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

Abstract

Current treatment regimens for gastric cancer are not adequate. Cancer stem cells (CSCs) may be a key driving factor for growth and metastasis of this tumor type. In contrast to the conventional clonal evolution hypothesis, CSCs can initiate tumor formation, self-renew, and differentiate into tumor-propagating cells. Because gastric cancer can originate from CSCs, it is necessary to review current targets of signaling pathways for CSCs in gastric cancer that are being studied in clinical trials. These pathways are known to regulate the self-renewal and differentiation process in gastric CSCs. A better understanding of the clinical results of trials that target gastric CSCs will lead to better outcomes for patients with gastric cancer. Cancer 2017;123:1303-1312. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Keywords: cancer stem cells; clinical trials; gastric cancer; napabucasin; targeted therapy; vismodeqib.

Figure 1

Primary models of cancer stem cells (CSCs) and tumor heterogeneity are illustrated.

Figure 2

Inhibiting the hedgehog (HH) signaling pathway with vismodegib is illustrated. Binding of an HH protein to the transmembrane receptor patched 1 (PTCH1) prevents PTCH1‐mediated inhibition of signaling by the transmembrane protein smoothened (SMO), leading to activation of the GLI family of transcription factors and the regulation of target genes. Vismodegib inhibits the HH pathway by binding to SMO.

Figure 3

Inhibiting the signal transducer and activator of transcription 3 (STAT3) signaling pathway with napabucasin is illustrated. STAT proteins are located in the cytoplasm in resting cells as inactive proteins. Phosphorylation of a specific tyrosine residue is essential for STAT activation. Once activated, STAT dimerizes, leading to its translocation into the nucleus, which then leads to the initiation of transcription. Napabucasin inhibits the STAT3, β‐catenin (β‐CAT), and NANOG signaling pathways and inhibits the critical genes necessary for maintaining stemness.