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The role of interaction between gastrins and peroxisome proliferator-activated receptor gamma in gastrointestinal cancers

Final Activity Report Summary - GI CANCER (The role of interaction between gastrins and peroxisome proliferator-activated receptor gamma in gastrointestinal cancers)

The work supported by this grant is in line with the cancer strategy of the European Commission's Sixth Research Framework Programme (FP6). It relates to understanding how gastrointestinal (GI) cancer becomes established and enabled cooperation between scientists from the Member States resulting in transfer of information between the collaborating partners.

Gastrointestinal (GI) cancer is one of the most common causes of mortality in the European Union with 25% of mortality attributable to GI cancer. Understanding the mechanisms leading to cancer development and its progression are crucial to enable early detection and therapy of GI cancers.

The hormone gastrin play an important pro-proliferative, anti-apoptotic, and carcinogenic role in GI cancers. We have shown that gastrin and its precursors exert promoting cell survival effects via activation of phosphorylation of PKB/Akt and by increasing anti-apoptotic signals such as Bcl-2 protein. It has been also reported that epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) increase transcription of the gastrin gene and that there is a possible link between gastrin and peroxisome proliferator-activated receptor gamma (PPARgamma). However, little was known about the relationship between gastrin and PPARgamma receptors in relation to apoptosis. PPAR? is involved in cell cycle withdrawal and can promote cell differentiation, exert an antiproliferative action and inhibit angiogenesis.

There are also studies showing that activation of PPARgamma promotes the development of colon cancer. These data are in sharp contrast with studies that attribute anticancer effects to PPARgamma in gastrointestinal malignancies. Probably, the action of PPARgamma on cell cycle and proliferation depends on the cell type and presence of other stimuli that predispose cells to cancer development and these mechanisms need further investigation.

Achievement of the scientific objectives:
1. There is a feedback loop between gastrin and PPARgamma. The aim will be to investigate molecular mechanisms of this relationship with a view to development of a new anti-GI cancer therapy.
2. PPARgamma expression is alternatively modulated by gastrin.
3. Gastrin peptide promotes cancer cells growth by increased level of annexin II cell surface concentration in these cells jointly with the tumour-promoting effects of PPARgamma agonists.

Achievement of broader objectives relating to knowledge transfer and collaboration:
1. The fellow used her new skills she gained during her previous Marie Curie Intra-European Fellowship at the Academic Unit of Cancer Studies, University of Nottingham In the United Kingdom, including molecular cloning, interfering RNA, real-time PCR.
2. Collaborative links during her fellowship were continued with partners in Germany and France.