Tumor-Initiating Cells: a criTICal review of isolation approaches and new challenges in targeting strategies

Abstract

Most cancers contain a subpopulation of highly tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Targeting TICs may be essential to achieve cure, because of their self-renewal and tumorigenic properties as well as their resistance to conventional therapies. Despite significant advances in TIC biology, their isolation and identification remain largely disputed and incompletely established. In this review, we discuss the latest developments in isolation and culturing approaches of TICs, with focus on colorectal cancer (CRC). We feature recent findings on TIC-relevant signaling pathways and the metabolic identity of TICs, as well as their current clinical implications. Lastly, we highlight the influence of inter- and intra-tumoral heterogeneity on TIC function and targeting approaches.

Keywords: Cancer stem cells; Colorectal cancer; Culturing conditions; Inter- and intra-tumor heterogeneity; Metabolic identity; Spheroid Culture Systems; Surface markers; Targeted therapy; Tumor-initiating cells.

Fig. 1

TICs display pronounced plasticity: self-renewal as well as tumor-initiation capacities of TICs are not restricted to phenotypically immature cells. Spheroid cultures display increased chemoresistance and expression of stemness markers, as well as reduced proliferation, compared to adherent differentiated counterparts. However, both spheroids and adherent counterparts have comparable self-renewal capacities and can lead to similar tumor formation when low cell numbers (10 cells per injection) are injected subcutaneously into immune-deficient mice