Abstract
Tumor relapse after chemotherapy is a major hurdle for successful cancer therapy. Chemotherapeutic drugs select for resistant tumor cells and reshape tumor microenvironment, including the blood supply system. Using animal models, we observed on macrophages in tumor tissue a close correlation between upregulated Tie2 expression and tumor relapse upon chemotherapy. Conditional deletion of Tie2 expression in macrophages significantly prohibited blood supply and regrowth of tumors. Tie2+ macrophages were derived from tumor-infiltrating Tie2-CD11b+ cells and hypoxia-induced Tie2 expression on these cells. Mechanistically, expression of Tie2 prevented macrophages from apoptosis in stress conditions via the AKT-dependent signaling pathway. Together, these results demonstrate that Tie2 expression by macrophages is necessary and sufficient to promote the reconstruction of blood vessels after chemotherapy, shedding new light on developing novel strategies to inhibit tumor relapse. Cancer Res; 76(23); 6828-38. ©2016 AACR.
Highlights
The molecular mechanisms leading to tumor relapse after treatment with cytotoxic drugs are still not completely understood [1]
Analyzing tumor sections by CD31 staining after chemotherapy, we observed that tumor relapse was associated with vigorous vessel reconstruction within 14 days
We examined tumor blood vessels at day 9 after chemotherapy when the vessel reconstruction stayed in an intermediate state
Summary
The molecular mechanisms leading to tumor relapse after treatment with cytotoxic drugs are still not completely understood [1]. Many studies focused on the analysis of chemoresistant, either intrinsically or acquired, characteristics of tumor cells during treatment [2]. Solid tumors are complex organs with a reactive stroma accompanying cancer cells. There is increasing evidence that the outcome of chemotherapy is dependent on non–tumor cell factors. It is widely accepted that tumorspecific immune responses can determine the efficacy of anticancer therapies with conventional cytotoxic drugs [3]. In another example of chemotherapy for prostate cancer, cytotoxic drugs
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