2021-01-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/675685"The tumor microenvironment contains not only tumor cells but also immune cells and stromal cells. Among the innate and adaptive immune cells that were recruited to the tumor site, macrophages are the most abundant immune cells in the tumor microenvironment and are present at all stages of tumor progression. Usually the major functions of macrophages are to clear dead cells, process antigens for presentation, and to protect hosts from invading pathogens or tumor development1. However, substantial evidence indicates that tumor-associated macrophages (TAMs) greatly reduce their phagocytic activity, suppress T cell immunity and promote many important features of tumor progression including angiogenesis, invasion, and metastasis. Upon macrophages migrating to the tumor site by the attraction of tumor-derived factors, they shape favorable environments, e.g. chronic low grade inflammation, decreased immune surveillance, and polarizing to M2 phenotypes, neo-angiogenesis and tumor metastasis. These changes would increase the difficulties for the treatment of cancers. We recently found that ZNRF1, an E3 ubiquitin ligase, would regulate the function of macrophages and change the polarization of macrophages2. Neo-angiogenesis is important for the growth of cancers. Besides tumor cells, immune cells in the tumor microenvironment also contribute to the growth of neo-vasculature. In order to study the effect of ZNRF1 in immune cells on angiogenesis, we subcutaneously injected Lewis lung carcinoma cells into mice with specific deletion of Znrf1 in hematopoietic cells, and found less tumor-induced neo-angiogenesis in hematopoietic cell-specific Znrf1-deleted mice. Our preliminary results clearly demonstrate that less tumor-induced neo-angiogenesis in hematopoietic cell-specific Znrf1-deleted mice. Thus, we hypothesize that ZNRF1 plays a crucial role in macrophages to influence tumor neo-angiogenesis. We proposed three specific aims in this subproject: Aim 1. To determine the role of ZNRF1 in the interaction between macrophages and endothelial cells. Aim 2. To investigate the influence of ZNRF1 in macrophages on tumor growth and migration and their possible mechanisms. Aim 3. To study the effect of ZNRF1 on cancer growth and metastasis in vivo. This study will provide new insights into the interplay among macrophages, endothelial cells and cancer cells, and their roles in the tumor microenvironment."腫瘤微環境腫瘤相關巨噬細胞血管生成tumor microenvironmenttumor-associated macrophag