Secreted frizzled-related protein 1 (Sfrp1) as key mediator of growth-factor induced invasion

Introduction/Aims Targeting an invading fibroblast phenotype may pose a therapeutic approach for neoplastic and non-neoplastic lung diseases. We uncovered the transcriptional profile of this phenotype and identified Secreted frizzled-related protein 1 (Sfrp1), a modulator of Wnt-signaling, as novel functional target. Methods/Results With a collagen-based 3D invasion assay, invading and non-invading MLg 2908 (MLg) or primary human lung fibroblasts (phF) were separated after 72 or 96h of invasion and RNA of both fractions was applied to whole transcriptome analysis. Within the profile of invading fibroblasts, Sfrp1 was the only Sfrp-isoform found to be substantially expressed and regulated. Further, the pro-fibrotic and -invasive cytokines TGFβ1 (5 ng/ml) and EGF (50 ng/ml) significantly down-regulated Sfrp1. Upstream regulator analysis (Ingenuity) identified FGF2 as putative inducer of fibroblast invasion (activation z-score 3.3) and FGF2 (10 ng/ml) significantly lowered Sfrp1 expression with a concomitant increase in invasion. Notably, Sfrp1 protein levels were found to be reduced in phF derived from lungs of ILD patients compared to lung transplant donors. Sfrp1 protein expression negatively correlated with the invading capacity of EGF-stimulated phF and staining revealed a mutual exclusion of Sfrp1 with αSMA+ phF. Consequently, specific inhibition of Sfrp1 by a diphenylsulfone-sulfonamide compound for 48h significantly augmented invasion (10.8±3.2% - 16±3.5%). Conclusion We postulate that reduced Sfrp1 levels pose an essential feature in the molecular signature of invading lung fibroblasts. Thus, Sfrp1 may serve as novel therapeutic target for neoplastic and non-neoplastic lung diseases.