Abstract
BackgroundStromal fibroblasts associated with pancreatic ductal adenocarcinoma (PDAC) play an important role in tumor progression through interactions with cancer cells. Our proposed combination strategies of in vitro and in silico biomarker screening through a cancer-stromal interaction model were previously identified several actin-binding proteins in human colon cancer stroma. The main aim of the present study was to identify novel prognostic markers in human PDAC stroma using our strategies.MethodsFive primary cultivated fibroblasts from human pancreas were stimulated by two types of pancreatic cancer-cell-conditioned medium (Capan-1 and MIA PaCa-2) followed by gene expression analysis to identify up-regulated genes. Publicly available microarray data set concomitant with overall survival was collected and prognostic marker candidates were selected among the genes that were found to be up-regulated. The mRNA expression levels of the selected genes were evaluated in 5 human fresh PDAC tissues. Finally, survival analysis was performed based on immunohistochemical results on tissue microarrays consisting of 216 surgically resected PDAC tissues.ResultsThe microarray data of the cancer-stromal interaction model revealed that 188 probes were significantly regulated in pancreatic fibroblasts. Further, six genes were selected using publicly available microarray data set, and a single Diaphanous-related formin-3 (DIAPH3), actin-binding protein, was identified as a stromal biomarker in PDAC fibroblasts by RNA validation analysis. DIAPH3 exhibited strong immunohistochemical expression in stromal fibroblasts. The high stromal expression of DIAPH3 was associated with shorter survival times of PDAC patients.ConclusionsDIAPH3 was identified as a prognostic marker in PDAC fibroblasts using our biomarker screening strategies through the cancer-stromal interaction model, indicating that stromal actin-binding proteins might have an important biological role in cancer progression. These strategies were also available in PDAC, and can be used for stromal biomarker screening in various cancers.
Highlights
Stromal fibroblasts associated with pancreatic ductal adenocarcinoma (PDAC) play an important role in tumor progression through interactions with cancer cells
Gene expression data concomitant with overall survival (OS) in PDAC was collected from The Cancer Genome Atlas (TCGA) and prognostic marker candidates were selected among the genes that were found to be up-regulated
Expression of selected genes in human pancreas and pancreas cancer tissue The mRNA expression levels of BRIP1, Diaphanous-related formin-3 (DIAPH3), MCM8, WDHD1, and GAPDH were evaluated by Real-time quantitative PCR (qRT-PCR) in the PDAC and non-PDAC tissues of five resected specimens (Fig. 3a, b, c, d)
Summary
Stromal fibroblasts associated with pancreatic ductal adenocarcinoma (PDAC) play an important role in tumor progression through interactions with cancer cells. The main aim of the present study was to identify novel prognostic markers in human PDAC stroma using our strategies. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor clinical prognosis. Despite the recent advances in the cancer treatments, the prognosis of PDAC remains poor. Pancreatic fibroblasts were activated through the interaction with cancer cells and played a major role in PDAC progression. Reciprocal interactions between cancer and stromal cells enhanced the metastatic potential and therapeutic resistance to treatments [3,4,5]. Stromal components, especially fibroblasts in PDAC gathered a lot of attention as potential therapeutic targets [6]
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.
