The prognostic significance of exosomal markers (CD63 and CD9) expression using immunohistochemistry in patients with pancreatic ductal adenocarcinoma.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 342-342
Author(s):  
Moh'd M. Khushman ◽  
Arun Bhardwaj ◽  
Girijesh K. Patel ◽  
Javier Laurini ◽  
Kelly Roveda ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Progression ◽  
Primary Tumor ◽  
Pancreatic Tumor ◽  
Failure Time ◽  
Prognostic Significance ◽  
Ductal Adenocarcinoma ◽  
The Mean ◽  
Metastatic Sites ◽  
Cd63 Expression

342 Background: Exosomes are important mediators of intercellular communications and play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are exosomal markers. In patients with pancreatic ductal adenocarcinoma (PDAC), positive correlation between CD9 expression and overall survival (OS) was reported. CD63 expression was conserved in all patients with no reported prognostic significance. This study explored the prognostic significance of CD63 and CD9 expression using immunohistochemistry (IHC) in patients with PDAC of mixed racial background. Methods: Between 2012 and 2016, 49 patients with PDAC had available tissues for CD63 and CD9 staining using IHC. Two pathologists independently scored CD63 and CD9 expression. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Results: Median age was 64 (range 42-85). 53% are males. 67% Caucasians, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV while 59% had stage I-III. The mean CD63 and CD9 Q scores are higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites (185 vs 102, p = 0.0002) and (48 vs 11, p = 0.0418) respectively. We fitted accelerated failure-time models to investigate the impacts of the covariates CD63 and CD9 on progression free survival (PFS) and OS. CD63 has significant impact on PFS (p = 0.0058) and OS (p = 0.0012). The higher the CD63 Q score, the longer the PFS and OS. CD9 doesn’t have significant impact on PFS (p = 0.8950) or OS (p = 0.7182). The mean CD63 and CD9 Q scores are slightly higher in AA compared to Caucasians (157 vs 149, p = 0.76) and (45 vs 29, p = 0.43) respectively. Conclusions: CD63 and CD9 expression is higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites. There is correlation between CD63 expression (but not CD9 in this cohort) and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC. A trend of higher expression of CD63 and CD9 among AA compared to Caucasians was noticed.

The prognostic significance of exosomal marker (CD63) expression using immunohistochemistry (IHC) in patients with pancreatic ductal adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15730-e15730
Author(s):  
Moh'd M. Khushman ◽  
Arun Bhardwaj ◽  
Girijesh K. Patel ◽  
Javier Laurini ◽  
Kelly Roveda ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Prognostic Significance ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Staining Intensity ◽  
Ductal Adenocarcinoma ◽  
Positive Correlation ◽  
The Mean ◽  
Metastatic Sites ◽  
Cd63 Expression

e15730 Background: Exosomes are important mediators of intercellular communication, and play pivotal roles in cancer progression, metastasis and chemoresistance. Exosomal membranes are enriched in endosomes-specific tetraspanins (CD63 and CD9). In patients with PDAC, positive correlation between CD9 expression and overall survival (OS) was reported. However, CD63 expression was conserved in all patients without reported prognostic significance. Here, we explored the prognostic significance of CD63 expression using IHC in patients with PDAC of mixed gender and racial background. Methods: Between 2012 and 2016, 49 patients with PDAC treated at Mitchell Cancer Institute had available tissue (pancreatic resected tissue/biopsy [N = 29] or metastatic site biopsy liver, omentum or bone (N = 20)) for CD63 staining using IHC. Two pathologists independently scored the expression of CD63. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Unpaired t test was used for statistical analysis. Results: Median age was 64 years (range 42-85). 53% are males. 67% white, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV disease while 49% had stage I, II and III. Tumor involved the head (51%), body (20%) and tail (29%). The mean CD63 Q score is slightly higher in AA compared to white (157 vs 149, P = 0.76). The mean CD63 Q score is higher in the pancreatic tissues compared to metastatic sites tissues (185 Vs 102, P = 0.0002). In our cohort, patients with mean CD63 Q score > = 140 had longer median OS compared to patients with mean Q score of < 140 (19 months Vs 3 months, P = 0.0003) and progression free survival (PFS) (12 months vs 1 month, P = 0.0043). Conclusions: In our cohort of patients with PDAC, there was no racial difference in CD63 expression between white and AA. The expression of CD63 is higher in the pancreas compared to metastatic sites (liver, omentum and bone). There is positive correlation between CD63 expression and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC.

