Age-related expression of PEDF/EPC-1 in human endometrial stromal fibroblasts: Implications for interactive senescence

Aging is the major risk factor for many cancers, and age-related changes in the tissue microenvironment can facilitate tumor growth. This study uses h uman endometrial cells to begin to test the hypothesis that age-related cha nges in pigment epithelium-derived factor/early population doubling cDNA-1 (PEDF/EPC-1) levels create an environment that is more permissive to tumor growth. Endometrial stromal fibroblasts (ESF) are the predominant cell type in the human endometrium and exert regulatory control over the glandular e pithelial cells, which are the source of most tumors. As ESF age in vitro, their ability to regulate appropriate growth and differentiation of epithel ial cells declines. Endometrial epithelial cells in primary culture express ed relatively low levels of PEDF/EPC-1 mRNA. In contrast, early passage qui escent ESF from adult donors produce higher levels of the 1.5-kb PEDF/EPC-1 mRNA and 50-kDa secreted protein than epithelial cells. As ESF age in vitr o the relative abundance of PEDF/EPC-1 mRNA declines, as does the level of PEDF/EPC-1 protein secreted into cell culture medium. Treatment with PEDF/E PC-1 protein had no effect on ESF proliferation but did inhibit anchorage-d ependent and anchorage-independent proliferation of endometrial carcinoma c ells in a dose- and time-dependent manner. These findings imply that an age -related loss of PEDF/EPC-1 expression by ESF could eliminate a negative re gulator of cancer cell growth and, thereby, contribute to the age-related i ncrease in cancer incidence. (C) 1999 Academic Press.