Abstract
The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with 5-year survival rates of roughly 8% [1]
The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA are small non-coding RNAs that regulate gene expression
MiRNA expression differs between cultured PC and TAS cells miRNA expression patterns of pancreatic cancer cell lines have been previously described [19, 20], yet a comprehensive data set describing miRNA expression in TAS cells is lacking
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with 5-year survival rates of roughly 8% [1]. Perhaps the most distinguishing histological characteristic of PDAC is the development of a fibrotic tumor-associated stroma (TAS) that integrates into the malignant epithelial compartment [2]. Numerous reports support the notion that TAS strongly contributes to the malignant phenotype of PDAC. TAS participates in critical paracrine signaling loops that promote PDAC cell survival, therapeutic resistance and metastasis [3]. TAS produces the dense extracellular matrix characteristic of PDAC, acting as a physical obstruction to infiltrating immune elements and the diffusion of chemotherapies [4, 5]. TAS depletion strategies were unsuccessful in clinical trials and may even accelerate PDAC progression in pre-clinical models [6]. The impact of TAS on PDAC within the tumor microenvironment remains controversial
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.
