PGD2CRI

The role of Prostaglandin D2 in cancer-associated inflammation

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 Obiettivo del progetto (Objective)

'Cancer associated inflammation is well known to contribute to tumour progression,and pro-inflammatory mediators, including cytokines and prostaglandins, can drive malignancy. Prostaglandins are generated from arachidonic acid by the action of cyclooxygenase (COX), and include PGE2 as a major pro-inflammatory mediator, and PGD2 that has anti-inflammatory activity. While it is well known that PGE2 promotes tumourogenesis, there is little known about the role of PGD2 in cancer. Our aim is to establish the role of PGD2 in tumour progression in vivo using a syngeneic transplantable mouse model of ovarian cancer and a two-stage skin carcinogenesis model. We also aim to investigate the role of PGD2 in modulation of cancer-associated inflammation and tumour-associated macrophage (TAM) phenotype. We will use a mouse ovarian cancer model that recapitulates the peritoneal spread of stage IV human ovarian cancer. We will evaluate the role of PGD2 and its’ receptor, DP-1, using transgenic mice and synthetic agonists/antagonists. We will also use a two-stage skin carcinogenesis model to study the role of PGD2 in carcinogen-induced inflammation-associated cancer. There is a great deal on interest in the therapeutic use of COX inhibitors in cancer, we hypothesise that the potential benefits of COX inhibitors in inflammation-associated cancer may be hampered by inhibition of protective, anti-inflammatory PGD2. Our preliminary data suggest PGD2 is indeed protective in a mouse model of stage IV ovarian cancer. These further studies will not only establish a rationale for selective inhibition of prostaglandin synthesis rather than COX in ovarian cancer but may also suggest DP-1 receptor agonists could offer a new therapeutic avenue in inflammation-associated cancer.'

Introduzione (Teaser)

A team of European scientists has investigated the links between molecular changes in the mouse immune system and development of tumour cells.

Descrizione progetto (Article)

A common feature of cancer is its ability to evade, or even avoid, immune system defences. Even more serious is the phenomenon whereby the presence of cancer actually hijacks the patient's immune system which results in the promotion of tumour growth.

The macrophage, a member of the body's innate defences, is a common target for the cancer in an attempt to defend itself against the ravages of the immune system. Macrophage production of cytokines and growth factors block the naturally occurring response against the tumour cells.

The EU-funded project 'The role of prostaglandin D2 in cancer-associated inflammation' (PGD2CRI) aimed to identify the signalling pathways triggered by contact with cancer cells. Exactly how the cascade chemicals promote cancer development could then be unravelled.

Project scientists concocted a 'conditioned medium' (CM) by incubating macrophages from ovarian cells in a culture medium. The CM induced changes inside the macrophages that made them more susceptible to pro-tumour polarisation while blocking the anti-tumour activity of the cells.

On analysis of the changes, the team found that loss of cholesterol in the cell membrane led to a reduction in so-called lipid rafts. Loss of specific micro-domains on the cell membrane could affect signalling with a corresponding increase in pro-tumour activities. Lipid rafts are also depleted in tumour-associated macrophages (TAMs).

Also found to play a part is the P13K signalling pathway which is key in the development of prostate cancer. Experimental data indicates that P13K activity in immune cells is necessary for the effects of CM on macrophages. Moreover, P13K in the immune cells is required for their tumour-promoting function. The bonus is that P13K inhibition could be beneficial for cancer treatment by increasing the number of anti-tumour macrophages.

Knowledge of molecular cascades and cross-talk is a very potent research avenue for the battle against cancer. The PGD2CRI project has successfully shed light on the delicate balance between cancer cells and status of the immune system.