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 CMSKOV3 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.
Highlights
Tumour stromal myofibroblasts can promote tumour invasion
Myofibroblasts in the experimental ovarian cancer stroma have increased Chloride intracellular channel 4 (CLIC4) expression Recent studies demonstrated that CLIC4 was markedly up-regulated in serum- or transforming growth factor- 1 (TGF- 1)-stimulated fibroblasts isolated from breast cancer
We hypothesised that CLIC4 may play an important functional role in causing stromal fibroblast to myofibroblast transdifferentiation, which is critical in ovarian cancer development and progression
Summary
Tumour 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. Stromal fibroblasts are located at the tumour border near the invasion front When these cells are activated by the tumour, they have a more profound influence on the development and progression of carcinomas than was previously appreciated [7]. Using an in vitro tumour-stroma model of skin carcinogenesis, Cat and colleagues (2006) demonstrated that myofibroblasts are recruited into cancer from different sources during cancer development and the invasion progression [10,11]. These cells were differentiated from the fibroblast population within the epithelial stroma after stimulation by transforming growth factor- 1 (TGF- 1) secreted by tumour cells. Many questions remain, including what molecules are involved in the process and what roles are they playing?
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