Abstract
The radiotherapy outcomes of patients with advanced esophageal squamous cell carcinoma (ESCC) remain poor due to hypoxia. Carbonic anhydrase IX (CAIX) is a membrane-associated enzyme that induces hypoxia, extracellular acidity, and upregulation of hypoxia-related factors in tumor microenvironment, thereby promoting tumor metastasis. CAIX is upregulated in ESCC tissues compared to normal surrounding tissues. In the current study, we aimed to investigate the effect of CAIX inhibition on the modulation of tumor microenvironment and radiotherapy efficacy in ESCC. Higher CAIX expression was correlated with poorer progression-free survival in ESCC patients. Then, the ethyl N-(4-methylphenyl) sulfonylcarbamate (S4) was used to inhibit CAIX expression in ESCC cells and mice xenografts. The pretreatment of ESCC cells with S4 significantly downregulated CAIX expression, decreased intracellular pH, reduced cell viability, resulting in decreased oxygen consumption and more sensitive response to X-ray irradiation. In mice inoculated with ESCC cells, the combination of X-ray irradiation with S4 further improved survival, delayed tumor growth, decreased hypoxia level, exaggerated DNA damage, and increased apoptosis compared with the groups treated solely with S4 or radiotherapy. In conclusion, our study showed that the inhibition of CAIX by S4 treatment altered hypoxic tumor micro-environment, exaggerated DNA damage, increased apoptosis, and thus enhanced radiotherapy efficacy in ESCC. These findings provided a potential therapeutic strategy for patients with resistant ESCC.
Highlights
Esophageal cancer is the sixth leading cause of cancer-associated death worldwide and esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of all esophageal cancer cases [1]
We investigated the effect of Carbonic anhydrase IX (CAIX) inhibition on the modulation of tumor hypoxia and radiotherapy efficacy in ESCC both in vitro and in vivo
To understand the role of CAIX in the ESCC tumor microenvironment, we compared the expression of CAIX between ESCC and paired adjacent normal tissues obtained from 23 ESCC patients
Summary
Esophageal cancer is the sixth leading cause of cancer-associated death worldwide and esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of all esophageal cancer cases [1]. Despite the wide use of radiotherapy for ESCC patients, its therapeutic efficacy is limited due to acquired resistance. Continuous efforts are being made to enhance therapy efficacy and improve the clinical outcomes of ESCC patients [4]. The tumorigenesis, invasion, and metastasis of ESCC are determined by cancer cells and the tumor microenvironment, a complex, functional niche where tumor progression occurs [5]. The damage to cancer cells, as well as epithelial cells and blood vessels, leads to the accumulation of radioresistant suppressor cells and the formation of hypoxia area in tumor microenvironment, which subsequently activates immunosuppressive pathways and weakens the antitumor effect of radiotherapy [7]. A delicate balance between effectively treating the tumor and limiting radiotherapy-induced damage needs to be maintained
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