Wachstumsfaktor-vermittelte Rekrutierung von Entzündungszellen ins Tumor-Stroma: Funktionelle Rolle in Angiogenese und Tumorprogression

在恶性肿瘤的HaCaT皮肤SCC模型中，持续的血管生成是肿瘤侵袭的先决条件，在此之前是诱导强烈和持续的炎症。在我们资助的第一年，我们展示了Gr1+/CD11b+细胞在皮肤SCCs的血管生成和肿瘤侵袭中的关键贡献。此外，我们发现IL-6和SDF-1以及基质金属蛋白酶-9和基质金属蛋白酶-13是促进炎症浸润性血管生成和侵袭的重要因素。基于这些数据，我们将继续分析炎性浸润物在肿瘤血管生成和侵袭中的作用。我们将根据MDSC的表型来描述促进血管生成的Gr1+/CD11b+细胞的表型。此外，我们将根据巨噬细胞与肿瘤相关的Gr1+/CD11b+细胞的相互作用来确定巨噬细胞(M1与/M2)的分化状态。巨噬细胞在诱导和维持血管生成中的不同功能将被识别。将分析IL-1、β、IL-6和SDF-1等特异性生长因子对肿瘤相关巨噬细胞和Gr1+细胞募集和分化的影响，以及它们在促进肿瘤发生中的作用。最终，我们的目标是阻止这些因子介导的相互作用，这些相互作用对于促进炎症渗透的血管生成和侵袭的招募和分化至关重要。

In malignant tumors of the HaCaT skin SCC model persistent angiogenesis, the prerequisite for tumor invasion, is preceded by the induction of a strong and persistent inflammation. In our 1rst year of funding we demonstrated a crucial contribution of Gr1+/CD11b+ cells to angiogenesis and tumor invasion in skinSCCs. Additionally, we identified IL-6 and SDF-1 as well as MMP-9 and MMP-13 as important contributors to the establishment of an angiogenesis and invasion promoting inflammatory infiltrate. Based on these data we will continue to analyze the function of the inflammatory infiltrate in tumor angiogenesis and invasion. We will characterize the phenotype of the angiogenesis promoting Gr1+/CD11b+ cells specifically with respect to an MDSC phenotype. Furthermore we will determine the differentiation status of macrophages (M1 versus TAM/M2) in the context of their interaction with tumor associated Gr1+/CD11b+ cells. Differential macrophage functions in the induction and maintenance of angiogenesis will be identified. The effect of specific growth factors such as IL-1β, IL-6 and SDF-1 on the recruitment and differentiation of tumor associated macrophages and Gr1+ cells will be analyzed and their influence on promoting tumor angogenesis will be characterized. Ultimately we aim at blocking those factor-mediated interactions that are essential for the recruitment and differentiation of an angiogenesis and invasion promoting inflammatory infiltrate.