Chromosome instability and tumor lethality suppression in carcinogenesis

Abstract

The maintenance and survival of each organism depends on its genome integrity. Alterations of essential genes, or aberrant chromosome number and structure lead to cell death. Paradoxically, cancer cells, especially in solid tumors, contain somatic gene mutations and are chromosome instability (CIN), suggesting a mechanism that cancer cells have acquired to suppress the lethal mutations and/or CIN. Herein we will discuss a tumor lethality suppression concept based on the studies of yeast genetic interactions and transgenic mice. During the early stages of the multistep process of tumorigenesis, incipient cancer cells probably have adopted genetic and epigenetic alterations to tolerate the lethal mutations of other genes that ensue, and to a larger extent CIN. In turn, CIN mediated massive gain and loss of genes provides a wider buffer for further genetic reshuffling, resulting in cancer cell heterogeneity, drug resistance and evasion of oncogene addiction, thus CIN may be both the effector and inducer of tumorigenesis. Accordingly, interfering with tumor lethality suppression could lead to cancer cell death or growth defects. Further validation of the tumor lethality suppression concept would help to elucidate the role of CIN in tumorigenesis, the relationship between CIN and somatic gene mutations, and would impact the design of anticancer drug development.

Role of hypoxia in the hallmarks of human cancer

“…It is well known that genomic instability is responsible for cellular changes that confer progressive transformation on cancer cells [Hanahan and Weinberg, 2000;Huang et al, 2007;Shen et al, 2008]. Genotoxic stress activates cell cycle checkpoints and delays cell cycle progression to allow for DNA repair [Bao et al, 2001].…”

Correlation of the melt rheological properties with the foaming behavior of immiscible blends of poly(2,6‐dimethyl‐1,4‐phenylene ether) and poly(styrene‐co‐acrylonitrile)

“…In case of heterogeneous nucleation, the nucleation efficiency is strongly related to the dispersion of the nucleation agent (nucleant) in the matrix and its size [35][36][37][38]. Additionally, the nucleant surface, more precisely, the surface tension, the shape as well as the roughness, are further important factors, which determine whether heterogeneous nucleation is energetically favored as compared to homogeneous nucleation [35][36][37][38]. Assuming uniformly distributed particles with uniform size and nucleation of one foam cell per nucle- ant, the potential cell density in a heterogeneously nucleated system, N th , can be estimated according to…”

“…As can be seen, all blends reveal dramatically higher cell densities compared to the neat SAN. This phenomenon is most likely due to the presence of the finely and homogeneously dispersed PPE phase throughout the whole specimens, providing effective heterogeneous nucleation sites that, under the selected experimental parameters, dominate the homogeneous nucleation [35][36][37][38]. However, the cell density in the blend systems appears, at first glance, surprisingly constant across the composition range, and is significantly lower than the theoretically predicted nucleation density, even for an assumed average particle size of PPE of 2.5 lm, well beyond the experimentally observed phase size at low PPE contents.…”

DNA copy number aberrations associated with aneuploidy and chromosomal instability in breast cancers

“…The defects of the mechanisms potentially cause abnormal mitosis and genetic alterations, leading to aneuploidy and/or genomic instability (12). There are multiple mechanisms to confer aneuploidy and CIN on a tumor cell (13). Tumor phenotype including aneuploidy and genomic instability is thus primarily affected by their genomic changes.…”