UCSF

In nature, there is a strong correlation between physiological aging and tumor susceptibility. Understanding how youthful animals resist tumors may provide new insights into tumor biology, particularly if genes that regulate aging influence tumor susceptibility. Mutations in the C. elegans gene gld-1 produce a lethal germline tumor. We find that mutations that extend C. elegans' lifespan, by caloric restriction, mitochondrial dysfunction, or a reduction in daf-2/insulin/IGF-1 signaling, confer resistance to these tumors. Remarkably, mutations that reduce daf-2 function, which double the lifespan of worms, can completely prevent the shortened lifespan caused by these tumors. daf-2 mutations protect tumorous animals by triggering apoptosis through the FOXO transcription factor DAF-16 and the tumor-suppressor p53, and by activating daf-16 dependent and daf-16-independent processes that inhibit tumor cell division. Interestingly, the inhibition of mitosis is specific to tumor cells. Together these findings suggest a fundamental link between mechanisms that promote cell maintenance and animal longevity and mechanisms that inhibit tumor cell proliferation.

To identify downstream components of this process, we have screened through 734 potential daf-16/FOXO targets and found 16 genes that are necessary for daf-2 mutations to fully suppress tumor growth, and 14 genes that normally promote tumor growth. Approximately one quarter of these genes are known to have roles in human cancer, suggesting that the other genes may be involved in mammalian cancer as well.