Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway

Abstract

Background Irradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy. Methods Fibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously. Results We found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties. Conclusions Together, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.

The Stromal and Immune Landscape of Nasopharyngeal Carcinoma and Its Implications for Precision Medicine Targeting the Tumor Microenvironment

“…Significantly, up-regulated genes in tumorderived fibroblasts were enriched in IFN response-related pathways (23). Meanwhile, fibroblasts are also considered as one of the vital factors maintaining the differentiation status of NPC cells because they are frequently associated with the epithelial-tomesenchymal transition (13,126). Targeting infiltrating fibroblasts might also result in decreasing the cancer stem cell pools in NPC to alleviate therapeutic resistance commonly possessed by high stemness cells (126).…”

“…Meanwhile, fibroblasts are also considered as one of the vital factors maintaining the differentiation status of NPC cells because they are frequently associated with the epithelial-tomesenchymal transition (13,126). Targeting infiltrating fibroblasts might also result in decreasing the cancer stem cell pools in NPC to alleviate therapeutic resistance commonly possessed by high stemness cells (126). CD248 has been found dynamically expressed by cancer-associated fibroblasts (CAFs), and lowly expressed by other stromal cells (127).…”

Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting

“…CAF may also protect cancer cells from radiation. Huang et al [ 74 ] found that radioresistant nasopharyngeal carcinoma had a higher infiltration of CAF compared with radiosensitive tissue, and showed that this radioprotective effect was modulated via IL-8/NF-κB signalling. This effect was diminished following treatment with Tranilast – a drug known to inhibit fibrosis and TGF-β signalling.…”

Identification of Prognostic Markers of Gynecologic Cancers Utilizing Patient-Derived Xenograft Mouse Models

“…Here, the tumor growth delay by inhibiting NF-kB activation was examined in a xenograft model [47,48]. PDX models can reenact the tumor microenvironment; in these models, activation of NF-κB is considered to have an important role in tissue growth.…”