1. Introduction
Cancer has been widely described as a process of Darwinian evolution. In a manner analogous to speciation, cancer cells genomically and phenotypically diverge into distinct populations (often referred to as clones or stem-lines) that coexist in the same tumor [1]. This heterogeneity is further bolstered by sub-clonal variations within these clonal populations [2], much like the heterogeneity observed between individuals of a species in nature. Advances in single cell analysis have provided an unprecedented look into the clonal and sub-clonal architecture of cancer [3] and uncovered considerable intra-tumor heterogeneity (ITH) at multiple biological levels. For example, tumors often show extensive cell-to-cell heterogeneity in epigenetic markers, gene mutations, and chromosome aberrations, as well as spatial heterogeneity in the conditions of the extracellular microenvironment [4,5,6]. Heterogeneity in one or more of these components can be associated with poor patient outcomes [4,5,6,7,8] and increased probability of disease recurrence [9,10,11,12,13]. Not surprisingly, these forms of heterogeneity underlie marked cell-to-cell heterogeneity in a range of phenotypes, including differences in protein biomarker expression, proliferation, cell and nuclear morphology, immune cell infiltration, motility, metabolism, angiogenic potential, differentiation status, and metastatic potential [14,15,16,17].Cell-to-cell heterogeneity emerges through evolutionary processes, in which new variants are generated by ongoing molecular changes and either survive or are eliminated by natural selection. Epigenetic changes are common in cancer and can occur in response to changes in the extracellular environment or due to perturbations in the cellular machinery that orchestrates epigenetic regulation [18]. For example, mutations or altered expression of genes involved in epigenetic regulation (e.g., regulating DNA methylation, histone modifications, and regulatory non-coding RNAs) can lead to increased rates of epigenetic change (known as epigenetic instability) and epigenetic heterogeneity in tumors [19,20,21,22,23,24,25]. Increased rates of mutation at the DNA sequence or chromosomal level, a phenomenon collectively known as genomic instability (GIN), occurs in the vast majority of tumors [26]. The rate of gene mutation can increase due to defective DNA damage repair (mismatch repair, nucleotide excision repair, homologous recombination), DNA replication stress, or structural damage to the chromosomes [8]. Chromosomal abnormalities are also widely observed in tumors [27]. These aberrations emerge through defective chromosome segregation or chromosomal damage (leading to gain or loss of whole or partial chromosomes, known as aneuploidy), or abnormal cell cycle events that lead to genome doubling (polyploidy) [28,29]. Chromosomal instability (CIN) refers to the form of GIN where numerical and/or structural chromosomal aberrations occur at an increased rate. CIN has been reported as being the most common form of genomic instability in human cancers [30,31,32], and both CIN and aneuploidy are present in most human tumors [27,33,34,35]. Despite the complexity involved with untangling the cellular effects of aneuploidy, studies in various model systems have made substantial progress in uncovering how chromosomal aberrations alter cell physiology. In addition to gene-specific effects associated with gain or loss of specific chromosomes or chromosome fragments, aneuploidy and polyploidy in general are associated with a number of cellular effects, including substantial alterations to proliferation rates, cellular metabolism, protein homeostasis, and other phenotypes (reviewed in [36]). Aneuploidy and polyploidy have each been shown to drive tumorigenesis in certain circumstances [37,38,39,40,41,42]. Large scale chromosome or genome level alterations, such as aneuploidy and polyploidy (hereafter referred to as karyotype aberrations), are expected to have a larger penetrance (i.e., more likely to have a phenotypic effect on the cell) than most sequence-level events [8]. Furthermore, chromosome copy number changes affect a larger portion of cancer genomes than any other form of mutation [43]. Therefore, this review will examine the role of karyotypic heterogeneity (i.e., chromosome copy number heterogeneity) in cancer, as well as the environmental context surrounding karyotype aberrations (for excellent reviews addressing sequence-level and epigenetic heterogeneity, please see [8,18,44,45]). There is a growing appreciation for the context-dependent (genetic, physiological, environmental, etc.) effects of karyotype aberrations on cell physiology and in cancer (reviewed in [46]). Aneuploid and polyploid cells can cause changes in the cellular and tissue environment [47,48,49], which may disrupt the normal contextual cues from the local environment that maintain tissue homeostasis. The maintenance of tissue homeostasis serves as a barrier to tumorigenesis [50,51], and deteriorating tissue health may create opportunities for cancer development. Although the importance of genomic and environmental changes in cancer development are generally accepted [7,52], our understanding of the details and ramifications of the interplay between genomic and environmental alterations is far from complete. The goal of this review is to discuss the causes and consequences of karyotype aberrations from the perspective of both the cell and the extracellular environment. We will focus on the role of aneuploidy and polyploidy within the context of tumorigenesis, specifically addressing factors that lead to the accumulation of aneuploidy, the effects of karyotype changes on intercellular and environmental interactions, and the disastrous impact this may have on the tumor microenvironment (TME) and cancer evolution.