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PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases
Phospholipase D-2 (PLD2) has a key role in breast cancer formation and metastasis formation with PLD small inhibitors reducing primary tumor growth. This study aimed to evaluate the importance of targeting PLD on the tumor microenvironment. We provide evidence about the beneficial effect of PLD inhi...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112812/ https://www.ncbi.nlm.nih.gov/pubmed/27851813 http://dx.doi.org/10.1371/journal.pone.0166553 |
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author | Henkels, Karen M. Muppani, Naveen Reddy Gomez-Cambronero, Julian |
author_facet | Henkels, Karen M. Muppani, Naveen Reddy Gomez-Cambronero, Julian |
author_sort | Henkels, Karen M. |
collection | PubMed |
description | Phospholipase D-2 (PLD2) has a key role in breast cancer formation and metastasis formation with PLD small inhibitors reducing primary tumor growth. This study aimed to evaluate the importance of targeting PLD on the tumor microenvironment. We provide evidence about the beneficial effect of PLD inhibitors [FIPI (dual PLD1/PLD2) or VU0155072-2 (PLD2 inhibitor)] on avoiding infiltration of tumor-helping macrophages and neutrophils. Tumor growth and metastasis within the primary tumors had low (<20% over controls) PLD enzyme activity. Unexpectedly, we found that the inhibitors also affected PLD2 gene expression and protein albeit at a lesser extent. The later could indicate that targeting both the actual PLD enzyme and its activity could be beneficial for potential cancer treatments in vivo. F4/80 and Ly6G staining of macrophages and neutrophils, respectively, and Arg1 staining data were consistent with M2 and N2 polarization. NOS2 staining increased in xenotransplants upon treatment with PLD2 inhibitors suggesting the novel observation that an increased recruitment of M1 macrophages occurred in primary tumors. PLD inhibitor-treated primary tumors had large, fragile, necrotic areas that were Arg1(+) for M2 macrophages. The xenotransplants also caused the formation of large F4/80(+) and Ly6G(+) (>100 μm) clusters in lungs. However, PLD inhibitors, particularly FIPI, were able to diminish leukocyte presence. Ex vivo chemotaxis and PLD activity of peripheral blood neutrophils (PMN) and peritoneal macrophages was also determined. Whereas PMN had impaired functionality, macrophages did not. This significantly increased (“emboldened”) macrophage function was due to PLD inhibition. Since tumor-associated leukocytes in primary tumors and metastases were targeted via PLD inhibition, we posit that these inhibitors have a key role in cancer regression, while still affording an appropriate inflammatory response at least from off-site innate immunity macrophages. |
format | Online Article Text |
id | pubmed-5112812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-51128122016-12-08 PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases Henkels, Karen M. Muppani, Naveen Reddy Gomez-Cambronero, Julian PLoS One Research Article Phospholipase D-2 (PLD2) has a key role in breast cancer formation and metastasis formation with PLD small inhibitors reducing primary tumor growth. This study aimed to evaluate the importance of targeting PLD on the tumor microenvironment. We provide evidence about the beneficial effect of PLD inhibitors [FIPI (dual PLD1/PLD2) or VU0155072-2 (PLD2 inhibitor)] on avoiding infiltration of tumor-helping macrophages and neutrophils. Tumor growth and metastasis within the primary tumors had low (<20% over controls) PLD enzyme activity. Unexpectedly, we found that the inhibitors also affected PLD2 gene expression and protein albeit at a lesser extent. The later could indicate that targeting both the actual PLD enzyme and its activity could be beneficial for potential cancer treatments in vivo. F4/80 and Ly6G staining of macrophages and neutrophils, respectively, and Arg1 staining data were consistent with M2 and N2 polarization. NOS2 staining increased in xenotransplants upon treatment with PLD2 inhibitors suggesting the novel observation that an increased recruitment of M1 macrophages occurred in primary tumors. PLD inhibitor-treated primary tumors had large, fragile, necrotic areas that were Arg1(+) for M2 macrophages. The xenotransplants also caused the formation of large F4/80(+) and Ly6G(+) (>100 μm) clusters in lungs. However, PLD inhibitors, particularly FIPI, were able to diminish leukocyte presence. Ex vivo chemotaxis and PLD activity of peripheral blood neutrophils (PMN) and peritoneal macrophages was also determined. Whereas PMN had impaired functionality, macrophages did not. This significantly increased (“emboldened”) macrophage function was due to PLD inhibition. Since tumor-associated leukocytes in primary tumors and metastases were targeted via PLD inhibition, we posit that these inhibitors have a key role in cancer regression, while still affording an appropriate inflammatory response at least from off-site innate immunity macrophages. Public Library of Science 2016-11-16 /pmc/articles/PMC5112812/ /pubmed/27851813 http://dx.doi.org/10.1371/journal.pone.0166553 Text en © 2016 Henkels 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Henkels, Karen M. Muppani, Naveen Reddy Gomez-Cambronero, Julian PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases |
title | PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases |
title_full | PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases |
title_fullStr | PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases |
title_full_unstemmed | PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases |
title_short | PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases |
title_sort | pld-specific small-molecule inhibitors decrease tumor-associated macrophages and neutrophils infiltration in breast tumors and lung and liver metastases |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112812/ https://www.ncbi.nlm.nih.gov/pubmed/27851813 http://dx.doi.org/10.1371/journal.pone.0166553 |
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