Cancer and Aging Section, Laboratory of Biosystems and Cancer

Summary of Research:

Neoplastic development of cancers is a multistep process requiring multiple genetic changes.  Significant advances have been made in the elucidation of the genes involved in genetic predisposition to cancer but less is known about the genes involved in the later stages of malignant progression.  Identification of the target genes for different steps in the cancer process is important in understanding the environmental causes of cancer as well as the endogenous causes of cancer, which include spontaneous mutations, aging, and hormones.  The role of aging in cancer is studied by cloning and characterizing genes involved in cellular aging.  Unlike tumor cells, normal cells have a finite lifespan and enter a state of irreversible growth arrest, termed cellular senescence, at the end of their lifespan.  We have shown that cellular senescence is genetically controlled and that multiple senescence genes are altered in immortal cancer cells.  Only a few senescence genes have been idnetified and efforts to clone new genes are actively being pursued.  Studies of the regulation of these genes by environmental factors may elucidate the causes of aging and cancer.

Oxidative stress is a major form of endogenous and exogenous damage to cells.  The role of oxidative stress in cell senescence and cell death  (apoptosis) is under study.  Interestingly, the same genes (e.g., p53 and Rb) are involved in cell senescence and cell death.  A better understanding of the molecular mechanism of signal transduction leading to cell sencescence or cell death through divergent pathways is required to understand cellular responses to environmental stresses, particularly oxidative damage.

As cells progress to cancer, their responses to apoptotic signals change.  Cancer cells die at a higher rate than normal cells, suggesting that environmental modulators of apoptosis can influence the rate of tumor growth.  One example of this is dietary restriction of animals, which reduces cancer progression by stimulating apoptosis of precancerous cells.  We have shown that this is in part due to modulation by dietary restricition of circulating IGF1 levels, which blocks apoptosis of cancer cells.  Further studies on the genetic controls of apoptosis may help elucidate the role of diet and other environmental factors in cancer.

Another area of active investigation is the mechanism of metastatic progression.  The malignant phenotype of a cancer cell is under both positive and negative controls but little is know about the genes that control metastasis.  We have recently cloned a novel metastasis suppressor gene, KAI1, which may be important in prostate, breast, lung, and possible other cancers.  Further studies of this and related genes may yield important new insights into cancer diagnosis and treatment.  In addition, molecular markers for the later stages of cancer progression may help define the environmental factors that influence malignant development.

Hormones are major factors in human cancers and the Cancer and Aging Section is actively involved in studying multiple aspects of hormonal carcinogenesis, including molecular alterations of hormonally associated cancers (breast, prostate, ovarian and endometrial), and the mechanisms of estrogen-induced chromosomal changes.

J. Carl Barrett, Ph.D., Chief
John Risinger
Naoki Nihei
Izumi Horikawa
Helen Tonoli
Naohiro Tsuyama