PGD2CRI · The role of Prostaglandin D2 in cancer-associated inflammation

The role of Prostaglandin D2 in cancer-associated inflammation

Cancer is a disease of old age and a major health challenge for western society with a rapidly increasing aged population. One of the common features of cancer development is the evasion of tumour cells from recognition by the immune system. Thus, even though the body tries to fight against the tumour, cancers cells develop strategies to block destruction by immune cells and even hijack the immune system to promote tumour growth. One of the main cell types in charge of this tumour-induced immune evasion is the macrophage. This versatile cell type acquires a profile that helps the tumour defend itself against immune system by the production of cytokines and growth factors that block the naturally occurring response against the tumour. In this project we have focused on uncovering the signalling pathways triggered inside macrophages upon contact with tumour cells and how they allow macrophages to promote cancer development. We observed that macrophages incubated in culture medium coming from ovarian cancer cells, what we call Conditioned medium (CM), induced changes inside the macrophages that made these macrophages more susceptible to pro-tumour polarisation while blocking anti-tumour activity of the cells. We observed that one of the effects of CM on macrophages was the loss of cholesterol in the cells membrane, which led to a decrease in specific micro-domains present on cell membrane called lipid rafts that are important in regulating how the cell responds to external signals. We speculate that the loss of these lipid rafts affects cell signalling in a way that specifically increases the pro-tumour activities of macrophages. Using a mouse model of ovarian cancer we confirmed that lipid rafts were also depleted in Tumour-associated macrophages (TAM). We found the PI3K-signalling pathway was crucial for the effects of CM on macrophages, we used mice that lacked of this protein only in the immune cells to study its role in ovarian cancer development. We observed that the number of TAM in the mice lacking this protein was higher than in normal mice, while the number of cancer cells was actually lower compared to that in normal mice. These data indicate that PI3K activity in immune cells is required for their tumour-promoting function, in the absence of PI3K immune cells can inhibit tumour growth. These experiments suggest PI3K-inhibition could be beneficial for the treatment of cancer by increasing number of antitumor macrophages within the tumour micro-environment, offering a new therapeutic approach that could be complementary to those already in use. In conclusion, we have shed some light onto the effects of tumour cells on macrophages, opening new lines of research for the development of potential new therapies for the treatment of cancer.

Data: CORDIS, © European Union