Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

Abstract

Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy.

Keywords: aneuploidy; cancer; karyotype aberrations; niche construction; polyploidy; tetraploidy; tumor ecology; tumor evolution; tumor microenvironment.

Figure 1

Cellular mechanisms leading to karyotype aberrations. Examples of (A) a normal mitosis and (B) abnormal mitoses leading to the missegregation of whole chromosomes (lagging chromosomes and chromosome non-disjunction; left column), chromosome fragments (right column, right daughter cell), or chromatin bridge-mediated chromosome missegregation (chromatin bridge, right column, left daughter cell; which can give rise to a variety of outcomes, including aneuploidy and tetraploidy [79,84]). Lagging chromosomes, chromatin bridges, and acentric fragments can all give rise to cells with micronuclei. (C) Examples of whole-genome duplication events, including endoreduplication, cytokinesis failure, mitotic slippage, and cell fusion (left to right).

Figure 2

Aneuploidy and polyploidy increase the ability of cells to tolerate mitotic errors and resulting karyotype aberrations. As populations of diploid cells (A, origin) evolve to become more aneuploid (move up the y-axis), the degree by which novel karyotypes can diverge from the modal karyotype and result in viable cells increases (“permissive zone”, represented roughly by the size of the blue zone at the given height). This would be expected to increase the amount of karyotypic heterogeneity in a cancer cell population and, in turn, its evolutionary potential. (B) Tetraploidy buffers against negative fitness effects caused by aneuploidy. Therefore, near-4N cells are expected to have a larger permissive zone than their near-2N counterparts, which may explain why whole genome doubling increases karyotypic heterogeneity and is a favorable route to complex aneuploid karyotypes.

Figure 3

Bidirectional, cell-environment interplay in tumor niche construction and the genomic evolution of cancer cells. (A) In normal tissues, cells and the environment interact to promote homeostasis by regulating cell growth, division, and other behaviors essential for proper health. Teal circles depict normal diploid cells and beige-colored square indicates a normal, healthy environment. (B) Over time, however, changes—either natural (aging) or from stress (smoking, obesity, inflammation, etc.)—may occur in either the cell or environment that disrupt this homeostasis. Spontaneous cellular errors may lead to genomic changes (red circle) that alter cell physiology and interactions with the environment, through senescence, cell death, or increased production of lactate, reactive oxygen species, and other signaling molecules, initiating the process of niche construction (thin dashed arrow). Alternatively, environmental conditions may change (light orange-colored square) that increase the frequency of mutations and mitotic errors in cells and select for cells with favorable genomic alterations and/or phenotypes (thin dashed arrow). The order of events that begin tumor niche construction can vary, starting from either a cellular or environmental change. (C) As this bidirectional interplay persists, genomic and environmental evolution continue to influence and shape each other. As the environment erodes and is replaced by a pro-tumorigenic one (dark orange-colored square), various stresses (hypoxia, acidosis, nutrient scarcity, etc.) may emerge that exert strong selective forces (thick dashed arrow) and favor the survival of tumor cells with advantageous genomic changes. In turn, the outgrowth of these abnormal cells amplifies their environmental effects (thick dashed arrow), which continue to modify selective pressures for their benefit. This cycle may serve as a destabilizing feedback loop that explains the substantial genomic and environmental alterations and heterogeneity (different colored circles) observed in malignant aneuploid tumors.