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Review
. 2017 Mar 14;4(1):55-63.
doi: 10.1016/j.jcmgh.2017.03.003. eCollection 2017 Jul.

Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells

Yana Zavros  1
Affiliations
Review

Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells

Yana Zavros. Cell Mol Gastroenterol Hepatol. .

Abstract

Gastric cancer is the third most common cause of cancer-related death. Although the incidence of gastric cancer in the United States is relatively low, it remains significantly higher in some countries, including Japan and Korea. Interactions between cancer stem cells and the tumor microenvironment can have a substantial impact on tumor characteristics and contribute to heterogeneity. The mechanisms responsible for maintaining malignant cancer stem cells within the tumor microenvironment in human gastric cancer are largely unknown. Tumor cell and genetic heterogeneity contribute to either de novo intrinsic or the therapy-induced emergence of drug-resistant clones and eventual tumor recurrence. Although chemotherapy often is capable of inducing cell death in tumors, many cancer patients experience recurrence because of failure to effectively target the cancer stem cells, which are believed to be key tumor-initiating cells. Among the population of stem cells within the stomach that may be targeted during chronic Helicobacter pylori infection and altered into tumor-initiating cells are those cells marked by the cluster-of-differentiation (CD)44 cell surface receptor. CD44 variable isoforms (CD44v) have been implicated as key players in malignant transformation whereby their expression is highly restricted and specific, unlike the canonical CD44 standard isoform. Overall, CD44v, in particular CD44v9, are believed to mark the gastric cancer cells that contribute to increased resistance for chemotherapy- or radiation-induced cell death. This review focuses on the following: the alteration of the gastric stem cell during bacterial infection, and the role of CD44v in the initiation, maintenance, and growth of tumors associated with gastric cancer.

Keywords: CD, cluster-of-differentiation; CD44v6; CD44v9; CD44v9, CD44 variant isoform containing exon v9; CSC, cancer stem cell; Cag, cytotoxin-associated gene; Helicobacter pylori; Inflammation; Lgr5, leucine-rich, repeat-containing, G-protein–coupled receptor 5; MDSC, myeloid-derived suppressor cell; PDL1, programmed cell death 1 ligand; PDTX, patient-derived tumor xenograft; ROS, reactive oxygen species; SPEM, spasmolytic polypeptide expressing metaplasia; xCT, SLC7A11.

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Figures

Figure 1
Figure 1
CD44 variant isoforms contain insertions close to the transmembrane region that are generated by messenger RNA splicing. Although the standard CD44 isoform (CD44s) is expressed predominantly in hematopoietic cells and normal epithelial cell subsets, CD44v8–10 is identified as a cancer stem cell marker. Recently, CD44v9 was shown to emerge during gastric regeneration.
Figure 2
Figure 2
Structure, binding sites, and interactions of CD44. The CD44 protein is composed of an extracellular N-terminal domain, a stem region, and the carboxyl terminal cytoplasmic domain/tail. The stem region, close to the transmembrane region, is the site of variant exon product insertion. The N-terminal domain contains highly conserved disulfide bonds (SS) that are essential for hyaluronan (HA) binding. The C-terminal cytoplasmic tail contains several phosphorylation (P) sites that regulate the interaction of CD44 with the cytoskeletal linker proteins for the regulation of cell proliferation and importantly migration. Note that CD44v6 acts as a co-receptor for c-Met signaling and c-Met ligands including hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) to regulate proliferation. CD44v9 stabilizes the cysteine–glutamate transporter xCT for the protection against ROS and subsequent cell survival and proliferation.
Figure 3
Figure 3
Illustration for the proposed development of gastric cancer initiated by chronic inflammation. During H pylori infection, CD44v9 expression emerges, a marker of the gastric cancer stem cell. Despite loss of H pylori infection over time, CD44v9 expression is maintained in cancer stem cells within the tumor. We may predict that tumor antigen secreted by the CD44v9+ cells activate dendritic cells that subsequently activate CD8+ cytotoxic T cells to express PD1 and CTLA-4, a mechanism by which cancer stem cells can evade the immune response via inactivation of T-cell effector function. TAM, tumor-associated macrophages.
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