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CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis

Compelling evidence shows that chemokine CXCL12 drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer...

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Autores principales: Ray, Paramita, Stacer, Amanda C., Fenner, Joseph, Cavnar, Stephen P., Meguiar, Kaille, Brown, Martha, Luker, Kathryn E., Luker, Gary D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261050/
https://www.ncbi.nlm.nih.gov/pubmed/24909174
http://dx.doi.org/10.1038/onc.2014.157
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author Ray, Paramita
Stacer, Amanda C.
Fenner, Joseph
Cavnar, Stephen P.
Meguiar, Kaille
Brown, Martha
Luker, Kathryn E.
Luker, Gary D.
author_facet Ray, Paramita
Stacer, Amanda C.
Fenner, Joseph
Cavnar, Stephen P.
Meguiar, Kaille
Brown, Martha
Luker, Kathryn E.
Luker, Gary D.
author_sort Ray, Paramita
collection PubMed
description Compelling evidence shows that chemokine CXCL12 drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, β, and γ showed cell-type specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. While all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL, contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways.
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spelling pubmed-42610502015-10-16 CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis Ray, Paramita Stacer, Amanda C. Fenner, Joseph Cavnar, Stephen P. Meguiar, Kaille Brown, Martha Luker, Kathryn E. Luker, Gary D. Oncogene Article Compelling evidence shows that chemokine CXCL12 drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, β, and γ showed cell-type specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. While all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL, contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways. 2014-06-09 2015-04-16 /pmc/articles/PMC4261050/ /pubmed/24909174 http://dx.doi.org/10.1038/onc.2014.157 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ray, Paramita
Stacer, Amanda C.
Fenner, Joseph
Cavnar, Stephen P.
Meguiar, Kaille
Brown, Martha
Luker, Kathryn E.
Luker, Gary D.
CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
title CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
title_full CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
title_fullStr CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
title_full_unstemmed CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
title_short CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
title_sort cxcl12-γ in primary tumors drives breast cancer metastasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261050/
https://www.ncbi.nlm.nih.gov/pubmed/24909174
http://dx.doi.org/10.1038/onc.2014.157
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