Carcinoma-associated fibroblasts (CAFs) within the stromal tumor microenvironment play a key role in promoting the development, progression and therapy resistance of prostate cancer (PCa). However, the stromal compartment is not targeted by current treatment strategies. Elevated secretion of transforming growth factor beta (TGFβ) by epithelial cells in prostate intraepithelial neoplasia (PIN) lesions and tumor cells induces fibroblast activation to the CAF phenotype and is associated with poor prognosis. We previously showed that elevated production of reactive oxygen species (ROS) by NADPH oxidase 4 (Nox4) is essential for TGFβ1-mediated stromal activation of primary prostate fibroblasts. Moreover, Nox4 mRNA levels are elevated in PCa patients that experienced biochemical relapse. This study aimed to determine whether pharmacological inhibition of Nox4 attenuates fibroblast activation as a potential therapeutic strategy. Nox4 inhibition attenuated TGFβ1-induced ROS production and fibroblast activation of primary normal tissue-associated prostate fibroblasts (NAFs) as indicated by abrogated induction of reactive stromal markers. Moreover, Nox4 inhibition attenuated fibroblast migration. Microarray analyses of primary patient matched NAF and CAFs reveal two molecularly distinct CAF subtypes with one subtype exhibiting elevated Nox4 mRNA levels. Similarly to TGFβ-activated fibroblasts, pharmacological inhibition of Nox4 in CAFs also leads to down-regulation of reactive stromal markers at both the mRNA and protein level. Similar results were obtained using Nox4-specific shRNA-mediated silencing. Collectively, these data indicate that targeting Nox4 attenuates key molecular and phenotypic hallmarks of activated fibroblasts. Further investigation of Nox4 inhibition as a potential treatment strategy for PCa is warranted.
Presenting author: Natalie Sampson, Department of Urology, Medical University of Innsbruck, Anichstraße 35, A6020, Innsbruck, Austria. Email: firstname.lastname@example.org.