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Molecular Cancer

, 8:78

First Online: 27 September 2009Received: 19 May 2009Accepted: 27 September 2009

Abstract

BackgroundTumour stromal myofibroblasts can promote tumour invasion. As these cells are genetically more stable than cancer cells, there has been enormous interest in developing targeted molecular therapies against them. Chloride intracellular channel 4 CLIC4 and reactive oxygen species ROS have been linked with promoting stromal cell transdifferentiation in various cancers, but little is known of their roles in ovarian cancer. In this study, we examined the functional roles that both CLIC4 and ROS play in the process of ovarian cancer cell-stimulated or TGF-β1 induced fibroblast-to-myofibroblast transdifferentiation. We also examine whether it is possible to reverse such a process, with the aim of developing novel therapies against ovarian cancer by targeting activated transdifferentiated myofibroblasts.

ResultsWe demonstrate that TGF-β1 induced or CM activate transdifferentiated myofibroblasts fibroblasts. These fibroblasts mimic -reactive- stromal myofibroblasts and demonstrate significant up-regulation of CLIC4 expression and increased level of ROS production. Blocking the production of ROS with an antioxidant consequently reduces the expression of CLIC4, and is accompanied by disappearance of α-smooth-muscle actin α-SMA, a myofibroblast marker, suggesting ROS acts as a signalling molecule that promotes and enhances CLIC4 activities in the myofibroblast transdifferentiaton process. Down-regulation of CLIC4 with a generic agent or specific siRNA both significantly reduces the expression of factors related to the phenotypes and functions of myofibroblasts, such as α-SMA, hepatocyte growth factor HGF and vascular endothelial growth factor VEGF, thus reversing the myofibroblast phenotype back to fibroblasts. These results convincingly show that ROS and CLIC4 are responsible for TGF-β1 induced fibroblast-to-myofibroblast transdifferentiaton and down-regulation of both is sufficient to block transdifferentiated myofibroblasts.

ConclusionMolecular targeting of ROS and CLIC4 has the potential to develop novel therapies for ovarian cancer.

List of abbreviationsCLIC4chloride intracellular channel 4

DCF-DA2-7-dihydrodichlorofluorescein diacetate

NACN-acetyl-L-cysteine

ROSreactive oxygen species

siRNAsmall interfering RNA

TGF-β1transforming growth factor-β1

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-8-78 contains supplementary material, which is available to authorized users.

A retraction note to this article can be found online at http:-dx.doi.org-10.1186-1476-4598-8-84.

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Autor: Qin Yao - Xun Qu - Qifeng Yang - David A Good - Shuzhen Dai - Beihua Kong - Ming Q Wei

Fuente: https://link.springer.com/







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