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Tumor-derived exosomes educate dendritic cells to promote tumor metastasis via HSP72/HSP105-TLR2/TLR4 pathway.

ABSTRACT: How the tumor microenvironment educates dendritic cells (DCs) to promote tumorigenesis remains largely unknown, and the role of tumor-derived exosomes (TEXs) in tumorigenesis is controversial. Here, we report that in addition to the activation of DCs, TEXs induce DCs to produce increased interleukin-6 (IL-6), which dramatically promotes tumor invasion by increasing signal transducer and activator of transcription 3 (STAT3)-dependent matrix metalloproteinases 9 transcription activity in tumor cells. HSP72 and HSP105 on the TEX surface induce IL-6 secretion of DCs in a TLR2- and TLR4-dependent manner. In addition, HSP72 and HSP105 are predominantly present on exosomes from sera of tumor patients but not healthy people, indicating their value in tumor prediction. Furthermore, TEXs are powerful activators of DCs, and the depletion of IL-6 converts TEXs from tumor promoters to tumor inhibitors in vivo. Therefore, our results reveal a novel mechanism for the TEX-mediated education of DCs and shed light on the conundrum that TEXs present by playing dual roles in tumorigenesis.

SUBMITTER: Shen Y

PROVIDER: S-EPMC5706613 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Tumor-derived exosomes educate dendritic cells to promote tumor metastasis via HSP72/HSP105-TLR2/TLR4 pathway.

Shen Yingying Y Guo Danfeng D Weng Lixia L Wang Shoujie S Ma Zeyu Z Yang Yunshan Y Wang Pingli P Wang Jianli J Cai Zhijian Z

Oncoimmunology 20170818 12

How the tumor microenvironment educates dendritic cells (DCs) to promote tumorigenesis remains largely unknown, and the role of tumor-derived exosomes (TEXs) in tumorigenesis is controversial. Here, we report that in addition to the activation of DCs, TEXs induce DCs to produce increased interleukin-6 (IL-6), which dramatically promotes tumor invasion by increasing signal transducer and activator of transcription 3 (STAT3)-dependent matrix metalloproteinases 9 transcription activity in tumor cel ...[more]

PMID: 29209566

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Project description:Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Dataset Information

Tumor-derived exosomes educate dendritic cells to promote tumor metastasis via HSP72/HSP105-TLR2/TLR4 pathway.

Publications

Tumor-derived exosomes educate dendritic cells to promote tumor metastasis via HSP72/HSP105-TLR2/TLR4 pathway.

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