APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice

Abstract

Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202–210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157–162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APCMin/+ mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of β-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer.

Cytokinesis and cancer

“…Recent observations indicate that APC (adenomatous polyposis coli) mutations found in human colorectal cancer may inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and thus blocking initiation of cytokinesis. This supports the idea that tetraploidy may represent a first step in genomic instability and eventually cancer [6]. Moreover, it was recently found that abscission mediated via inactivation of the regulatory kinase Aurora B promotes completion of chromosome segregation and thus protects against tetraploidization and cancer [5].…”

Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer

“…Whether the defects we observe in MT dynamics and centrosomes arise from specific loss of p120 or from consequential reduction in other cadherincatenin components in mKers remains unclear. In this regard, it may be relevant that adenomatous polyposis coli is often an associate of AJs because loss of adenomatous polyposis coli function appears to result in genomic instability in colon cancer cells (32,33).…”

Loss of Rassf1a enhances p53-mediated tumor predisposition and accelerates progression to aneuploidy

“…Mitotic dysfunction is often associated with tetraploidization (Caldwell et al, 2007;Ganem et al, 2007). Tetraploid cells are genetically unstable and highly predisposed to the development of aneuploidy during neoplastic progression (Storchova and Kuffer, 2008).…”