Tumor-Derived Pancreatic Stellate Cells Promote Pancreatic Cancer Cell Invasion Through Release of Thrombospondin-2

Background: Tumor derived pancreatic stellate cells (TDPS) cells are key cellular components of the pancreatic tumor microenvironment. These stellate cells can release growth factors, proteases, and extracellular matrix proteins that may stimulate the spread of pancreatic cancer. We sought to determine whether TDPS cells promote the local invasion of pancreatic cancer cells and mechanisms involved. Methods: TDPS and panc-1 cells were grown in coculture to determine directional migration and panc-1 invasiveness was quantified using Matrigel invasion chambers, comparing TDPS cells to human foreskin fibroblasts (HFFs). ELISA was used to determine the secretion of growth factors, proteases, and extracellular matrix proteins from TDPS cells and HFFs, and then siRNAs used to knockdown expression of factors. Results: In coculture panc-1 cells migrate toward TDPS cells, creating nests of cancer cells within the stromal cells. TDPS cells promote the invasion of panc-1 cells and release thrombospondin 2 (TSP-2), whereas HFFs did not. When TSP-2 expression is reduced in TDPS cells using selective siRNAs, pancreatic cancer cell invasion was inhibited. Conclusion: Tumor-derived pancreatic stellate cells stimulate pancreatic cancer cell invasion, likely through release of TSP-2. Targeting pro-invasive elements, such as TSP-2, within the tumor microenvironment may inhibit local invasion, thus permitting more patients to undergo curative resection of pancreatic cancer. [Copyright &y& Elsevier]