The Role of Chromosomal Instability in Cancer and Therapeutic Responses

Abstract

Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses.

The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels

“…CIN can be structural or numerical. Structural CIN results in phenotypic manifestations, such as the formation of micronuclei, binuclei, or multinuclei, whereas numerical CIN gives rise to aneuploidy-an abnormal number of chromosomes 8 . However, the prominent effect in chromosomally unstable cells is an increase in the formation of micronuclei, reflecting the fact that this outcome may arise from two major chromosomal segregation errors-lagging chromosome or chromatin bridge formation-during the preceding mitosis.…”

Comparative analysis of the bioenergetics of human adenocarcinoma Caco-2 cell line and postoperative tissue samples from colorectal cancer patients

“…However, it remains unknown to what extent their metabolic and bioenergetic profile corresponds to that in the primary tumor. In vitro studies are also complicated by complex intratumoral heterogeneity (Fessler and Medema 2016) and genetic instability of cancer cells (Vargas-Rondon et al 2017). In vitro research with HCC cell lines often do not take into account the possible impact of (micro) environmental conditions on the tumor gene expression profile and its metabolism.…”

Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

“…cell-to-cell heterogeneity) or micronucleus formation may hold diagnostic, prognostic or therapeutic value within the clinic; however, future studies are required to specifically investigate the correlation between changes in nuclear areas or micronucleus formation with treatment response and disease outcome for all relevant cancer types. In addition, the genomic alterations resulting in reduced expression may represent genetic susceptibilities that can be leveraged for highly specific and targeted killing of cancer cells (reviewed in 10,[58][59][60] ). Synthetic lethality is one such approach that is now showing potential within the clinic and may hold tremendous therapeutic potential is targeting the reduced expression of cohesion genes in many cancer types 61,62 .…”