Faculty Collaboration Database

Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma. Lab Invest 2017 Mar;97(3):302-317

Date

01/17/2017

Pubmed ID

28092365

Pubmed Central ID

PMC5334280

DOI

10.1038/labinvest.2016.146

Scopus ID

2-s2.0-85014533549 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

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.

Author List

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

Authors

Michael B. Dwinell PhD Center Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin
Emily Vonderhaar in the CTSI department at Medical College of Wisconsin - CTSI

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma, Pancreatic Ductal
Cell Line
Cell Line, Tumor
Cells, Cultured
Chemokines
Chemotaxis
Coculture Techniques
Enzyme-Linked Immunosorbent Assay
Epithelial Cells
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Mice
Pancreatic Neoplasms
Pancreatic Stellate Cells
Receptors, Chemokine
Reverse Transcriptase Polymerase Chain Reaction