The role of interleukin-1 in interactive senescence and age-related human endometrial cancer

The causes of the age-related increase in cancer rates are poorly understood. One cause could be age-related changes in the stromal/epithelial cell interactions that facilitate tumorigenesis. We tested the hypothesis that aging of human endometrial stromal fibroblasts (ESF) alters their influence over endometrial epithelial cells. ESF from adults were found to inhibit anchorage-independent proliferation, to restrain colony outgrowth, and to induce formation of normal tissue architecture by human endometrial cancer cells. As ESF age, these inhibitory influences on malignant-like behaviors by epithelial cells are altered, becoming stimulatory. Age-related change in interleukin-1alpha (IL-1alpha) expression is a molecular determinant of ESF/epithelial cell interactions. Levels of IL-1alpha and IL-1-induced mRNAs increase in ESF with age. Treatment with IL-1 accelerates age-related changes in mRNA abundance and loss of ESF restraint over malignancy-associated behaviors by epithelial cells. Transfection of ESF with the intracellular IL-1 receptor antagonist preserved the young phenotype with respect to interactions with epithelial cells and prevented age-associated increases in groalpha and IL-8 mRNA levels. Our results indicate that aging of ESF is accompanied by an interactive senescence that alters ESF signaling to cancer cells and could contribute to increased cancer rates by providing a microenvironment that is more conducive to tumorigenesis.