The tissue microenvironment, which is mostly comprised of extracellular matrix, adipocytes, blood vessels, immune, and mesenchymal fibroblast cells, plays an important role in normal organogenesis, tissue homeostasis, and can lead to carcinogenesis when pathologically disrupted. Tissue recombination studies have shown that mesenchymal signals direct the fate of adjoining epithelial cells. For example, recombination of vaginal epithelium with uterine mesenchyme results in development of uterine epithelium. The importance of the microenvironment in cancer has been reported in human studies showing that paracrine signals from cancer associated fibroblast (CAF) cells play an important role in tumour development, progression and drug resistance. Gene sequencing of breast cancers and endometrial polyps has revealed genetic mutations in the stromal component. However, the contribution of the stromal microenvironment to the progression of endometrial hyperplasia and cancer has not been well explored.
We studied age related changes in mouse and human uteri, and examined their contributions to the development of endometrial hyperplasia and cancer. Our studies revealed that with age, stromal cells of human and mouse uteri progressively express alpha Smooth Muscle Actin, which is not normally expressed in endometrial stromal fibroblasts and suggests that the aged stromal cells have differentiated into the carcinogenic CAF phenotype. Using a co-culture method, we showed that aged fibroblast cells actively promote the growth of human endometrial cancer cells. Proteomic analysis of aged and young uteri revealed higher expression of the growth promoting factors such as VEGF in aged uteri. Collectively, our results have shown the significance of stromal cells in endometrial cancer.
SMS and JG contributed equally to this study