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

葡萄膜黑色素瘤是最常见的原发性眼内肿瘤在成年白人人口。虽然原发肿瘤的局部治疗是非常有希望的，但预后与肝转移的发生密切相关。在我们的小鼠肿瘤模型中，眼内注射的肿瘤细胞形成具有侵袭性黑色素瘤组织学特征（如血管生成、血管生成性mimcry和巨噬细胞浸润）的肿瘤块，与人葡萄膜黑色素瘤和其他肿瘤相似。由于眼睛代表了一个半封闭的隔间，获得恒定的血液供应，这些眼内肿瘤代表了一个模型，在一般的肿瘤biology.The目的的孤立参数的研究是相互影响的巨噬细胞和肿瘤细胞的巨噬细胞极化和血管相关的血管生成拟态的分析。我们假设促血管生成M2巨噬细胞通过刺激肿瘤细胞建立血管生成拟态来促进肿瘤生长。我们的目的是确定参与这一过程的因素，特别是关于血管生成拟态和巨噬细胞极化。我们还希望建立一个可靠的标记血管生成拟态。在transwell膜细胞培养系统中使用人和鼠肿瘤细胞和相应巨噬细胞的设计体外实验。我们的小鼠模型用于体外发现的形态学对照。我们还想建立一个3D细胞培养，它可能会取代我们的小鼠模型来解决特定的问题。在第二步骤中，参与血管生成拟态和巨噬细胞极化的产生的因子将被鉴定并选择性地敲除，以研究特定的信号传导途径和潜在的治疗策略。研究了CCR2依赖性募集与CX3CR1依赖性募集之间的关系以及巨噬细胞对肿瘤生长和血管结构发育的特定作用。和CX3CR1敲除小鼠。总之，这些研究将有助于了解肿瘤和巨噬细胞之间的相互作用以及肿瘤相关巨噬细胞的起源，巨噬细胞极化和血管生成拟态的产生与转移密切相关，因此预后较差。

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.