scholarly journals Native glycan fragments detected by MALDI mass spectrometry imaging are independent prognostic factors in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Na Sun ◽  
Marija Trajkovic-Arsic ◽  
Fengxia Li ◽  
Yin Wu ◽  
Corinna Münch ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cell ◽  
Patient Survival ◽  
Therapy Resistance ◽  
High Mass ◽  
Ductal Adenocarcinoma ◽  
Ion Cyclotron Resonance ◽  
Cell Compartment ◽  
Cell Region ◽  
Stromal Compartment

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates. Results We analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan–Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions. Conclusion Our method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer–stroma communication.

scholarly journals Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Beate Gündel ◽  
Xinyuan Liu ◽  
Matthias Löhr ◽  
Rainer Heuchel
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Treatment Options ◽  
3D Cell Culture ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
The Past ◽  
Slow Progress

Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.

scholarly journals Fibroblasts as a Biological Marker for Curative Resection in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (11) ◽  
pp. 3890 ◽  
Author(s):  
Eriko Katsuta ◽  
Omar M. Rashid ◽  
Kazuaki Takabe
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cell ◽  
Cancer Biology ◽  
Curative Resection ◽  
Biological Marker ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Small Subset ◽  
Inverse Association ◽  
Anti Cancer

Achievement of microscopic tumor clearance (R0) after pancreatic ductal adenocarcinoma (PDAC) surgery is determined by cancer biology rather than operative technique. Fibroblasts are known to play pro-cancer roles; however, a small subset was recently found to play anti-cancer roles. Therefore, we hypothesized that intratumor fibroblasts contribute to curative resection and a better survival of PDAC. Utilizing a large, publicly available PDAC cohort, we found that fibroblast composition was associated with R0 curative resection. A high amount of fibroblasts in PDACs was significantly associated with a higher amount of mature vessels, but not with blood angiogenesis. A high amount of fibroblasts was also associated with a higher infiltration of anti-cancer immune cells, such as CD8+ T-cells and dendritic cells, together with higher inflammatory signaling, including IL2/STAT5 and IL6/JAK/STAT3 signaling. Further, the fibroblast composition was inversely associated with cancer cell composition in the bulk tumor, along with an inverse association with proliferative characteristics, such as MYC signaling and glycolysis. The patients with high-fibroblast PDACs showed an improved prognosis. In conclusion, we found that PDACs with high fibroblasts were associated with a higher R0 resection rate, resulting in a better prognosis. These findings may be due to less aggressive biology with a higher vascularity and anti-cancer immunity, and a low cancer cell component.

scholarly journals Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

Gut ◽  
2015 ◽  
Vol 64 (12) ◽  
pp. 1921-1935 ◽  
Author(s):  
Bruno Sainz ◽  
Sonia Alcala ◽  
Elena Garcia ◽  
Yolanda Sanchez-Ripoll ◽  
Maria M Azevedo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Cell Compartment ◽  
Stem Cell Compartment

scholarly journals Cancer Models to Defeat Therapy Resistance in Pancreatic Ductal Adenocarcinoma

2021 ◽  
pp. 43-62
Author(s):  
Britney He
Keyword(s):  
Cancer Research ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapy Resistance ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
Multi Drug Resistance ◽  
In Vivo Models ◽  
Incidence And Mortality

One of the largest hurdles to the efficacy of cancer therapeutics, and a main cause of relapse, is therapy resistance. In response, researchers have developed model systems to better understand therapy resistance. Cancer research employs several model systems that reflect the biology of actual human tumors: in vitro models (2D, 3D cell cultures), in vivo models (PDX, GEMMS, transgenic), proteomic models, and computational or mathematical models. One cancer that has been extensively modeled is pancreatic ductal adenocarcinoma (PDAC). PDAC is the third most common cause of annual cancer deaths in developed countries; as its incidence and mortality rates continue to increase, PDAC is projected to be the second leading cause of cancer deaths by 2030. Although chemotherapy is a pillar of clinical PDAC treatment, its outcome typically leads to multi-drug resistance, drastically restricting the curative effect of drugs for a variety of tumors. Elucidating the underlying mechanisms for resistance through different models is essential for the development of new strategies and therapies. This review provides insight into the range of in vitro and in vivo models of pancreatic cancer used in preclinical research. This paper provides an overview of platforms for cancer research with a focus on those devoted to resistance mechanisms in PDAC and to the primary therapeutic intervention for PDAC, gemcitabine (GEM).

