Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer

Research output: Contribution to journalArticle

Michael John Sax, Christin Gasch, Vineel Rag Athota, Ruth Freeman, Parisa Rasighaemi, David Elton Westcott, Christopher John Day, Iva Nikolic, Benjamin Elsworth, Ming Wei, Kelly Rogers, Alexander Swarbrick, Vivek Mittal, Normand Pouliot, Albert Sleiman Mellick

It has recently been suggested that the chemokine receptor (CCR5) is required for bone marrow (BM) derived endothelial progenitor cell (EPC) mediated angiogenesis. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the BM alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in EPC biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma. In support of this hypothesis, we have also shown: (i) that endothelial cell CCR5 levels increases in response to tumorconditioned media; (ii) that the amount of CCR5+ tumor vasculature correlates with invasive grade; and (iii) that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole, this work demonstrates that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer.

Original languageEnglish (US)
Pages (from-to)85437-85449
Number of pages13
JournalOncotarget
Volume7
Issue number51
DOIs
StatePublished - 2016

PMID: 27863423

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Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer. / Sax, Michael John; Gasch, Christin; Athota, Vineel Rag; Freeman, Ruth; Rasighaemi, Parisa; Westcott, David Elton; Day, Christopher John; Nikolic, Iva; Elsworth, Benjamin; Wei, Ming; Rogers, Kelly; Swarbrick, Alexander; Mittal, Vivek; Pouliot, Normand; Mellick, Albert Sleiman.

In: Oncotarget, Vol. 7, No. 51, 2016, p. 85437-85449.

Research output: Contribution to journalArticle

Harvard

Sax, MJ, Gasch, C, Athota, VR, Freeman, R, Rasighaemi, P, Westcott, DE, Day, CJ, Nikolic, I, Elsworth, B, Wei, M, Rogers, K, Swarbrick, A, Mittal, V, Pouliot, N & Mellick, AS 2016, 'Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer' Oncotarget, vol. 7, no. 51, pp. 85437-85449. https://doi.org/10.18632/oncotarget.13387

APA

Sax, M. J., Gasch, C., Athota, V. R., Freeman, R., Rasighaemi, P., Westcott, D. E., ... Mellick, A. S. (2016). Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer. Oncotarget, 7(51), 85437-85449. https://doi.org/10.18632/oncotarget.13387

Vancouver

Sax MJ, Gasch C, Athota VR, Freeman R, Rasighaemi P, Westcott DE et al. Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer. Oncotarget. 2016;7(51):85437-85449. https://doi.org/10.18632/oncotarget.13387

Author

Sax, Michael John ; Gasch, Christin ; Athota, Vineel Rag ; Freeman, Ruth ; Rasighaemi, Parisa ; Westcott, David Elton ; Day, Christopher John ; Nikolic, Iva ; Elsworth, Benjamin ; Wei, Ming ; Rogers, Kelly ; Swarbrick, Alexander ; Mittal, Vivek ; Pouliot, Normand ; Mellick, Albert Sleiman. / Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer. In: Oncotarget. 2016 ; Vol. 7, No. 51. pp. 85437-85449.

BibTeX

@article{ceedabde999e41ef984a7928748c00f0,
title = "Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer",
abstract = "It has recently been suggested that the chemokine receptor (CCR5) is required for bone marrow (BM) derived endothelial progenitor cell (EPC) mediated angiogenesis. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the BM alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in EPC biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma. In support of this hypothesis, we have also shown: (i) that endothelial cell CCR5 levels increases in response to tumorconditioned media; (ii) that the amount of CCR5+ tumor vasculature correlates with invasive grade; and (iii) that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole, this work demonstrates that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer.",
keywords = "Angiogenesis, Breast cancer, CCL5, CCR5, ShRNAi",
author = "Sax, {Michael John} and Christin Gasch and Athota, {Vineel Rag} and Ruth Freeman and Parisa Rasighaemi and Westcott, {David Elton} and Day, {Christopher John} and Iva Nikolic and Benjamin Elsworth and Ming Wei and Kelly Rogers and Alexander Swarbrick and Vivek Mittal and Normand Pouliot and Mellick, {Albert Sleiman}",
year = "2016",
doi = "10.18632/oncotarget.13387",
language = "English (US)",
volume = "7",
pages = "85437--85449",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "51",

}

RIS

TY - JOUR

T1 - Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer

AU - Sax, Michael John

AU - Gasch, Christin

AU - Athota, Vineel Rag

AU - Freeman, Ruth

AU - Rasighaemi, Parisa

AU - Westcott, David Elton

AU - Day, Christopher John

AU - Nikolic, Iva

AU - Elsworth, Benjamin

AU - Wei, Ming

AU - Rogers, Kelly

AU - Swarbrick, Alexander

AU - Mittal, Vivek

AU - Pouliot, Normand

AU - Mellick, Albert Sleiman

PY - 2016

Y1 - 2016

N2 - It has recently been suggested that the chemokine receptor (CCR5) is required for bone marrow (BM) derived endothelial progenitor cell (EPC) mediated angiogenesis. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the BM alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in EPC biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma. In support of this hypothesis, we have also shown: (i) that endothelial cell CCR5 levels increases in response to tumorconditioned media; (ii) that the amount of CCR5+ tumor vasculature correlates with invasive grade; and (iii) that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole, this work demonstrates that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer.

AB - It has recently been suggested that the chemokine receptor (CCR5) is required for bone marrow (BM) derived endothelial progenitor cell (EPC) mediated angiogenesis. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the BM alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in EPC biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma. In support of this hypothesis, we have also shown: (i) that endothelial cell CCR5 levels increases in response to tumorconditioned media; (ii) that the amount of CCR5+ tumor vasculature correlates with invasive grade; and (iii) that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole, this work demonstrates that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer.

KW - Angiogenesis

KW - Breast cancer

KW - CCL5

KW - CCR5

KW - ShRNAi

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U2 - 10.18632/oncotarget.13387

DO - 10.18632/oncotarget.13387

M3 - Article

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ER -

ID: 38715196