Evolving concepts of tumor heterogeneity

Abstract

Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.

Keywords: Cancer stem cell; Omic analysis and personalized therapy; Tumor evolution; Tumor heterogeneity; Tumor microenvironment.

Figure 1

Timeline of the evolving concepts of tumor heterogeneity.

Figure 2

Tumor evolution and compositional heterogeneity. A, Evolution drives heritable heterogeneity and subsequent outgrowth of malignant clones. Selection pressures from the local microenvironment (e.g. hypoxia, secretion of growth-inhibiting factors, chemotherapeutic agents, etc.) challenge tumor cell survival, often resulting in cell death in early cancer initiation. In order to survive these in a given tissue niche, cancer cells must acquire mutations that promote survival and tumor formation with regard to spatiotemporal context. Robust cells capable of surviving multiple selection events acquire proliferative advantages, eventually resulting in tumor progression and evidence of genetic heterogeneity within a tumor. B, Snapshots of natural selection events within the TME paint a heterogeneous portrait of tumor composition in a spatial context. The TME refers to both the tumor and its local environment of diverse resident and migratory cell types. 1) Infiltrated immune cells shape the tumor development; 2) Tumor stromal cells interact with tumor cells and change the local cancer stem cell niche; 3) Bi-directional plasticity between stem-like cancer cells and tumor cells. 4) Disseminated tumor cells.