肿瘤是个难以愈合的“伤口”。化疗对肿瘤微环境的反复破坏常引起由巨噬细胞和成纤维细胞等肿瘤间质细胞参与的血管重建和组织修复，后者很可能成为肿瘤化疗抵抗或转移的重要原因。本组前期工作发现，肿瘤中巨噬细胞增生，激活成纤维细胞促进纤维化；靶向成纤维细胞包膜可增进肿瘤化疗效果；化疗中侵入坏死区的巨噬细胞，表达Tie2参与血管修复。然而，化疗对这些细胞积聚与分化的影响，化疗后组织损伤修复的细胞与分子机制目前多有不明。 . 本项目拟采用多种间质细胞特异的转基因小鼠，构建肿瘤化疗伤口愈合模型，结合临床样本大数据分析，研究这些细胞参与血管修复的分子机制，包括：1）化疗伤口的细胞及分子特征；2）血管修复中各间质细胞间的相互作用；3）化疗引起的巨噬细胞／成纤维细胞激活与分化； 4）功能干预及5）它们与临床肿瘤病人预后的关系。本研究将有助于深入阐明化疗抵抗机制，为提高肿瘤化疗效果提供新思路。

Tumors are "wounds that never heal". Tissue repair responses often affect both tumor development and tumor therapy. During chemotherapy, repeated tissue damage and repair, including destruction and reconstruction of blood vessels, may influence not only therapeutic effect, but also tumor metastasis. Our previous works show that macrophages massively accumulate in tumor microenvironment and they are involved in liver injury repair by activating hepatic stellate cells and promoting liver fibrosis; targeting tumor associated fibroblasts enhances chemotherapeutic effect; and in response to chemotherapy, macrophages infiltrate into tumor necrotic area and express Tie2, which is related to vascular repair and tumor relapse. However, how chemotherapy influences accumulation and differentiation of host cells as well as the detail of cellular and molecular mechanism of tissue repair responses upon chemotherapy remain largely unclear..This project aims to investigate how the key stromal cell players are involved in tissue repair responses, especially blood vessel reconstruction upon chemotherapy. We will employ various macrophage/fibroblast-specific transgenic mice to establish chemotherapy-induced tumor injury-repair mouse models and analyze the clinical significance of experimental findings. It will focus on: 1) cellular and molecular characteristics of chemotherapy-induced tumor injury; 2) interaction of different tumor stromal cells in vascular repair; 3) polarization of macrophages and/or fibroblasts during tissue repair; 4) their function and possible modification; and 5) correlation of basic findings with the clinical observation of chemotherapy. The study may help us to understand the mechanism of tumor resistance more precisely and to improve the tumor current chemotherapeutic strategy.