Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

Abstract

Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles’ heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.

Advancements in the Management of Cervical Intraepithelial Neoplasia: A Comprehensive Review

“…CIN, a common cancer feature, drives tumor evolution and heterogeneity. Studies have elucidated that cancer cells can tolerate certain levels of CIN, granting them adaptive advantages, genetic diversity, and resilience against environmental stresses, including anti-cancer therapies [ 8 ]. However, excessive CIN levels can be detrimental to tumor survival and progression, indicating the existence of CIN thresholds that tumor cells can withstand [ 8 ].…”

“…Studies have elucidated that cancer cells can tolerate certain levels of CIN, granting them adaptive advantages, genetic diversity, and resilience against environmental stresses, including anti-cancer therapies [ 8 ]. However, excessive CIN levels can be detrimental to tumor survival and progression, indicating the existence of CIN thresholds that tumor cells can withstand [ 8 ]. The research underscores that optimal levels of CIN may enable clonal populations to circumvent selection barriers, highlighting the intricate interplay between CIN levels and tumor development.…”

“…While low levels of CIN can foster genetic diversity and adaptive advantages, heightened rates of chromosome missegregation can exert tumor-suppressive effects. This dual role of CIN and aneuploidy as both oncogenic triggers and tumor suppressors underscores the complex balance in cancer progression [ 8 ]. Moreover, studies have demonstrated that CIN can profoundly affect the tumor microenvironment, modulate immune responses, and influence metabolic signaling pathways.…”

The two sides of chromosomal instability: drivers and brakes in cancer

“…[424][425][426] While enhancing CIN could potentially be a powerful method to eradicate tumors, the feasibility of such therapies will depend on many factors including CIN status and the capacity of the tumor cells to tolerate CIN. 267,[427][428][429][430][431][432][433][434][435][436][437] Moreover, it is important to consider that untransformed cells will also be affected by the CIN-inducing agents and thus will suffer from low to moderate CIN rates. This may predispose these cells to become tumorigenic, leading to therapy-induced tumorigenesis subsequently.…”

“…Furthermore, while several SAC inhibitors that increase CIN show promising potential for reducing tumor growth and have already entered clinical trial phase, the success of such therapies depends on factors such as CIN status and the capacity of the tumor cells to tolerate CIN. 267,[427][428][429][430][431][432][433][434][435][436][437] Despite these challenges, recent advances suggest promising possibilities for a new, personalized, CIN-specific approach to anti-tumor therapy. 358,406,410,411,[423][424][425][426]438,[451][452][453][454][455] Moreover, considering CIN as the fuel for genomic diversity, it is important to acknowledge the challenges posed by tumor evolution.…”