scholarly journals Transcriptional regulation of SLIT2 expression in pancreatic cancer cell lines

2020 ◽  
Author(s):  
Brenna A. Rheinheimer ◽  
Lukas Vrba ◽  
Bernard W Futscher ◽  
Ronald L Heimark
Keyword(s):  
Pancreatic Cancer ◽  
Transcriptional Regulation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Trichostatin A ◽  
Cancer Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Liver Cancers

AbstractBackgroundSLIT2 has been shown to serve as a tumor suppressor in breast, lung, colon, and liver cancers. Additionally, expression of SLIT2 has been shown to be epigenetically regulated in prostate cancer. Therefore, we sought to determine transcriptional regulation of SLIT2 in pancreatic ductal adenocarcinoma.MethodsRNA expression of SLIT2, SLIT3, and ROBO1 was examined in a panel of pancreatic ductal adenocarcinoma cell lines while protein expression of ROBO1 and SLIT2 was examined in tumor tissue. Methylation of the SLIT2 promoter was determined using Sequenom while histone modifications were queried by chromatin immunoprecipitation. Reexpression of SLIT2 was tested by treatment with 5-aza-2’deoxycytidine and Trichostatin A.ResultsPancreatic cancer cell lines fall into three distinct groups based on SLIT2 and ROBO1 expression. The SLIT2 promoter is methylated in pancreatic ductal adenocarcinoma and SLIT2 expression is dependent on the level of methylation at specific CpG sites. Treatment with 5-aza-2’deoxycytidine (but not Trichostatin A) led to SLIT2 reexpression. The SLIT2 promoter is bivalent in pancreatic ductal adenocarcinoma and histone marks around the transcriptional start site are responsible for transcription.ConclusionsLoss of SLIT2 expression modulated by epigenetic silencing may play a role in pancreatic ductal adenocarcinoma progression.

scholarly journals Aptamers: a novel targeted theranostic platform for pancreatic ductal adenocarcinoma

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Q. Li ◽  
S. H. Maier ◽  
P. Li ◽  
J. Peterhansl ◽  
C. Belka ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Three Dimensional ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
Generation Process ◽  
Current Implementation ◽  
Early Tumor ◽  
Conventional Cell ◽  
Local Enrichment

AbstractPancreatic ductal adenocarcinoma (PDAC) is an extremely challenging disease with a high mortality rate and a short overall survival time. The poor prognosis can be explained by aggressive tumor growth, late diagnosis, and therapy resistance. Consistent efforts have been made focusing on early tumor detection and novel drug development. Various strategies aim at increasing target specificity or local enrichment of chemotherapeutics as well as imaging agents in tumor tissue. Aptamers have the potential to provide early detection and permit anti-cancer therapy with significantly reduced side effects. These molecules are in-vitro selected single-stranded oligonucleotides that form stable three-dimensional structures. They are capable of binding to a variety of molecular targets with high affinity and specificity. Several properties such as high binding affinity, the in vitro chemical process of selection, a variety of chemical modifications of molecular platforms for diverse function, non-immunoreactivity, modification of bioavailability, and manipulation of pharmacokinetics make aptamers attractive targets compared to conventional cell-specific ligands. To explore the potential of aptamers for early diagnosis and targeted therapy of PDAC - as single agents and in combination with radiotherapy - we summarize the generation process of aptamers and their application as biosensors, biomarker detection tools, targeted imaging tracers, and drug-delivery carriers. We are furthermore discussing the current implementation aptamers in clinical trials, their limitations and possible future utilization.

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