Could gastrointestinal tumor-initiating cells originate from cell-cell fusionin vivo?

Abstract

Tumor-initiating cells (TICs) or cancer stem cells are believed to be responsible for gastrointestinal tumor initiation, progression, metastasis, and drug resistance. It is hypothesized that gastrointestinal TICs (giTICs) might originate from cell-cell fusion. Here, we systemically evaluate the evidence that supports or opposes the hypothesis of giTIC generation from cell-cell fusion both in vitro and in vivo . We review giTICs that are capable of initiating tumors in vivo with 5000 or fewer in vivo fused cells. Under this restriction, there is currently little evidence demonstrating that giTICs originate from cell-cell fusion in vivo . However, there are many reports showing that tumor generation in vitro occurs with more than 5000 fused cells. In addition, the mechanisms of giTIC generation via cell-cell fusion are poorly understood, and thus, we propose its potential mechanisms of action. We suggest that future research should focus on giTIC origination from cell-cell fusion in vivo, isolation or enrichment of giTICs that have tumor-initiating capabilities with 5000 or less in vivo fused cells, and further clarification of the underlying mechanisms. Our review of the current advances in our understanding of giTIC origination from cell-cell fusion may have significant implications for the understanding of carcinogenesis and future cancer therapeutic strategies targeting giTICs.

Adopted neoplastic cells and the consequences of their existence

“…This hypothesis had laid fallow for six decades, until a serendipitous discovery revealed that human cancers grafted into laboratory animals can become metastatic and evade the immune response by forming hybrids with the cells of the host [25,26]. Since then, the ability of cell fusion to enable metastases in a variety of animal systems has been confirmed by many studies (reviewed in: [27][28][29][30]) and complemented by findings that cell fusion can also produce dormant tumor cells, change their drug sensitivity, suppress the ability to form tumors, which led to the concept of tumor suppressors [31], induce genomic and phenotypic instability [32], affect tumor cell evolution [33,34], change cell metabolism, produce circulating tumor cells, affect immune response, and, in synergy with oncogenes, produce invasive tumors that are similar to human cancers (reviewed in [27,29,[35][36][37][38][39][40][41][42]) Are these observations relevant to human cancers? This question prompted a search for cell hybrids in human tumors.…”