Role of macrophages and the tumor suppressor PTEN in colon associated cancer

Colorectal cancer (CRC) originates from epithelial cells lining the colon or rectum of the gastrointestinal tract and represents the third most common form of cancer worldwide. One subtype of CRC is called colitis-associated cancer (CAC) and develops at high frequency in patients with inflammatory bowel disease. Cells of the innate and adaptive immune system are such as dendritic cells, tumor-associated M2-like macrophages (TAMs), myeloid derived suppressor cells (MDSCs), B- and T-cells are present in the tumor stroma of CRCs. The immune cells in the stroma provide an inflammatory microenvironment that can promote tumorigenesis but inflammatory infiltrates can also execute a profound anti-tumorigenic activity. The interplay and activation of inflammatory cells determine their pro- and anti-tumorigenic activities. However, molecular mechanisms regulating the innate and adaptive immune response in CRC are still weakly defined. We have recently demonstrated that the Phosphatidylinositol-3 Kinase (PI3K)/PTEN signaling pathway is a crucial regulator of the innate immune response in macrophages. Deletion of the PI3K antagonist PTEN in macrophages, which results in sustained and enhanced PI3K activity, reduces the inflammatory response leading to diminished cytokine production. Preliminary data suggest that PTEN besides its inflammatory properties, is involved in the polarization of M1 and M2 macrophages, but it is unclear whether the IKK/NFB pathway is directly affected by modulation of the PI3K/PTEN signaling axis. Therefore, we want to study the role of PTEN in NFkB dependent pro-inflammatory gene expression as well as macrophage polarization and plasticity in more detail and would like to evaluate our in vitro findings for cancer development using a colitis associated cancer model in mice.

Macrophages are a relevant innate immune cell type in the host defense against various pathogens. One of their most important features is plasticity, which gives macrophages the opportunity to react rapidly to drastic changes in the tissue microenvironment. In particular in tumors immune cells play important functions to control proliferation and metastasis. Macrophages function as a double edged sword. On the one hand they react to cellular transformation and are able to kill tumor cells, but on the other hand the tumor may benefit from infiltrating macrophages. In some cases tumor associated macrophages are a negative prognostic marker. Therefore it is vital to understand the different activation states macrophages can acquire and how this is controlled on a cellular level. One of the pathways important in this respect is the PI3K/PTEN signaling pathway. With this project we wanted to shed some light on the role of these relevant signaling molecules in macrophage plasticity in health and disease.