Mutual influence of tumor cells, extracellular matrix and macrophages in intraocular murine melanoma

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Uveal melanoma is the most common primary intraocular tumor in the adult Caucasian population. While local treatment of the primary tumor is very promising, prognosis worsens dramatically with the occurrence of liver metastasis. Several studies were able to show that macrophages are involved in the pathogenesis of uveal melanoma and other malignancies.In our murine tumor model, intraocularly injected tumor cells develop tumor masses with histologic characteristics of aggressive melanoma (such as angiogenesis, vasculogenic mimcry and infiltration with macrophages) similar to human uveal melanoma and other tumors. Since the eye represents a semi-closed compartment with access to constant blood supply, these intraocular tumors represent a model for studies of isolated parameters in general tumor biology.The purpose of our studies is the analysis of the mutual influence of macrophages and tumor cells with respect to macrophage polarisation and prognostically relevant vasculogenic mimicry. We hypothesize that proangiogenic M2 macrophages contribute to tumor growth via the stimulation of tumor cells to build vasculogenic mimicry. Our aim is to identify the factors involved in this process, in particular with regard to vasculogenic mimicry and macrophage polarisation. We further want to establish a reliable marker for vasculogenic mimicry. The designed in vitro experiments with human and murine tumor cells and respective macrophages in a transwell-membrane cell culture system. Our mouse model is used for a morphological control of the in vitro findings. We further want to establish a 3D cell culture, which might replace our mouse model for specific questions. In a second step, factors involved in the production of vasculogenic mimicry and macrophage polarisation will be identified and selectively knocked out in order to study specific signalling pathways and potentially therapeutic strategies.The origin of tumor-associated macrophages (CCR2-dependent versus CX3CR1-dependent recruitment) and the specific role of macrophages on tumor growth and the development of vascular structures are investigated in CCR2- and CX3CR1-knockout mice. In summary, these studies will help to understand the interaction between the tumor and macrophages as well as the origin of tumor-associated macrophages with respect to macrophage polarisation and producation of vasculogenic mimicry which are prognostically relevant for metastases and thus a worse prognosis.