Abstract 2348P
Background
Esophageal squamous cell carcinoma is a malignance with high invasiveness. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment (TME), promotes tumor initiation and progression. Our previous studies revealed that CAFs mediated ESCC cells significant resistance to a variety of chemotherapeutic drugs and ionizing irradiation. How to inhibit the tumor-promoting activity of CAFs is of critically important for the radical treatment of ESCC.
Methods
Using high-throughput screening, 157 inhibitors of cytokines/chemokines were tested for their effect on the cell viability of CAFs, matched normal fibroblasts (NFs), ESCC cells as well as normal esophageal epithelial cell Het-1A. We also investigated the effect of the inhibitors on cell cycle distribution, ROS accumulation and cell apoptosis of CAFs. The expressions of α-SMA, a marker of CAFs activation, was detected in CAFs treated with the inhibitors. By establishment of xenograft tumors in BALB/c mice, the effect of the inhibitors on CAFs-promoted ESCC growth was studied.
Results
By high-throughput screening, GSK1838705A, an inhibitor of IGF-1R kinase, was discovered as a potent inhibitor of CAFs activity in ESCC. Compared with NFs, ESCC cells as well as Het-1A, the viability of CAFs was significantly reduced when exposure to GSK1838705A. Furthermore, GSK1838705A arrested the cell cycle of CAFs in G2/M phase, promoted cell apoptosis and ROS accumulation. The expression of α-SMA was signifcantly reduced when CAFs were treated with GSK1838705A. In vivo studies demonstrated that GSK1838705A significantly repressed the tumor-promoting activity of CAFs. Immunohistochemical analysis showed that GSK1838705A significantly reduced the percentage of CAFs in xenograft tumor tissues.
Conclusions
GSK1838705A is a potent inhibitor of CAFs which promote ESCC progression. The combination of GSK1838705A and chemoradiotherapy may be a promising strategy against ESCC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
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