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

Abstract

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 might have an anticancer 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 Transwell system. To test our hypothesis, we used COX-2-transfected cell lines as stromal cells in our model. When we cocultured cancer cells (LS174T cells without COX-2 expression) with COX-2-high stromal cells in the Transwell membrane system, we observed that the proliferation of cancer cells was promoted and vascular endothelial growth factor synthesis was up-regulated significantly. These effects were blocked completely by COX-2 inhibitors and phosphoinositide-3-kinase inhibitors and partially by the PG E 2 receptor 4 antagonist. Even if some cancer cells did not express COX-2, they were found to have expression of PG receptors and PG-related downstream signaling molecules associated with cell viability. 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.

Antiproliferative Effects of Fluoxetine on Colon Cancer Cells and in a Colonic Carcinogen Mouse Model

“…Considering that angiogenesis takes place within PCCS, and proliferation as well as stem cell markers might be related to that [15]–[16], [29]–[30], we investigated the potential connection between these events under FLX treatment. CD133-positive cells expressing VEGF were found within PCCS in mice subjected either to MNNG or MNNG+FLX treatments (Figure 4A).…”

“…Tumor stroma constitutes 60–90% of the colon tumor mass [14], and PCCS surrounding the cryptal bottom has been reported to initiate certain steps in colon tumor development, such as increased proliferation, microvessel formation, VEGF-synthesis, regulation of self-renewal and differentiation of intestinal cells [15]–[18]. ACFs are considered a suitable experimental model for studying early stages of colon cancer formation, mainly due to their close resemblance with the development of cancer in rodents and humans [17], [19].…”

Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention

“…In a stromal cell system, COX-2 transfected stromal cells significantly increased colorectal tumor cell proliferation as well as VEGF synthesis. This effect was partially inhibited by EP4 antagonism [105]. A second critical mechanism underlying the proliferative effects of PGE 2 was recently demonstrated by showing that the pro-metastatic protein, human enhancer of filamentation 1 (HEF1; NEDD9), links PGE 2 to the cell-cycle machinery in colon cancer cells [106].…”

Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model

“…It has been reported that AA-derived prostaglandins enhance cell proliferation in colon cancer cells ( 26 ). Because intestinal PGE 2 was decreased in Fads1 null mice (described above), we examined the level of cell proliferation in mouse colon crypts.…”