Abstract
Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. Mol Cancer Ther; 16(6); 1187-98. ©2017 AACR.
Highlights
Gastric cancer is a major health burden worldwide
Gastric cancer stem cells (GCSC) could be enriched by in vivo consecutive passage of gastric cancer cells in NOD/SCID mice treated with chemotherapy
Chemotherapy-induced drug resistance remains a major obstacle to the clinical management of gastric cancer, resulting in relapse and metastasis
Summary
Gastric cancer is a major health burden worldwide. Its incidence ranks second among men and third among women, and the associated mortality still remains second for both males and females despite a downward trend in 2015 [1]. The delivery of chemotherapeutic agents, including cisplatin (DDP) and fluoropyrimidine, following surgical resection is currently the standard treatment for advanced gastric cancer patients [2]. Multiagent chemotherapy can improve gastric cancer outcomes, almost all patients develop chemotherapy resistance, and the 5-year survival rate continues to be poor [3]. The cancer stem cell (CSC) hypothesis proposes that CSCs are a group of heterogeneous cells that exhibit self-renewal, multiple differentiation potential, high tumorigenicity, and drug resistance [4, 5]. CSCs may have a central role in tumor
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