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CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One 2014;9(3):e90400

Date

03/07/2014

Pubmed ID

24594697

Pubmed Central ID

PMC3942415

DOI

10.1371/journal.pone.0090400

Scopus ID

2-s2.0-84897093538   62 Citations

Abstract

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

Author List

Roy I, Zimmerman NP, Mackinnon AC, Tsai S, Evans DB, Dwinell MB

Authors

Michael B. Dwinell PhD 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
Susan Tsai MD Professor in the Surgery department at Medical College of Wisconsin




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

Animals
Anoikis
Carcinoma, Pancreatic Ductal
Cell Adhesion
Cell Line, Tumor
Cell Proliferation
Chemokine CXCL12
Chemotaxis
Disease Models, Animal
Epigenesis, Genetic
Epithelium
Gene Expression Regulation, Neoplastic
Humans
Ligands
Mice, SCID
Neoplasm Metastasis
Pancreatic Neoplasms
Receptors, CXCR
Receptors, CXCR4
Survival Analysis
Transfection
Xenograft Model Antitumor Assays