Abstract
Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in USA and has one the lowest survival rates for solid cancers [1]
It must be noted that CA19-9 is not specific for pancreatic cancer alone, as it is expressed in some other cancers such as cholangiocarcinoma, and benign conditions such as cholangitis and chronic pancreatitis [10,11,12,13]
No clinically useful interventions to screen for patients with PDAC are available. The purpose of this project was to evaluate the protein expression profiles of pancreatic juice samples harvested from the pancreatic duct at the time of surgery to potentially identify unique markers that could be used to differentiate benign from malignant pancreatic masses and further delineate different grades of PDAC. 65 proteins were seen only in adenocarcinomas and 4 proteins were observed solely in the benign pancreatic masses
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in USA and has one the lowest survival rates for solid cancers [1]. Most patients diagnosed with pancreatic cancer die within 12 months, and only 4% survive 5 years after diagnosis. This is largely due to late presentation by affected patients, thereby making therapeutic intervention difficult [2]. Diagnosis of pancreatic cancer, including pre-neoplastic lesions (designated as pancreatic intraepithelial neoplasia or PanIN) in average-risk and high-risk patients is desperately needed to improve the survival rate of pancreatic cancer patients [3,4,5]. Carbohydrate antigen 19-9 (CA 19-9), known as sialylated Lewis (a) antigen is the only reliable and widely used biomarker for diagnosis of pancreatic cancer (sensitivity 70%, specificity 87%) [6,7]; its use is largely limited to following the course of disease [8,9]. Several approaches have been used to find candidate biomarker for pancreatic cancer to facilitate early diagnosis including microarrays and proteomics [14,15,16,17,18,19,20,21,22,23]
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