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.

Figure 1

Origination of gastric tumor-initiating cells. A: Evidence suggests that the gastric stem cell (GSC) is one major origin of the gastric tumor-initiating cell (GATIC). GSCs exist in the isthmus and bottom of the gastric pit. Certain genetic, epigenetic, and/or environmental factors potentially transform these GSCs into malignant GATICs. For instance, Mist(+) and Villin(+) GSCs in the isthmus and Lgr5(+) GSCs in the bottom could act as the origins of GATICs through multiple signaling pathways; B: GATICs are also presumed to originate partially from bone marrow-derived cells (BMDCs). The recruitment of BMDCs to stomach by chemokines and other factors is in parallel with the multi-step progression of gastric cancer (GC), which lays the basis for the presumption that BMDCs undergo the malignant transformation into GATICs and promote GC development, the underlying mechanism of which requires further investigation.

Figure 2

Plasticity of gastric tumor-initiating cells. A: Gastric tumor-initiating cells (GATICs) give rise to both daughter GATICs and non-TIC gastric cancer (GC) cells (asymmetric division) while maintain their self-renewal capacity and “stemness”. Notably, recent studies demonstrate that differentiated non-TIC GC cells could undergo dedifferentiation and re-acquire the properties (or status) of GATICs. Thus, the bi-directional transition between TIC and non-TIC indicates the plasticity of GATICs, which is regulated by both genetic/epigenetic alterations and tumor microenvironmental factors; B: GATICs reside in the tumor-microenvironment, which consists of cancer cells (GATICs and non-TIC GC cells) as well as non-cancerous cells, such as cancer-associated fibroblast, extracellular matrix, blood supply, hypoxia (hypoxia-inducing factor), and other secreted factors, such as cytokines, growth factors. GATICs interact with these factors within the TIC niche, which exerts regulatory influence on the plasticity of GATICs through various signaling pathways.