Yonsei Med J.  2018 Dec;59(10):1150-1158. 10.3349/ymj.2018.59.10.1150.

Gastric Cancer Stem Cells: Mechanisms and Therapeutic Approaches

• Fu Y
• Du P
• Zhao J
• Hu C
• Qin Y
• Huang G

• KMID: 2426328
• DOI: http://doi.org/10.3349/ymj.2018.59.10.1150

Abstract

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC stem-like cells (GCSCs), with unlimited self-renewal, differentiation, and tumor-regenerating capacities, contribute significantly to the refractory features of GC and have gained increasing attention for their role in GC drug resistance, relapse, and metastasis. Therapies targeting GCSCs seem to be one of the most promising methods to improve the outcomes of GC patients. Extensive investigations have attempted to outline the regulatory mechanisms in GCSCs and to develop GCSCs-targeting therapies with which to diminish GC drug resistance, metastasis and relapse. To the best of our knowledge, there is a lack of reviews summarizing these studies. In this review, we systematically recapitulated findings regarding the regulatory mechanisms of GCSCs, as well as therapies that target GCSCs, hoping to support the development of prognostic biomarkers and GCSCs-targeting anticancer therapies in GC.

Keyword

Cancer stem cells; gastric cancer; identification and isolation; molecular mechanism; targeted therapy

MeSH Terms

Biomarkers
Drug Resistance
Hope
Humans
Neoplasm Metastasis
Neoplastic Stem Cells
Recurrence
Stem Cells*
Stomach Neoplasms*
Biomarkers

Figure

• 

  Fig. 1 Three signal pathways contribute to stemness properties of gastric cancer stem-like cells: Wnt/β-catenin signal pathway, Notch signal pathway, and Hedgehog signal pathway. (A) Wnt/β-catenin signal pathway: Wnt binds to its receptor-Frizzled to activate Dsh protein. The activated Dsh protein enhances the phosphorylation of GSK3β (a component of the cytoplasmic complex that promotes phosphorylation of β-catenin and its degradation), which inhibits the ability of GSK3β, further causing the accumulation of free and unphosphorylated β-catenin in the cytoplasm that is then translocated to the nucleus. In the nucleus, β-catenin binds to TCF/LEF to promote downstream target genes expression. (B) Notch signal pathway: Ligand binding-induced Notch activation causes γ-secretase (including Presenilin and Nicastrin) to cleave Notch COOH-terminal fragment to release NICD into the cytoplasm. Then, NICD translocates to the nucleus to interact with SKIP and CSL, which lead to SMRT/HDACs dissociation, further converting CSL to a transcriptional activator to initiate downstream gene expression. (C) Hedgehog signal pathway: Ptc-induced inhibition of Smo is reversed by Hh binding with Ptc, leading to the release of the complex of GLI (GLI/SUFU/SKT36) from microtubules, with GLI protein entering the nucleus to transcriptionally activate downstream target genes.

• 

  Fig. 2 GCSC niche. CAF, cancer-associated fibroblast; GCSC, gastric cancer stem-like cell; ECM, extracellular matrix.

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  Fig. 3 GCSC-targeting therapies. GCSC, gastric cancer stem-like cell.

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