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  • Extracellular Matrix Composition Significantly Influences Pancreatic Stellate Cell (PSC) Gene Expression Pattern: Role of Transgelin in PSC Function.
    (2013) Apte, Minoti; Yang, Lu; Phillips, Phoebe; Xu, Zhihong; Kaplan, Warren; Cowley, Mark
    Journal Article
    Activated pancreatic stellate cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs cultured on plastic, a non-physiological surface. However, PSCs cultured on physiological matrices e.g. MatrigelTM (normal basement membrane) and collagen (fibrotic pancreas), may have distinctly different behaviours compared to cells cultured on plastic. Therefore, we aimed to i) compare PSC gene expression after culture on plastic, MatrigelTM and collagen I; ii) validate the gene array data for transgelin, the most highly dysregulated gene in PSCs grown on activating versus non-activating matrices, at mRNA and protein levels; iii) examine the role of transgelin in PSC function; and iv) assess transgelin expression in human chronic pancreatitis sections. Culture of PSCs on different matrices significantly affected their gene expression pattern. 146, 619 and 432 genes respectively were differentially expressed (p < 0.001) in PSCs cultured on collagen I vs MatrigelTM, MatrigelTM vs plastic and collagen I vs plastic. The highest fold change (12.5 fold upregulation) in gene expression in cells on collagen I vs MatrigelTM, was observed for transgelin (an actin stress fibre associated protein). Transgelin was significantly increased in activated PSCs versus quiescent PSCs. Silencing transgelin expression decreased PSC proliferation and also reduced platelet derived growth factor (PDGF)-induced PSC migration. Notably, transgelin was highly expressed in chronic pancreatitis in stromal areas and peri-acinar spaces but was absent in acinar cells. These findings suggest that transgelin is a potentially useful target protein to modulate PSC function so as to ameliorate pancreatic fibrosis.
  • Role of Pancreatic Stellate Cells in Pancreatic Cancer Metastasis
    (2010) Xu, Zhihong; Vonlaufen, Alain; Phillips, Phoebe; Fiala-Beer, Eva; Zhang, Xuguo; Yang, Lu; Biankin, Andrew; Goldstein, David; Pirola, Romano; Wilson, Jeremy; Apte, Minoti
    Recorded/Rendered Creative Work
    ABSTRACT Pancreatic stellate cells (PSCs) produce the stromal reaction of pancreatic cancer (PC) and their interaction with cancer cells facilitates cancer progression. This study investigated the role of human PSCs (hPSCs) in the metastatic process and tumor angiogenesis using an in vivo (orthotopic model) and in vitro (cultured PSC and PC cells) approach. A gender mismatch study [injection of male hPSCs + female PC cells into the pancreas of female mice] was conducted to determine whether hPSCs accompany cancer cells to metastatic sites. Metastatic nodules were examined by fluorescent in situ hybridization for the presence of the y chromosome. Angiogenesis was assessed by i) immunostaining tumors for CD31, an endothelial cell marker; and ii) in vitro quantifying human microvascular endothelial cell (HMEC-1) tube formation upon exposure to conditioned media from hPSCs. Transendothelial migration was assessed by examining the movement of fluorescently labeled hPSCs through an endothelial cell monolayer. Human PSCs i) were found in multiple metastatic sites in each mouse injected with male hPSCs + female PC cells; ii) increased CD31 expression in primary tumors from mice injected with MiaPaCa-2 and hPSCs and stimulated tube formation by HMEC-1 in vitro; iii) exhibited transendothelial migration which was stimulated by cancer cells. Human PSCs accompany cancer cells to metastatic sites, stimulate angiogenesis and have the capacity to intravasate/extravasate to and from blood vessels.