Abstract
Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1-regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC.
Highlights
Esophageal cancer is the eighth leading cause of malignancies worldwide with its incidence on the rise [1]
esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries
The results showed that CE146T has remarkably higher migration and invasion abilities than CE81T (Fig 1A and 1B), which was identified as a well differentiated cancer cell
Summary
Esophageal cancer is the eighth leading cause of malignancies worldwide with its incidence on the rise [1]. It represents 1% of cancers diagnosed in the United States, with an estimated 17,500 new cases reported in 2012 [2]. ESCC accounts for about 90% of esophageal cancer diagnosed in Asian countries. Since early detection strategies have not been well applied to clinical screen, these tumors are often diagnosed in advanced stages. Cancer mortality significantly increases [3]. The lack of fundamental knowledge regarding radiation and chemotherapy resistance in these tumor cells has been a major clinical barrier to acquire a better outcome. The limited understanding of the molecular biology of tumors has left us with empiricism in the clinic
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