Aging and cancer development

Division Of Basic Sciences - Nci

Investigators

Abstract

BACKGROUND. Our understanding of how aging impacts tumor development is limited. While the self-renewing capacity of somatic stem cells diminishes with age, potentially reducing their susceptibility to oncogenic transformation, age-associated inflammation and declining immune function often promote tumor growth. This interplay of factors suggests that a given genetic lesion could exert different effects on tumor development depending on an individual's age. Mouse models of Ras mutant cancer offer a powerful system to investigate how aging influences both tumor cells and their microenvironment. By initiating tumors with defined genetic alterations in a temporally controlled manner in either young or aged animals, we can directly study the effects of aging on tumor progression. OBJECTIVES. 1) To examine age-shifted gene expression and functional changes in tumor initiating cells to understand how these changes affect the ability of these cells to form tumors; and 2) to characterize age-shifted tumor microenvironment to understand how fibroblasts and immune cells affect tumor development. MAJOR ACTIVITIES, SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Characterizing age-dependent changes in normal and Ras-transformed keratinocytes. We characterized the efficiency and growth rate of chemically-induced squamous cell carcinomas in young and old mice. Concurrently, we performed gene expression analysis on normal and Ras-transformed keratinocytes from both age groups. These analyses uncovered previously unknown age-associated changes in gene expression. We are currently investigating the functional consequences of these alterations in the context of skin tumor initiation. 2) Investigating the impact of aging on skin fibroblast function. We performed gene expression analysis on skin fibroblasts from young and old mice. These fibroblasts are known to produce several pro-inflammatory cytokines and are critical for keratinocyte-mediated tumor initiation in the skin. Our analysis revealed age-associated changes in fibroblast gene expression, and we are currently investigating how these changes alter fibroblast function.