Insights on processes of evolutionary tumor growth

Abstract

Application of traditional somatic evolutionary theory can offer an appropriate context for studying tumor growth at the molecular level. However, high degrees of heterogeneity (especially genome-level heterogeneity) within tumors coupled with a lack of common driver mutations have posed a challenge to the generally accepted stepwise concept of cancer evolution, where clonal expansion is the key. In order to account for multiple levels of heterogeneity and better understand tumor growth and progression, a new, holistic conceptual framework must be applied in cancer research. Herein, we discuss one such framework, the genome theory of cancer evolution, with respect to tumor growth. This includes detailing the ultimate importance of chromosome aberrations in cancer, the somatic cell evolutionary pattern, and single-cell/population growth dynamics. Under this new framework, tumor growth is a highly dynamic process where emergent outlier subpopulations can greatly influence the pattern of progression and the direction of evolution. Further, genome level changes have a greater impact on cancer evolution than individual gene mutations in most cancer types, as karyotype alteration often results in altered system inheritance which defines the network structure and even can change the meaning of individual genes (representing 'parts inheritance' by changing the gene context. Based on this analysis, we call for a focus shift back on cytogenetic and cytogenomic alterations (especially on non-clonal chromosomal aberrations) in monitoring population growth, identifying the emergence of new subpopulations and studying patterns of evolutionary dynamics. This new insight has implications in understanding cancer evolution in general as well as searching for new diagnostic and treatment strategies.

The Role of Chromosomal Instability in Cancer and Therapeutic Responses

“…However, while some studies have associated high CIN with poor patient outcomes and drug resistance [ 127 ], others have indicated that it is associated with better responses [ 4 , 128 ]. In fact, it has been indicated that targeting CIN for cancer therapy can induce genome chaos, which contributes to an increased CIN and therefore to the possible acquisition of proliferative advantages and resistance to therapy [ 129 , 130 ].…”

New Insights in the Cytogenetic Practice: Karyotypic Chaos, Non-Clonal Chromosomal Alterations and Chromosomal Instability in Human Cancer and Therapy Response

“…In this regard, it has been indicated that chromosomal alterations in individual cancer cells (NCCAs) can lead to variable drug sensitivity, promoting the survival of a fraction of the tumor cell population [ 99 ] ( Figure 2 ). Further, according to Horne et al [ 100 ], the administration of high-dose chemotherapeutics can also result in the generation of new NCCAs, ultimately giving the disease a chance for recovery and resistance ( Figure 3 ). In fact, we demonstrated that low doses of Tamoxifen (TAM) promotes the production of specific chromosomal abnormalities in breast cancer cell lines, which could contribute to the selection of clones with proliferative advantages, thereby favoring cell survival and therapy resistance [ 101 ].…”

A Postgenomic Perspective on Molecular Cytogenetics

“…Now, the cancer genome sequencing project has proven otherwise, and interest in studying heterogeneity is strongly coming back. Interestingly, molecular cytogenetics approaches can play an important role in studying the mechanism of heterogeneity [ 37 - 40 ]. Third, there is an urgent need to rethink the genetic/genomic theories, as well as evolutionary theory, in the light of cellular evolution and disease initiation and progression.…”