that went undetected under BL. With adjustments to the LED light source, we could simultaneously detect tumor lesions of different fluorescent colors and surrounding structures with minimal autofluorescence. Conclusions: The use of FL and fluorophore-labeled anti-CEA antibodies permits rapid detection and accurate localization of primary and metastatic CEA-expressing human pancreatic cancer, including tumors that were undetectable with BL. The introduction of an LED light source allows simultaneous identification of fluorescent tumor of different wavelengths without compromising background illumination. Further development of this technology for clinical use can improve the staging and treatment of pancreatic cancer.

Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 290-290 ◽  
Author(s):  
Thomas B Brunner ◽  
Serena Lunardi ◽  
Nigel B Jamieson ◽  
Su Yin Lim ◽  
Kristin L Griffiths ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

scholarly journals O-GlcNAc modification of oncogenic transcription factor Sox2 promotes protein stability and regulates self-renewal in pancreatic cancer

2018 ◽  
Author(s):  
Nikita S Sharma ◽  
Vineet K Gupta ◽  
Patricia Dauer ◽  
Kousik Kesh ◽  
Roey Hadad ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
The United States ◽  
Tumor Initiation ◽  
Self Renewal ◽  
Pancreatic Cancer Cells ◽  
Glcnac Transferase ◽  
First Time

AbstractPancreatic cancer is among the 3rdleading cause of cancer related deaths in the United States along with a 5-year survival rate of 7%. The aggressive biology of the disease is responsible for such dismal outcome and is manifested by an increase in self-renewal capacity of the cancer cells, which leads to an increased rate of tumor-recurrence, contributing to poor prognosis. Transcription factor SOX2 maintains a critical balance between differentiation and “stemness” and is thus tightly regulated within a cell. In cancer, SOX2 is aberrantly “turned-on” leading to activation of self-renewal pathways in cancer. Regulation of Sox2 in cancer is poorly understood. In the current study, we show for the first time that in pancreatic cancer, Sox2 is modified by addition of O-GlcNAc moiety, catalyzed by OGT (O-GlcNAc Transferase) at S246. This activates Sox2 transcriptional activity by stabilizing the protein in the nucleus. A CRISPR-OGT knockout in pancreatic cancer cell line S2VP10 resulted in a delayed tumor initiation. We further showed that mutation of this site (S246A) prevents the modification of Sox2 and its downstream activity. Our study also demonstrated that targeting OGTin vivowith a small molecule inhibitor OSMI, results in decreased tumor burden, delayed tumor progression and a decreased expression of SOX2 in pancreatic cancer cells. Our study highlights for the first time that that the O-GlcNAc transferase dependent SOX2 glycosylation has a profound effect on the transcriptional activity of SOX2 and is instrumental in determining self-renewal in pancreatic cancer.SignificanceOur study highlights for the first time that that the O-GlcNAc transferase dependent SOX2 glycosylation determines self-renewal in pancreatic cancer which is responsible for tumor initiation.

scholarly journals Genetic Inactivation of Peroxiredoxin-I Impairs the Growth of Human Pancreatic Cancer Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 570
Author(s):  
Hajar Dahou ◽  
Marie-Albane Minati ◽  
Patrick Jacquemin ◽  
Mohamad Assi
Keyword(s):  
Pancreatic Cancer ◽  
Oxidative Dna Damage ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Autophagic Flux ◽  
Pancreatic Cancer Cells ◽  
Ros Accumulation ◽  
Peroxiredoxin I

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with few therapeutic options. The identification of new promising targets is, therefore, an urgent need. Using available transcriptomic datasets, we first found that Peroxiredoxin-1 gene (PRDX1) expression was significantly increased in human pancreatic tumors, but not in the other gastrointestinal cancers; its high expression correlated with shortened patient survival. We confirmed by immunostaining on mouse pancreata the increased Peroxiredoxin-I protein (PRX-I) expression in pancreatic neoplastic lesions and PDAC. To question the role of PRX-I in pancreatic cancer, we genetically inactivated its expression in multiple human PDAC cell lines, using siRNA and CRISPR/Cas9. In both strategies, PRX-I ablation led to reduced survival of PDAC cells. This was mainly due to an increase in the production of reactive oxygen species (ROS), accumulation of oxidative DNA damage (i.e., 8-oxoguanine), and cell cycle blockade at G2/M. Finally, we found that PRX-I ablation disrupts the autophagic flux in PDAC cells, which is essential for their survival. This proof-of-concept study supports a pro-oncogenic role for PRX-I in PDAC.

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

2010 ◽  
Vol 999 (999) ◽  
pp. 1-11
Author(s):  
P. Ulivi ◽  
C. Arienti ◽  
W. Zoli ◽  
M. Scarsella ◽  
S. Carloni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Antitumor Efficacy ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2017
Author(s):  
Lital Sharvit ◽  
Rinat Bar-Shalom ◽  
Naiel Azzam ◽  
Yaniv Yechiel ◽  
Solomon Wasser ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Culture Liquid ◽  
Human Pancreatic Cancer ◽  
P53 Signaling ◽  
Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

scholarly journals Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 249
Author(s):  
Ruediger Goess ◽  
Ayse Ceren Mutgan ◽  
Umut Çalışan ◽  
Yusuf Ceyhun Erdoğan ◽  
Lei Ren ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Islet Cells ◽  
Human Pancreatic Cancer ◽  
Type I ◽  
Type Iv ◽  
Pancreatic Cancer Cells

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

Sign in / Sign up

Export Citation Format

Share Document