CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis

Ishan Roy, Noah P. Zimmerman, A. Craig Mackinnon, Susan Tsai, Douglas B. Evans, Michael B. Dwinell

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere90400
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 4 2014
Externally publishedYes

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Chemokine CXCL12
pancreatic neoplasms
Pancreatic Neoplasms
metastasis
Tumors
Neoplasm Metastasis
neoplasms
Cells
Growth
cell lines
chemokines
Neoplasms
Chemokines
Ducts
pancreatic ducts
suppressor cells
Cell Line
Chemokine Receptors
Medical problems
adenocarcinoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Roy, I., Zimmerman, N. P., Mackinnon, A. C., Tsai, S., Evans, D. B., & Dwinell, M. B. (2014). CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One, 9(3), [e90400]. https://doi.org/10.1371/journal.pone.0090400

CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. / Roy, Ishan; Zimmerman, Noah P.; Mackinnon, A. Craig; Tsai, Susan; Evans, Douglas B.; Dwinell, Michael B.

In: PLoS One, Vol. 9, No. 3, e90400, 04.03.2014.

Research output: Contribution to journalArticle

Roy, I, Zimmerman, NP, Mackinnon, AC, Tsai, S, Evans, DB & Dwinell, MB 2014, 'CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis', PLoS One, vol. 9, no. 3, e90400. https://doi.org/10.1371/journal.pone.0090400
Roy I, Zimmerman NP, Mackinnon AC, Tsai S, Evans DB, Dwinell MB. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One. 2014 Mar 4;9(3). e90400. https://doi.org/10.1371/journal.pone.0090400
Roy, Ishan ; Zimmerman, Noah P. ; Mackinnon, A. Craig ; Tsai, Susan ; Evans, Douglas B. ; Dwinell, Michael B. / CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. In: PLoS One. 2014 ; Vol. 9, No. 3.
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