Abstract
The clinical management of pancreatic ductal adenocarcinoma (PDAC) is hampered by the lack of reliable biomarkers. This study investigated the value of soluble stroma‐related molecules as PDAC biomarkers. In the first exploratory phase, 12 out of 38 molecules were associated with PDAC in a cohort of 25 PDAC patients and 16 healthy subjects. A second confirmatory phase on an independent cohort of 131 PDAC patients, 30 chronic pancreatitis patients, and 131 healthy subjects confirmed the PDAC association for MMP7, CCN2, IGFBP2, TSP2, sICAM1, TIMP1, and PLG. Multivariable logistic regression model identified biomarker panels discriminating respectively PDAC versus healthy subjects (MMP7 + CA19.9, AUC = 0.99, 99% CI = 0.98–1.00) (CCN2 + CA19.9, AUC = 0.96, 99% CI = 0.92–0.99) and PDAC versus chronic pancreatitis (CCN2 + PLG+FN+Col4 + CA19.9, AUC = 0.94, 99% CI = 0.88–0.99). Five molecules were associated with PanIN development in two GEM models of PDAC (PdxCre/LSL‐KrasG12D and PdxCre/LSL‐KrasG12D/+/LSL‐Trp53R172H/+), suggesting their potential for detecting early disease. These markers were also elevated in patient‐derived orthotopic PDAC xenografts and associated with response to chemotherapy. The identified stroma‐related soluble biomarkers represent potential tools for PDAC diagnosis and for monitoring treatment response of PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive epithelial malignancies, with a 5-year survival rate of 6% (Tempero et al, 2013)
Tumor-stroma-associated pancreatic ductal adenocarcinoma (PDAC) biomarkers were selected from eight proteomic studies on circulating proteins that are differentially expressed in PDAC and healthy subjects (Yu et al, 2005; Bloomston et al, 2006; Faca et al, 2008; Kojima et al, 2008; Fiedler et al, 2009; Rong et al, 2010; Xue et al, 2010; Pan et al, 2011)
In accordance with the statistical procedure adopted, the resulting panel consisting of Mm.PT.58.30682575 (TIMP1); Mm.PT.58.8800692 (MMP7) and CA19.9 statistically better discriminated PDAC versus healthy subjects with an Areas under the curve (AUC) of 0.99 compared with CA19.9 (AUC = 0.87, 99% CI = 0.81–0.93)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive epithelial malignancies, with a 5-year survival rate of 6% (Tempero et al, 2013). Progression from tumor initiation to advanced invasive cancer may take up to about 10 years (Yachida et al, 2010), PDAC is often diagnosed at an advanced stage, because of non-specific symptomatology, the absence of effective imaging tests to identify early disease, and the lack of specific and sensitive diagnostic circulating biomarkers (Korc, 2007). The biomarker CA19.9, currently used to detect and monitor PDAC, is not sufficiently sensitive and specific to have reliable diagnostic value. It is not expressed in approximately 20% of the Lewis antigen-negative population. Recent proteomic studies have identified circulating molecules or autoantibodies that are up-regulated in PDAC, but few have been investigated further as a serological diagnostic or prognostic biomarker for the disease (Brand et al, 2011; Capello et al, 2013, 2017; Chan et al, 2014; Shaw et al, 2014; Zhang et al, 2014; Balasenthil et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
