期刊
CELL REPORTS
卷 16, 期 11, 页码 2914-2927出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.08.035
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类别
资金
- American Cancer Society [121839-RSG-12-076-01-LIB]
- National Cancer Institute Cancer Center [P30 CA008748]
- National Cancer Institute fellowship [5F31CA167863]
- graduate training programs of the Weill Cornell Medical School
- Gerstner Sloan-Kettering Graduate School
Tumor-associated macrophages play critical roles during tumor progression by promoting angiogenesis, cancer cell proliferation, invasion, and metastasis. Cysteine cathepsin proteases, produced by macrophages and cancer cells, modulate these processes, but it remains unclear how these typically lysosomal enzymes are regulated and secreted within the tumor microenvironment. Here, we identify a STAT3 and STAT6 synergy that potently upregulates cathepsin secretion by macrophages via engagement of an unfolded protein response (UPR) pathway. Whole-genome expression analyses revealed that the T(H)2 cytokine interleukin (IL)-4 synergizes with IL-6 or IL-10 to activate UPR via STAT6 and STAT3. Pharmacological inhibition of the UPR sensor IRE1 alpha blocks cathepsin secretion and blunts macrophage-mediated cancer cell invasion. Similarly, genetic deletion of STAT3 and STAT6 signaling components impairs tumor development and invasion in vivo. Together, these findings demonstrate that cytokine-activated STAT3 and STAT6 cooperate in macrophages to promote a secretory phenotype that enhances tumor progression in a cathepsindependent manner.
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