Regulation of mast cell survival and apoptosis
A sign of many inflammatory disorders is mast cell hyperplasia that often correlates with the severity of the disease. This hyperplasia can be regulated by several means; i.e., proliferation, differentiation, migration and survival/apoptosis. Since the number of mast cells and other immune cells increases at the site of inflammation, the process of apoptosis is essential to diminish the enhanced amount of cells and regain homeostasis again after inflammation. The importance and regulation of BCl-2 family members, a big group of both pro-survival and pro-apoptotic proteins, for mast cell survival and apoptosis have been described. We have performed these studies mainly by taking advantage of mice, or embryonic stem cells, deficient in genes for members of the bcl-2 family.
In order to break an ongoing inflammatory response, i.e., chronic inflammation, apoptosis could be induced in the inflammatory cells. This could be done in several ways; e.g., increase the expression of pro-apoptotic proteins, decrease the expression of survival proteins, or inhibit the interaction between bcl-2-family members that will lead to apoptosis. All three possibilities will be investigated in this proposal. Several techniques are applied to investigate the mechanisms for regulation of mast cell apoptosis, including in vitro studies and in vivo or ex vivo studies in mouse models or human tissue samples. Small molecular inhibitors are screened for their usefulness to induce mast cell apoptosis.
There is a great need for new therapeutic targets for the treatment of e.g., severe allergic inflammations such as chronic asthma and atopic eczema. Mast cells are attractive direct targets, where limiting their life span, and thereby their number in the chock organ, should have beneficial effects on the resolution of allergic inflammation. To decipher the regulation of mast cell survival and to identify ways to induce apoptosis in these cells therefore have obvious clinical implications.
Mast cells in tumourigenesis
Mast cells are inflammatory cells of distributed in almost all tissues in the body. Upon activation, mast cells release their granule content (e.g., histamine and proteases like tryptase, chymase and metalloproteinases), generate lipid mediators and secrete cytokines and growth factors. Although best known for their role in allergic reaction, mast cells are today considered to be versatile effector and regulatory cells, involved in many disorders such as chronic inflammations and tumours.
Mast cells are often present in tumours or in the surrounding tumour stroma. An association between mast cells and tumors is clear but the relevance of this relationship is not. There is a growing body of data indicating that mast cells promote tumor growth and metastasis via release of various mediators rather than provide active defense against tumors. Direct evidence for the contribution of mast cell derived proteases during experimental skin carcinogenesis in mice has been reported. Mast cells can stimulate tumor growth either directly through cell-cell interactions and release of cytokines and growth factors, or indirectly by facilitating angiogenesis and tissue remodeling. Mast cells are associated with angiogenesis in tumors such as hemangioma, carcinomas, lymphoma and multiple myeloma. Many mediators produced by mast cells are known to promote angiogenesis either directly, such as histamine, IL-8 and VEGF, or indirectly by proteases that degrade extracellular matrix leading to the release of matrix-associated growth factors. A potential role for mast cells in tumor development is thus evident, but to fully understand their role in the process, the mechanisms behind the accumulation of these cells in tumor areas and the specific triggers that set them into action need to be defined.
In our research we are primarily investigating the role of mast cells in lymphomas. We investigate the presence and activation of mast cells in biopsies taken from patients, and perform mechanistic studies in vitro. One important project is to understand how mast cells in some tumours might promote tumourigenesis, while in others they fight the tumour.