Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell

Abstract

Gastric cancer (GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell (TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC (GATIC), substantial studies have been performed to (1) identify the putative specific cell markers for purification and functional validation of GATICs; (2) trace the origin of GATICs; and (3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors (TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.

Keywords: Gastric cancer; Tumor heterogeneity; Tumor-initiating cell

Core tip: Gastric cancer (GC) remains a severe malignancy with high incidence and mortality rates. One major underlying mechanism of GC rapid progression, extensive spreading, and chemoresistance is tumor heterogeneity could be explained by the gastric tumor-initiating cell (GATIC). Since the initial identification of putative GATICs in 2007, substantial studies have been performed to investigate various aspects of GATICs. Here, we systemically discuss the tumor heterogeneity of GC from the view of GATICs by reviewing studies on the identification and validation of GATICs, origination of GATICs, plasticity of GATICs and its underlying mechanism, and current status of chemotherapeutic agents targeting GATICs.