Voltage-dependent calcium channel α2δ1 subunit is a specific candidate marker for identifying gastric cancer stem cells

Purpose: Cancer stem cells (CSCs) are a subpopulation of cancer cells with self-renewal property and responsible for tumor malignancy, progression and drug resistance. Researches on CSC-specific markers in gastric cancer remain limited. Our current study explored the expression of voltage-dependent calcium channel a2d1 subunit and the potential of using alpha 2 delta 1 as a CSC marker in gastric cancer. We also compared the specificity of alpha 2 delta 1 and CD44 in identifying gastric cancer stem cells (GCSCs). Materials and methods: Expression of alpha 2 delta 1 was analyzed in gastric cancer cell lines, patient-derived xenograft (PDX) models and clinical samples of malignant ascites of gastric cancer patients. alpha 2 delta 1(+) gastric cancer cells were isolated from gastric cancer cell lines. CSC properties of alpha 2 delta 1(+) gastric cancer cells were then verified by subsequent tests both in vitro and in vivo. Results: The expression level of alpha 2 delta 1 was found to differ drastically among gastric cancer cell lines, PDX models and clinical samples of malignant ascites. alpha 2 delta 1(+) gastric cancer cells sorted from HGC-27 and SGC-7901 cell lines demonstrated significant self-renewal properties, including tumorigenic capacity, sphere-formation capacity and asymmetric differentiation potential. Knockdown of alpha 2 delta 1 in alpha 2 delta 1(+) HGC-27 significantly inhibited CSC properties and rendered HGC-27 more sensitive to chemotherapy. Flow cytometry showed that a2d1+ gastric cancer cells accounted for a small fraction of CD44(+) gastric cancer cells. Isolated CD44(+) alpha 2 delta 1(+) HGC-27 cells displayed more significant tumorigenic capacity and sphereforming capacity compared with their CD44(+) alpha 2 delta 1-counterparts. Conclusion: alpha 2 delta 1(+) gastric cancer cells possessed CSC properties. alpha 2 delta 1 could be a proper marker in identifying GCSCs with superior specificity than CD44. The combination of alpha 2 delta 1 and CD44 could be used to identify GCSCs with improved accuracy. Knockdown of alpha 2 delta 1 combined with chemotherapy displayed higher therapeutic efficacy on gastric cancer cells, suggesting that alpha 2 delta 1 could be a potential target for anticancer treatment.