Deletion of IKKβ in activated fibroblasts promotes tumor progression in melanoma

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and play critical roles in tumorigenesis. CAFs consists of multiple subpopulations, which have diverse functions. The detailed mechanism, including the role of NF-kappa B, a critical transcription factor for inflammation and cell survival, in CAFs has not been adequately explored. In this study, we examined the roles of IKK beta, a key kinase for NF-kappa B activation, in activated CAFs by using mice (KO mice) with deletion of IKK beta in activated fibroblasts (aFbs). We found that melanoma cells implanted in KO mice showed significantly more growth than those implanted in control mice. To exclude the effects of deletion of IKK beta in cells other than aFbs, we implanted a mixture of melanoma cells and IKK beta-deleted aFbs in wild-type mice and observed that the mixture showed greater growth than a mixture of melanoma cells and normal aFbs. In exploring the mechanisms, we found that conditioned medium from IKK beta-deleted aFbs promotes the proliferation of melanoma cells, and the expression of growth arrest-specific 6 (GAS6) and hepatocyte growth factor (HGF), which are major tumor-promoting factors, was upregulated in IKK beta-deleted aFbs. These results indicated the tumor-suppressing function of IKK beta in activated CAFs. (C) 2022 The Authors. Published by Elsevier Inc.

Automated summary

Cancer-associated fibroblasts (CAFs) are important components of the tumor microenvironment and play critical roles in tumorigenesis. In this study, the researchers investigated the role of IKK beta, a key kinase for NF-kappa B activation, in activated CAFs. The results showed that IKK beta has a tumor-suppressing function in activated CAFs, and its deletion leads to enhanced tumor growth and upregulation of tumor-promoting factors.