PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer

Abstract Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therap...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xiaoting Li, Tian Fang, Sen Xu, Ping Jin, Dongchen Zhou, Zhengzheng Wang, Huayi Li, Zongyuan Yang, Gang Chen, Xu Zheng, Yu Xia, Xiao Wei, Zeyu Zhang, Xin Yang, Ya Wang, Qinglei Gao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/90a6f8e5df184f2fb37d9f01e26a9b3a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:90a6f8e5df184f2fb37d9f01e26a9b3a
record_format	dspace
spelling	oai:doaj.org-article:90a6f8e5df184f2fb37d9f01e26a9b3a2021-12-02T15:02:49ZPARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer10.1038/s41698-021-00189-w2397-768Xhttps://doaj.org/article/90a6f8e5df184f2fb37d9f01e26a9b3a2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00189-whttps://doaj.org/toc/2397-768XAbstract Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.Xiaoting LiTian FangSen XuPing JinDongchen ZhouZhengzheng WangHuayi LiZongyuan YangGang ChenXu ZhengYu XiaXiao WeiZeyu ZhangXin YangYa WangQinglei GaoNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Xiaoting Li Tian Fang Sen Xu Ping Jin Dongchen Zhou Zhengzheng Wang Huayi Li Zongyuan Yang Gang Chen Xu Zheng Yu Xia Xiao Wei Zeyu Zhang Xin Yang Ya Wang Qinglei Gao PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer
description	Abstract Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.
format	article
author	Xiaoting Li Tian Fang Sen Xu Ping Jin Dongchen Zhou Zhengzheng Wang Huayi Li Zongyuan Yang Gang Chen Xu Zheng Yu Xia Xiao Wei Zeyu Zhang Xin Yang Ya Wang Qinglei Gao
author_facet	Xiaoting Li Tian Fang Sen Xu Ping Jin Dongchen Zhou Zhengzheng Wang Huayi Li Zongyuan Yang Gang Chen Xu Zheng Yu Xia Xiao Wei Zeyu Zhang Xin Yang Ya Wang Qinglei Gao
author_sort	Xiaoting Li
title	PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer
title_short	PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer
title_full	PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer
title_fullStr	PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer
title_full_unstemmed	PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer
title_sort	parp inhibitors promote stromal fibroblast activation by enhancing ccl5 autocrine signaling in ovarian cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/90a6f8e5df184f2fb37d9f01e26a9b3a
work_keys_str_mv	AT xiaotingli parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT tianfang parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT senxu parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT pingjin parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT dongchenzhou parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT zhengzhengwang parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT huayili parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT zongyuanyang parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT gangchen parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT xuzheng parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT yuxia parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT xiaowei parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT zeyuzhang parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT xinyang parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT yawang parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer AT qingleigao parpinhibitorspromotestromalfibroblastactivationbyenhancingccl5autocrinesignalinginovariancancer
_version_	1718389089666859008

PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer

Ejemplares similares