Vincent R. Torti, Ph.D.

Dissertation research performed under the guidence of Dr. David G. Kaufman

ABSTRACT
    Aging is the primary risk factor for many prevalent cancers including some of the highest incidence cancers such as prostate cancer in men and breast and uterine cancers in women. Despite this, little is know about how advanced age contributes to the increased incidences of cancer. Most cancer are derived from epithelial cells. Stromal cells have been shown to exert potent influences over epithelial cell growth, function and state of differentiation. Furthermore stromal cells have been shown to undergo profound growth, biochemical and gene expression changes as they age. We therefore hypothesize that these age-associated changes occur in stromal cells such that their regulatory influence over epithelial cells is altered. We believe the age-associated alterations in stromal cells are such that they make the tissue micro-environment favorable for epithelial tumorigenesis. To address this hypothesis we use human endometrial tissue as a model for stromal-epithelial interactions that change with stromal cell aging. We have obtained a young (low cumulative population doubling (cpd)) and an old (high cpd) endometrial stromal cell strains. We have shown that age-associated changes in these stromal cells affect the proliferation, morphology, colony forming efficiency and anchorage independent growth of endometrial epithelial cells. Soluble factors secreted by old stromal cells stimulate the growth of epithelial cells as compared to factors secreted by young stromal cells demonstrating a paracrine mechanism of interaction. Paracrine stimulation of growth by old stromal cells is maintained in stromal-epithelial cell coculture interactions as well. We have further demonstrated that interleukin-1b (IL-1b) is a potent inhibitor of epithelial cell growth, that stromal cell secreted IL-1b levels decline with age and are partially responsible for the increased growth of epithelial cells in medium conditioned by old stromal. cells. In addition, levels of intracellular IL-1a levels increase with the growth inhibition of epithelial cells in vitro and in vivo and appear to be absent in cancerous tissue and carcinoma-derived cell lines. Taken together, these results suggest stromal cell secreted IL-1b acts as an age-regulated paracrine inhibitor of epithelial cell proliferation while IL-1a may act intracellularly as a growth inhibitor in normal or differentiated epithelial cells.