Exosomal markers (CD63 and CD9) expression and their prognostic significance using immunohistochemistry in right-sided and left-sided colon cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 182-182
Author(s):  
Ben McCormick ◽  
Pranitha Prodduturvar ◽  
Wadad Mneimneh ◽  
Valeria Dal Zotto ◽  
Leander Grimm ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Staining Intensity ◽  
Normal Mucosa ◽  
Free Survival ◽  
Adjacent Normal Mucosa ◽  
The Mean ◽  
Cd63 Expression

182 Background: Exosomes play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are widely accepted exosomal markers. Their pattern of expression and prognostic significance in patients with RSCC and LSCC is unknown. This study explored CD63 and CD9 expression and prognostic significance in patients with RSCC and LSCC using immunohistochemistry (IHC). Methods: Between 2015 and 2018, 63 patients underwent surgical resection of colon cancer for whom we had available tissues for CD63 and CD9 IHC staining. Two pathologists independently scored the CD63 and CD9 expression in the tumor and adjacent normal mucosa (ANM). Staining intensity was graded 1-3 and staining percentage was estimated in 10% increments. Mean Quick-score (Q-score) (intensity X percentage of staining) was calculated. Results: RSCC and LSCC represented 52% and 48% of the patients respectively. The ANM and Tumor CD63 Q-scores were 225 vs 191 (p = 0.009) in RSCC and 224 vs 154 (p = 0.0001) in LSCC, respectively. The ANM and Tumor CD9 Q-scores were 134 vs 152 (p = 0.142) in RSCC and 135 vs 154 (p = 0.137) in LSCC, respectively. In patients with RSCC and LSCC, the mean Tumor CD63 Q-score was 191 vs 154 (p = 0.024), while the mean ANM CD63 Q-score was 225 vs 224 (p = 0.920). The mean Tumor CD9 Q-score was 152 and 154 (p = 0.883), and the mean ANM CD9 Q-score was 134 vs 135 (p = 0.926). In our cohort, there was no difference in progression free survival (PFS) between patients with RSCC and LSCC (p = 0.2349). In all patients, there was no difference in PFS in patients with CD63 expression < 100 and ≥100 (p = 0.8284). Among patients with RSCC, there was a significantly lower PFS in patients with CD63 expression < 100 vs. ≥100 (p = 0.0259). However, among patients with LSCC, there was no difference in PFS in patients with CD63 expression < 100 vs. ≥100 (p = 0.3494). Conclusions: To our knowledge, this is the first study to show a difference in exosomal marker (CD63) expression pattern and its prognostic significance in patients with RSCC and LSCC. There was a significant positive correlation between progression free survival in patients with RSCC and higher exosomal expression.

Prognostic Significance of Plasma Fibrinogen/Serum Albumin Ratio in the Postoperative Outcome of Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 40 (12) ◽  
pp. 7017-7023
Author(s):  
KOICHI TOMITA ◽  
SHIGETO OCHIAI ◽  
TAKAHIRO GUNJI ◽  
KOSUKE HIKITA ◽  
TOSHIMICHI KOBAYASHI ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Significance ◽  
Postoperative Outcome ◽  
Plasma Fibrinogen ◽  
Ductal Adenocarcinoma ◽  
Albumin Ratio

