The Effects of the Stromal Cell-Derived Cyclooxygenase-2 Metabolite Prostaglandin E2 on the Proliferation of Colon Cancer Cells

It is well known that tumor-surrounding stromal tissues support tumor development through secreting soluble factors such as various cytokines, chemokines and growth factors. It has also been suggested that tumor-associated fibroblast and immune cells have a high expression of cyclooxygenase-2 (COX-2) and produce and secrete several prostaglandins (PGs) to adjacent cancer tissues. From these findings, we assumed that COX-2 inhibition may have an anti-cancer effect on cancer cells even without COX-2 expression in COX-2-dependent mechanisms through blocking the effect of stroma-derived PGs. Here, because of the complex involvement of various factors in vivo, we investigated this possibility with an in vivo-mimicking model using a trans-well system. To test our hypothesis, we used COX-2-transfected cell lines as stromal cells in our model. When we co-cultured cancer cells (LS174T without COX-2 expression) with COX-2-high-stromal cells in the trans-well membrane system, we observed that proliferation of cancer cells was promoted and VEGF synthesis was up-regulated significantly. These effects were blocked completely by COX-2 inhibitors and PI3K inhibitors and partially by the EP4 antagonist. Even if some cancer cells do not express COX-2, they were found to have expression of PG receptors and PG-related downstream signaling molecules associated to cell viability and our observation suggests that these cells can be influenced by PGs derived from stromal tissues. These findings also suggest that COX-2 inhibitors can be used to control the interaction between cancer and surrounding stromal tissues and suppress the proliferation of cancer cells regardless of the expression of COX-2 in cancer cells.