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.
Loss of the extracellular matrix following enzyme harvest of islets for transplantation renders them susceptible to a new environment, and is hypothesized to contribute to decreased graft function and survival. The matrix provides structural support for islets as well as mediating growth factor and cytokine interactions. SPARC, or secreted protein acidic and rich in cysteine, is a collagen‐binding matricellular protein that plays a role in matrix assembly and regulates cellular responses to the extracellular environment. Our data shows that SPARC is expressed by stromal cells within islets, and that SPARC expression in these cells is regulated by metabolic factors. Furthermore, SPARC inhibits growth factor signalling in both beta cells and primary islet tissue. Our data suggests that understanding the effect of matricellular proteins will be necessary to create a matrix environment that supports islet expansion. We have developed a model in which matricellular protiens are incorporated into a 3D collagen matrix to test the effect of matricellular proteins on primary islet growth and survival.
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