TGF-β1 activates neutrophil signaling and gene expression but not migration.
Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. The presence of transforming growth factor-beta (TGF-β) in the tumor microenvironment reportedly contributes to the skewing of neutrophils to a more pro-tumor phenotype. The effe...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0290886 |
| _version_ | 1797686784611581952 |
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| author | Lauren E Hein Shuvasree SenGupta Gaurie Gunasekaran Craig N Johnson Carole A Parent |
| author_facet | Lauren E Hein Shuvasree SenGupta Gaurie Gunasekaran Craig N Johnson Carole A Parent |
| author_sort | Lauren E Hein |
| collection | DOAJ |
| description | Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. The presence of transforming growth factor-beta (TGF-β) in the tumor microenvironment reportedly contributes to the skewing of neutrophils to a more pro-tumor phenotype. The effects of TGF-β on neutrophil signaling and migration are, however, unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether it directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil chemotaxis in transwell or underagarose migration assays. TGF-β1 does activate canonical signaling through SMAD3 and noncanonical signaling through ERK1/2 in neutrophils in a time- and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) of invasive breast cancer cells results in SMAD3 activation. We discovered that TCM induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying the range of neutrophil recruitment. However, TGF-β1 alone does not induce secretion of LTB4. RNA-sequencing revealed that TGF-β1 and TCM alter gene expression in HL-60 cells, including the mRNA levels of the pro-tumor oncostatin M (OSM) and vascular endothelial growth factor A (VEGFA). These new insights into the role and impact of TGF-β1 on neutrophil signaling, migration, and gene expression have significant implications in the understanding of the changes in neutrophils that occur in the tumor microenvironment. |
| first_indexed | 2024-03-12T01:09:49Z |
| format | Article |
| id | doaj.art-6c3acf28cd5046ffb7d7eb184c1ba6ff |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-12T01:09:49Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6c3acf28cd5046ffb7d7eb184c1ba6ff2023-09-14T05:31:36ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01189e029088610.1371/journal.pone.0290886TGF-β1 activates neutrophil signaling and gene expression but not migration.Lauren E HeinShuvasree SenGuptaGaurie GunasekaranCraig N JohnsonCarole A ParentTumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. The presence of transforming growth factor-beta (TGF-β) in the tumor microenvironment reportedly contributes to the skewing of neutrophils to a more pro-tumor phenotype. The effects of TGF-β on neutrophil signaling and migration are, however, unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether it directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil chemotaxis in transwell or underagarose migration assays. TGF-β1 does activate canonical signaling through SMAD3 and noncanonical signaling through ERK1/2 in neutrophils in a time- and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) of invasive breast cancer cells results in SMAD3 activation. We discovered that TCM induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying the range of neutrophil recruitment. However, TGF-β1 alone does not induce secretion of LTB4. RNA-sequencing revealed that TGF-β1 and TCM alter gene expression in HL-60 cells, including the mRNA levels of the pro-tumor oncostatin M (OSM) and vascular endothelial growth factor A (VEGFA). These new insights into the role and impact of TGF-β1 on neutrophil signaling, migration, and gene expression have significant implications in the understanding of the changes in neutrophils that occur in the tumor microenvironment.https://doi.org/10.1371/journal.pone.0290886 |
| spellingShingle | Lauren E Hein Shuvasree SenGupta Gaurie Gunasekaran Craig N Johnson Carole A Parent TGF-β1 activates neutrophil signaling and gene expression but not migration. PLoS ONE |
| title | TGF-β1 activates neutrophil signaling and gene expression but not migration. |
| title_full | TGF-β1 activates neutrophil signaling and gene expression but not migration. |
| title_fullStr | TGF-β1 activates neutrophil signaling and gene expression but not migration. |
| title_full_unstemmed | TGF-β1 activates neutrophil signaling and gene expression but not migration. |
| title_short | TGF-β1 activates neutrophil signaling and gene expression but not migration. |
| title_sort | tgf β1 activates neutrophil signaling and gene expression but not migration |
| url | https://doi.org/10.1371/journal.pone.0290886 |
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