Gastric cancer stem cells: evidence, potential markers, and clinical implications

Abstract

Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches.

Identifying and targeting cancer stem cells in the treatment of gastric cancer

“…It is believed that BMDCs differentiate in the gastric mucosa by cell‐cell fusion with local gastric epithelial cells and induce CSCs. However, the majority of dysplastic lesions do not arise from BMDCs 21. More studies are needed to fully understand the pathogenesis of gastric CSCs.…”

“…Specific cellular markers have been used to identify, isolate and therapeutically target CSCs 21, 22, 23. Several potential gastric CSC markers have been identified.…”

“…CD133‐positive CSCs have demonstrated resistance to traditional chemotherapies,36, 37 and quantitative polymerase chain reaction analyses indicate that high CD133 expression is a marker for a poor prognosis 34. In addition, CD44 is expressed in up to 80% of primary gastric cancer resection specimens and is associated with more advanced clinicopathologic features and a poorer prognosis 21. CD44 expression also denotes a subpopulation of gastric cancer cells in which Hedgehog signaling pathway proteins are up‐regulated and also promote chemotherapy resistance and thus a poorer prognosis 21, 38.…”

“…In addition, CD44 is expressed in up to 80% of primary gastric cancer resection specimens and is associated with more advanced clinicopathologic features and a poorer prognosis 21. CD44 expression also denotes a subpopulation of gastric cancer cells in which Hedgehog signaling pathway proteins are up‐regulated and also promote chemotherapy resistance and thus a poorer prognosis 21, 38. A variant of CD44 (CD44v8‐10) was identified as the predominant CD44 variant expressed in gastric cancer cells and contributes to tumor initiation, possibly through enhancing oxidative stress defense 39.…”

“…A variant of CD44 (CD44v8‐10) was identified as the predominant CD44 variant expressed in gastric cancer cells and contributes to tumor initiation, possibly through enhancing oxidative stress defense 39. It has also been demonstrated that CD44 and CD133 expression in gastric cancers is associated with statistically significant histology for intestinal‐type tumors and that CD44v5 is significantly associated with Signet ring histology 21. However, markers of CSCs have limitations, in that some CSC populations do not express these markers, whereas non‐CSC cancer cells may express them.…”