scholarly journals Discovering key transcriptomic regulators in pancreatic ductal adenocarcinoma using Dirichlet process Gaussian mixture model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sk Md Mosaddek Hossain ◽  
Aanzil Akram Halsana ◽  
Lutfunnesa Khatun ◽  
Sumanta Ray ◽  
Anirban Mukhopadhyay
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Mixture Model ◽  
Cancer Progression ◽  
Dirichlet Process ◽  
Network Inference ◽  
Correlation Method ◽  
Gaussian Mixture ◽  
Ductal Adenocarcinoma ◽  
Gene Regulatory Network Inference ◽  
Gene Modules

AbstractPancreatic Ductal Adenocarcinoma (PDAC) is the most lethal type of pancreatic cancer, late detection leading to its therapeutic failure. This study aims to determine the key regulatory genes and their impacts on the disease’s progression, helping the disease’s etiology, which is still mostly unknown. We leverage the landmark advantages of time-series gene expression data of this disease and thereby identified the key regulators that capture the characteristics of gene activity patterns in the cancer progression. We have identified the key gene modules and predicted the functions of top genes from a reconstructed gene association network (GAN). A variation of the partial correlation method is utilized to analyze the GAN, followed by a gene function prediction task. Moreover, we have identified regulators for each target gene by gene regulatory network inference using the dynamical GENIE3 (dynGENIE3) algorithm. The Dirichlet process Gaussian process mixture model and cubic spline regression model (splineTimeR) are employed to identify the key gene modules and differentially expressed genes, respectively. Our analysis demonstrates a panel of key regulators and gene modules that are crucial for PDAC disease progression.

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 Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 22 (10) ◽  
pp. 5138
Author(s):  
Aditi Kothari ◽  
Matthew J. Flick
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Reciprocal Relationship ◽  
Coagulation System ◽  
Ductal Adenocarcinoma ◽  
Protease Activated Receptors ◽  
Major Mechanism ◽  
Signaling Axis ◽  
Venous Thromboembolic

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a 5-year survival rate of less than 10% following diagnosis. The aggressive and invasive properties of pancreatic cancer tumors coupled with poor diagnostic options contribute to the high mortality rate since most patients present with late-stage disease. Accordingly, PDAC is linked to the highest rate of cancer-associated venous thromboembolic disease of all solid tumor malignancies. However, in addition to promoting clot formation, recent studies suggest that the coagulation system in PDAC mediates a reciprocal relationship, whereby coagulation proteases and receptors promote PDAC tumor progression and dissemination. Here, upregulation of tissue factor (TF) by tumor cells can drive local generation of the central coagulation protease thrombin that promotes cell signaling activity through protease-activated receptors (PARs) expressed by both tumor cells and multiple stromal cell subsets. Moreover, the TF-thrombin-PAR1 signaling axis appears to be a major mechanism of cancer progression in general and PDAC in particular. Here, we summarize the current literature regarding the role of PAR1 in PDAC and review possibilities for pharmacologically targeting PAR1 as a PDAC therapeutic approach.

scholarly journals GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jung Hyun Jo ◽  
Sun A Kim ◽  
Jeong Hoon Lee ◽  
Yu Rang Park ◽  
Chanyang Kim ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Progression ◽  
Biomarker Discovery ◽  
Disease Free Survival ◽  
Tumor Formation ◽  
Ductal Adenocarcinoma ◽  
Curative Surgery ◽  
In Vitro Proliferation

Abstract Background Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

scholarly journals Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

2018 ◽  
Vol 115 (16) ◽  
pp. E3769-E3778 ◽  
Author(s):  
Carlos A. Orozco ◽  
Neus Martinez-Bosch ◽  
Pedro E. Guerrero ◽  
Judith Vinaixa ◽  
Tomás Dalotto-Moreno ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Pancreatic Tumor ◽  
Therapeutic Potential ◽  
Tumor Formation ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Regulatory Pathways

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

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