Intra-tumor heterogeneity from a cancer stem cell perspective

Abstract

Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Heterogeneity is evident between cancers from different patients (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). The latter includes phenotypic diversity such as cell surface markers, (epi)genetic abnormality, growth rate, apoptosis and other hallmarks of cancer that eventually drive disease progression and treatment failure. Cancer stem cells (CSCs) have been put forward to be one of the determining factors that contribute to intra-tumor heterogeneity. However, recent findings have shown that the stem-like state in a given tumor cell is a plastic quality. A corollary to this view is that stemness traits can be acquired via (epi)genetic modification and/or interaction with the tumor microenvironment (TME). Here we discuss factors contributing to this CSC heterogeneity and the potential implications for cancer therapy.

Keywords: Cancer stem cell; Stemness; Tumor heterogeneity; Tumor microenvironment.

Fig. 1

The original CSC model (unidirectional hierarchy) assumes that only CSCs are able to generate the bulk of tumor via symmetric division (to self-renew) or asymmetric division (to generate differentiated cells). In this case, the hierarchy is strictly unidirectional and precludes the concept of cell fate reversibility from the progenitor cells. In contrast, accumulating evidence demonstrate that the hierarchy is more fluid than originally thought. In the CSCs plasticity model, (cancer) cell posses the dynamic ability of bidirectional conversion from a non-CSC state to a CSC state and vice versa. In this model, the stemness and CSCs plasticity are determined by diverse intrinsic and extrinsic cues that work simultaneously or independently overtime. Consequently, non-CSCs can serve as reservoir to create CSC populations throughout tumorigenesis. In the figure this is indicated with a lightning bolt and can be the result of a microenvironmental cue or a (epi-)genetic change

Fig. 2

Next to intrinsic factors, the tumor microenvironment plays a crucial role in influencing cell state. The tumor microenvironment, in addition to hosting the tumor cells, possess a dynamic topography within the tumor involving diverse supportive ECM scaffolds, growth factors, a vascular bed and immune cell interactions [6]. The right combination of microenvironment components, for example inflammation, hypoxia, vascularized niche or rigid matrix, potentially contribute to stemness and enhanced tumorigenicity [52, 62, 68, 87, 91]. Multiple (distinct) niches may co-exist within a tumor, leading to cellular diversity