Although phenotypic intratumoral heterogeneity was first described many decades ago, the advent of next-generation sequencing has provided conclusive evidence that in addition to phenotypic diversity, significant genotypic diversity exists within tumors. Tumor heterogeneity likely arises both from clonal expansions, as well as from differentiation hierarchies existent in the tumor, such as that established by cancer stem cells (CSCs) and non-CSCs. These differentiation hierarchies may arise due to genetic mutations, epigenetic alterations, or microenvironmental influences. An additional differentiation hierarchy within epithelial tumors may arise when only a few tumor cells trans-differentiate into mesenchymal-like cells, a process known as epithelial-to-mesenchymal transition (EMT). Again, this process can be influenced by both genetic and non-genetic factors. In this review we discuss the evidence for clonal interaction and cooperation for tumor maintenance and progression, particularly with respect to EMT, and further address the far-reaching effects that tumor heterogeneity may have on cancer therapy.
Keywords: CLL, chronic lymphoblastic leukemia; CSC, cancer stem cell; EMP, epithelial-mesenchymal plasticity; EMT, epithelial-to-mesenchymal transition; GFP, green fluorescent protein.; MET, mesenchymal-to-epithelial transition; MMTV, mouse mammary tumor virus; NGS, next generation sequencing; OxR, oxaliplatin resistant; SCLC, small cell lung cancer; TGF-β, transforming growth factor-β; cancer stem cells/CSCs; clonal evolution; epithelial-mesenchymal transition (EMT); hPDGF human platelet-derived growth factor; intratumoral heterogeneity; metastasis; miRNA, microRNA; non-cell autonomous; tumor microenvironment.