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Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment

BACKGROUND: Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood. METHODS: The expression of PKD, mast...

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Autores principales: Xu, Wanfu, Qian, Jiabi, Zeng, Fangyin, Li, Songyu, Guo, Wenjing, Chen, Liping, Li, Guihuan, Zhang, Zhishuai, Wang, Qiming Jane, Deng, Fan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404326/
https://www.ncbi.nlm.nih.gov/pubmed/30841931
http://dx.doi.org/10.1186/s13046-019-1118-y
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author Xu, Wanfu
Qian, Jiabi
Zeng, Fangyin
Li, Songyu
Guo, Wenjing
Chen, Liping
Li, Guihuan
Zhang, Zhishuai
Wang, Qiming Jane
Deng, Fan
author_facet Xu, Wanfu
Qian, Jiabi
Zeng, Fangyin
Li, Songyu
Guo, Wenjing
Chen, Liping
Li, Guihuan
Zhang, Zhishuai
Wang, Qiming Jane
Deng, Fan
author_sort Xu, Wanfu
collection PubMed
description BACKGROUND: Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood. METHODS: The expression of PKD, mast cells and microvessel density were examined by IHC. The clinical significance was determined by statistical analyses. The biological function of PKD and the underlying mechanisms were investigated using in vitro and in vivo models. RESULTS: PKD2/3 contributed to MCs recruitment and tumor angiogenesis in the prostate cancer microenvironment. Clinical data showed that increased activation of PKD at Ser744/748 in prostate cancer was correlated with mast cell infiltration and microvascular density. PKD2/3 silencing of prostate cancer cells markedly decreased MCs migration and tube formation of HUVEC cells. Moreover, PKD2/3 depletion not only reduced SCF, CCL5 and CCL11 expression in prostate cancer cells but also inhibited angiogenic factors in MCs. Conversely, exogenous SCF, CCL5 and CCL11 reversed the effect on MCs migration inhibited by PKD2/3 silencing. Mechanistically, PKD2/3 interacted with Erk1/2 and activated Erk1/2 or NF-κB signaling pathway, leading to AP-1 or NF-κB binding to the promoter of scf, ccl5 and ccl11. Finally, PKD-specific inhibitor significantly reduced tumor volume and tumor growth in mice bearing RM-1 prostate cancer cells, which was attributed to attenuation of mast cell recruitment and tumor angiogenesis. CONCLUSIONS: These results demonstrate a novel PKDs function that contributes to tumor angiogenesis and progression through mast cells recruitment in prostate cancer microenvironment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1118-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-64043262019-03-18 Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment Xu, Wanfu Qian, Jiabi Zeng, Fangyin Li, Songyu Guo, Wenjing Chen, Liping Li, Guihuan Zhang, Zhishuai Wang, Qiming Jane Deng, Fan J Exp Clin Cancer Res Research BACKGROUND: Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood. METHODS: The expression of PKD, mast cells and microvessel density were examined by IHC. The clinical significance was determined by statistical analyses. The biological function of PKD and the underlying mechanisms were investigated using in vitro and in vivo models. RESULTS: PKD2/3 contributed to MCs recruitment and tumor angiogenesis in the prostate cancer microenvironment. Clinical data showed that increased activation of PKD at Ser744/748 in prostate cancer was correlated with mast cell infiltration and microvascular density. PKD2/3 silencing of prostate cancer cells markedly decreased MCs migration and tube formation of HUVEC cells. Moreover, PKD2/3 depletion not only reduced SCF, CCL5 and CCL11 expression in prostate cancer cells but also inhibited angiogenic factors in MCs. Conversely, exogenous SCF, CCL5 and CCL11 reversed the effect on MCs migration inhibited by PKD2/3 silencing. Mechanistically, PKD2/3 interacted with Erk1/2 and activated Erk1/2 or NF-κB signaling pathway, leading to AP-1 or NF-κB binding to the promoter of scf, ccl5 and ccl11. Finally, PKD-specific inhibitor significantly reduced tumor volume and tumor growth in mice bearing RM-1 prostate cancer cells, which was attributed to attenuation of mast cell recruitment and tumor angiogenesis. CONCLUSIONS: These results demonstrate a novel PKDs function that contributes to tumor angiogenesis and progression through mast cells recruitment in prostate cancer microenvironment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1118-y) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-06 /pmc/articles/PMC6404326/ /pubmed/30841931 http://dx.doi.org/10.1186/s13046-019-1118-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Xu, Wanfu
Qian, Jiabi
Zeng, Fangyin
Li, Songyu
Guo, Wenjing
Chen, Liping
Li, Guihuan
Zhang, Zhishuai
Wang, Qiming Jane
Deng, Fan
Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
title Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
title_full Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
title_fullStr Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
title_full_unstemmed Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
title_short Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
title_sort protein kinase ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404326/
https://www.ncbi.nlm.nih.gov/pubmed/30841931
http://dx.doi.org/10.1186/s13046-019-1118-y
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