Abstract
SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.
Highlights
The extracellular matrix (ECM) provides both structural support and regulates cellular responses
We have shown that SMOC-1 and SMOC-2 are widely expressed in the pancreas, and that specific SMOC-1 isoforms are expressed in endothelial cells and βcells
Compared to other SPARC family proteins that we have shown to be highly expressed throughout islets and in βcells, FSTL-1 and SPARC are the only SPARC family proteins detected in stromal cells and not in βcells by western blotting and IHC
Summary
The extracellular matrix (ECM) provides both structural support and regulates cellular responses. Disruption of the basement membrane composition can lead to changes in apicobasal polarity and cause changes in cell shape and behavior This has been shown to drive increased cell proliferation and tumourigenesis[16,17,18]. Stromal cells such as stellate cells, fibroblasts, endothelial cells and macrophages produce ECM proteins and growth factors and cytokines that make up the extracellular environment. The regulation of cell growth and migration by the ECM and stromal cells underlies their important role in the progression of both pancreatic cancer and diabetes. Central to the regulation of ECM structure and cell-matrix interactions are non-structural matricellular proteins such as the SPARC family[22]. SPARC determines cell responses to the ECM and controls multiple pathways fundamental to cell growth and adhesion
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