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

在HaCaT皮肤SCC模型的恶性肿瘤中，持续的血管生成是肿瘤侵袭的先决条件，在此之前诱导强烈且持续的炎症。在第一年的资助中，我们证明了Gr 1 +/CD 11b+细胞对皮肤SCC中血管生成和肿瘤侵袭的重要贡献。此外，我们鉴定了IL-6和SDF-1以及MMP-9和MMP-13作为建立血管生成和侵袭促进炎性浸润的重要贡献者。基于这些数据，我们将继续分析炎症浸润在肿瘤血管生成和侵袭中的作用。我们将描述促进血管生成的Gr 1 +/CD 11b+细胞的表型，特别是相对于MDSC表型。此外，我们将确定巨噬细胞（M1与TAM/M2）在与肿瘤相关的Gr 1 +/CD 11b+细胞相互作用的背景下的分化状态。将鉴定不同巨噬细胞在诱导和维持血管生成中的功能。将分析特异性生长因子如IL-1β、IL-6和SDF-1对肿瘤相关巨噬细胞和Gr 1+细胞的募集和分化的作用，并表征其对促进肿瘤血管生成的影响。最终，我们的目标是阻断那些因子介导的相互作用，这些相互作用对于促进炎症浸润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.