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Roy I , Boyle KA , Vonderhaar EP , Zimmerman NP , Gorse E , Mackinnon AC , Hwang RF , Franco-Barraza J , Cukierman E , Tsai S , Evans DB , Dwinell MB
Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma
Lab Invest. 2017 Mar;97(3) :302-317
PMID: 28092365    PMCID: PMC5334280    URL: https://www.ncbi.nlm.nih.gov/pubmed/28092365
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The mechanisms by which the extreme desmoplasia observed in pancreatic tumors develops remain unknown and its role in pancreatic cancer progression is unsettled. Chemokines have a key role in the recruitment of a wide variety of cell types in health and disease. Transcript and protein profile analyses of human and murine cell lines and human tissue specimens revealed a consistent elevation in the receptors CCR10 and CXCR6, as well as their respective ligands CCL28 and CXCL16. Elevated ligand expression was restricted to tumor cells, whereas receptors were in both epithelial and stromal cells. Consistent with its regulation by inflammatory cytokines, CCL28 and CCR10, but not CXCL16 or CXCR6, were upregulated in human pancreatitis tissues. Cytokine stimulation of pancreatic cancer cells increased CCL28 secretion in epithelial tumor cells but not an immortalized activated human pancreatic stellate cell line (HPSC). Stellate cells exhibited dose- and receptor-dependent chemotaxis in response to CCL28. This functional response was not linked to changes in activation status as CCL28 had little impact on alpha smooth muscle actin levels or extracellular matrix deposition or alignment. Co-culture assays revealed CCL28-dependent chemotaxis of HPSC toward cancer but not normal pancreatic epithelial cells, consistent with stromal cells being a functional target for the epithelial-derived chemokine. These data together implicate the chemokine CCL28 in the inflammation-mediated recruitment of cancer-associated stellate cells into the pancreatic cancer parenchyma.Laboratory Investigation advance online publication, 16 January 2017; doi:10.1038/labinvest.2016.146.
1530-0307 Roy, Ishan Boyle, Kathleen A Vonderhaar, Emily P Zimmerman, Noah P Gorse, Egal Mackinnon, A Craig Hwang, Rosa F Franco-Barraza, Janusz Cukierman, Edna Tsai, Susan Evans, Douglas B Dwinell, Michael B P30 CA006927/CA/NCI NIH HHS/United States R01 CA113451/CA/NCI NIH HHS/United States T32 GM080202/GM/NIGMS NIH HHS/United States Journal Article United States Lab Invest. 2017 Jan 16. doi: 10.1038/labinvest.2016.146.