Molecular mechanism for development of malignant tumors: Does elucidation of molecular mechanisms contribute to the development of new therapeutic approaches?

Maintenace of genomic integrity following DNA damage depends upon the coordinated action of DNA repair and checkpoint systems. Checkpoints control a signaling system that changes the activity of cyclin-dependent kinases (cdks), resulting in delayed cell cycle progression. Arrest in G1 is thought to prevent aberrant replication of damaged DNA, while arrest in G2 allows cells to avoid segregation of defective chromosomes. The failure of the checkpoint system leads to genomic instability, which causes multiple DNA sequence alterations and chromosomal aberrations, resulting in a disposition to develop cancer. On the other hand, it has been elucidated that checkpoint abnormality is the major reason why cancer cells are sensitive to genotoxic agents, such as anti-cancer drugs and X-radiation. In normal cells, DNA damage activates checkpoints, resulting in cell cycle arrest. However, cancer cells which have checkpoint abnormalities cannot be arrested and the abrogation of the checkpoint system induces cell death via an unknown mechanism called "biochemical crush". Tumor cells which have more malignant phenotypes are considered to have defects in cell death signals which are induced by biochemical crush, and such cells are able to survive even with severe DNA damage. Accumulation of basic knowledge regarding checkpoint regulation and the cell death system is imortant for developing new therapeutic approaches for dealing with malignant tumors.