期刊
JOURNAL OF EXTRACELLULAR VESICLES
卷 11, 期 12, 页码 -出版社
WILEY
DOI: 10.1002/jev2.12294
关键词
angiogenesis; exosomes; head and neck squamous cell carcinoma; macrophages; small extracellular vesicles; TGF beta
类别
资金
- National Institutes of Health [R01-CA 168628, U01-DE-029759]
- Deutsche Akademie der Naturforscher Leopoldina - Nationale Akademie der Wissenschaften [LPDR 2019-02, LPDS 2017-12]
- Narodowe Centrum Nauki [UMO-2017/26/M/NZ5/00877, 2016/22/M/NZ5/00667]
- Medical University of Warsaw [MB/M/48(79)]
- Walter Schulz Foundation
- Verein zur Foerderung der wissenschaftlichen Zahnheilkunde (VFwZ)
Transforming growth factor beta (TGF beta) is a major component of tumor-derived small extracellular vesicles (TEX) that can promote tumor growth and pro-tumor activities in the tumor microenvironment (TME). TGF beta(+) TEX can stimulate macrophage chemotaxis and reprogram primary human macrophages to promote angiogenesis and tumor progression. Inhibition of TGF beta signaling in TEX can suppress these pro-tumor activities in head and neck squamous cell carcinoma (HNSCC).
Transforming growth factor beta (TGF beta) is a major component of tumor-derived small extracellular vesicles (TEX) in cancer patients. Mechanisms utilized by TGF beta(+) TEX to promote tumor growth and pro-tumor activities in the tumor microenvironment (TME) are largely unknown. TEX produced by head and neck squamous cell carcinoma (HNSCC) cell lines carried TGF beta and angiogenesis-promoting proteins. TGF beta(+) TEX stimulated macrophage chemotaxis without a notable M1/M2 phenotype shift and reprogrammed primary human macrophages to a pro-angiogenic phenotype characterized by the upregulation of pro-angiogenic factors and functions. In a murine basement membrane extract plug model, TGF beta(+) TEX promoted macrophage infiltration and vascularization (p < 0.001), which was blocked by using the TGF beta ligand trap mRER (p < 0.001). TGF beta(+) TEX injected into mice undergoing the 4-nitroquinoline-1-oxide (4-NQO)-driven oral carcinogenesis promoted tumor angiogenesis (p < 0.05), infiltration of M2-like macrophages in the TME (p < 0.05) and ultimately tumor progression (p < 0.05). Inhibition of TGF beta signaling in TEX with mRER ameliorated these pro-tumor activities. Silencing of TGF beta emerges as a critical step in suppressing pro-angiogenic functions of TEX in HNSCC.
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