High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation

Abstract

Expression of a truncated allele of the Apc tumor suppressor causes intestinal tumors with a low rate of chromosomal instability (CIN). Increasing the rate of CIN suppresses tumor growth without inhibiting tumor initiation in both the small intestine and colon, suggesting that increasing CIN is a useful chemotherapeutic strategy.

Chromosomal instability: A common feature and a therapeutic target of cancer

“…An alternative strategy is, instead, to increase the severity of CIN beyond the threshold level, so that cells become lethal. This approach must be technically feasible considering that cancer cells with CIN must have defective function in controlling mitosis [173]. Identification of the molecular basis of such a threshold point should allow the development of molecular targets (Figure 3).…”

Germline mutation contribution to chromosomal instability

“…In a landmark study, increased CIN associated with reduced CENP-E expression in CENP-E +/− mice was found to promote tumor development in lymphocytes and lungs, where aneuploidy is inherently low, but inhibited tumor growth in the liver, which has inherently higher levels of aneuploidy (Weaver et al 2007). More recently, it has been demonstrated that the increased rate of chromosome mis-segregation in compound mutant Apc Min/+ CENP-E +/− mice is associated with greater cell death and suppression of tumor progression compared to singly mutant Apc Min/+ and CENP-E +/− mice (Zasadil et al 2016). These observations collectively suggest elevating CIN as a potential chemotherapeutic strategy in a genetically sensitized background.…”

“…In vitro and in vivo observations from several studies have demonstrated that low levels of CIN may promote tumor initiation but at elevated levels, CIN may actually be protective and inhibit tumorigenesis (Rao et al 2005, 24:9 Weaver et al 2007, Silk et al 2013, Zasadil et al 2016. It was noticed in an earlier investigation that BubR1 +/− Apc Min/+ compound mutant mice, which exhibited increased karyotypic instability, were found to have increased formation of colonic polyps but at the same time, a notable decrease in small intestine adenomas (Rao et al 2005).…”

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[16,32,72,95,96] These inconsistent findings may be explained by different rates and types of CIN in the various models. Indeed, it has been suggested that high rates of CIN inhibit tumor progression, while lower CIN rates allow for tumor evolution [5,93,94] (also see Figure 2b and c). Importantly, CIN does not only seem to affect cancer growth, but also the ability of cancer to adapt and spread as transient CIN induction can lead to tumor recurrence.…”

“…On the one hand CIN itself can lead to tumorigenesis in some models, [91,92] but on the other hand, CIN has been found to act as a tumor suppressor in other models. [75,93,94] Furthermore, yet other CIN models are suggesting that CIN only enhances tumorigenesis in a tumorprone background. [16,32,72,95,96] These inconsistent findings may be explained by different rates and types of CIN in the various models.…”