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CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis
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 p...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942415/ https://www.ncbi.nlm.nih.gov/pubmed/24594697 http://dx.doi.org/10.1371/journal.pone.0090400 |
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author | Roy, Ishan Zimmerman, Noah P. Mackinnon, A. Craig Tsai, Susan Evans, Douglas B. Dwinell, Michael B. |
author_facet | Roy, Ishan Zimmerman, Noah P. Mackinnon, A. Craig Tsai, Susan Evans, Douglas B. Dwinell, Michael B. |
author_sort | Roy, Ishan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3942415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39424152014-03-06 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. PLoS One Research Article 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. Public Library of Science 2014-03-04 /pmc/articles/PMC3942415/ /pubmed/24594697 http://dx.doi.org/10.1371/journal.pone.0090400 Text en © 2014 Roy et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article 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 |
title | CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis |
title_full | CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis |
title_fullStr | CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis |
title_full_unstemmed | CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis |
title_short | CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis |
title_sort | cxcl12 chemokine expression suppresses human pancreatic cancer growth and metastasis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942415/ https://www.ncbi.nlm.nih.gov/pubmed/24594697 http://dx.doi.org/10.1371/journal.pone.0090400 |
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