Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

Abstract

Most cancer cells are aneuploid. The chromosomal instability hypothesis contends that aneuploidy is the catalyst for transformation, whereas the gene mutation hypothesis asserts that cancer is driven by mutations to proto-oncogenes and tumor-suppressor genes, with the aneuploidy a side effect of tumorigenesis. Because genotoxic stress induced by "culture shock" can obscure the transforming potential of exogenous genes, we cultured wild-type and p53 −/− mouse embryo fibroblasts in a more physiological (serum-free) environment. Under these conditions, the cells were immortal and, more importantly, chromosomally stable. Expression of oncogenic H-RasV12 did not induce senescence, but sensitized these cells to p53-dependent apoptosis. In addition, H-RasV12 induced chromosomal instability, as well as accumulation and phosphorylation of p53. Significantly, whereas cells grown under standard conditions could be transformed by coexpression of H-RasV12 and E1A, the chromosomally stable cells were refractory to transformation, as measured by anchorage-independent growth and tumor formation in nude mice. These oncogenes required a third genetic alteration that abolished the p53 pathway to create a permissive environment that promotes rapid chromosomal instability and transformation. Oncogene-induced chromosomal instability and transformation was attenuated by antioxidants. These data indicate that chromosomal instability could be a catalyst for oncogenic transformation, and bring together aspects of the chromosomal instability hypothesis and the gene mutation hypothesis for tumorigenesis.[Keywords: Chromosomal instability; oncogenic Ras; p53; transformation] Supplemental material is available at http://www.genesdev.org.

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

“…Indeed, the same HA-RAS allele was previously reported to increase the intracellular level of reactive oxygen species in human fibroblasts, which could trigger various types of DNA damage . Of note, human oncogenic HA-RAS alleles were reported to induce genomic instability in certain cell types (see for example (Denko et al, 1994;Woo and Poon, 2004) but not in others , as in our case with human fibroblasts (Figure 2). The reason of these discrepancies are not known but could rely on cell-type differences, culture conditions and/or levels of Ras activation.…”

Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability

“…39 For example, E1A/Ras transformed p53 À / À MEFs display increased GIN caused by increased ROS production. 39 We have recently reported that caspase-2 deficiency leads to increased ROS and oxidative stress in old mice 13 but whether this is the reason for the increased GIN in casp2 À / À primary cells and tumours is unclear. Interestingly, we have shown that casp2 À / À MEFs readily escape replication-induced senescence in culture and this is associated with low levels of p16 INK4a and p19 Arf .…”

p38α limits the contribution of MAP17 to cancer progression in breast tumors

“…However, ROS may be involved in the regulation of signal transduction pathways (Hancock et al, 2001;Yoon et al, 2002;Apel and Hirt, 2004). ROS can also cooperate with other oncogenic signals in cellular transformation and cancer (Suh et al, 1999;Woo and Poon, 2004). The protumoral effects by ROS, including gene expression regulation (Allen and Tresini, 2000), increased mutagenic rates (Irani et al, 1997) and genomic instability (Woo and Poon, 2004) may occur at different levels.…”

“…ROS can also cooperate with other oncogenic signals in cellular transformation and cancer (Suh et al, 1999;Woo and Poon, 2004). The protumoral effects by ROS, including gene expression regulation (Allen and Tresini, 2000), increased mutagenic rates (Irani et al, 1997) and genomic instability (Woo and Poon, 2004) may occur at different levels. High levels of ROS have been detected in cancer cell lines and tumors from different tissues (Fernandez-Pol et al, 1982;Szatrowski and Nathan, 1991;Toyokuni et al, 1995), supporting the causal link between oxidative stress and cancer (Ames, 1983;Wagner and Nebreda, 2009;Cuadrado and Nebreda, 2010).…”