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 human endometrial cells to begin to test the hypothesis that age-related changes 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 epithelial cells, which are the source of most tumors. As ESF age in vitro, their ability to regulate appropriate growth and differentiation of epithelial cells declines. Endometrial epithelial cells in primary culture expressed relatively low levels of PEDF/EPC-1 mRNA. In contrast, early passage quiescent 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 vitro 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/EPC-1 protein had no effect on ESF proliferation but did inhibit anchorage-dependent and anchorage-independent proliferation of endometrial carcinoma cells 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 regulator of cancer cell growth and, thereby, contribute to the age-related increase in cancer incidence.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
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D
Palmieri
J M
JM
Watson
C A
CA
Rinehart
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D016922:Cellular Senescence / Q000502:physiology*; D016889:Endometrial Neoplasms / Q000473:pathology; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D005136:Eye Proteins; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D009414:Nerve Growth Factors; D014176:Protein Biosynthesis; D011506:Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D015843:Serpins / Q000096:biosynthesis* / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099174:Pigment Epithelium-Derived Factor
D000970:Antineoplastic Agents; D005136:Eye Proteins; D006131:Growth Inhibitors; D009414:Nerve Growth Factors; D011506:Proteins; D012333:RNA, Messenger; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor