MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells

Shao, Lijuan; Zhang, Bo; Wang, Lingxiong; Wu, Liangliang; Kan, Quancheng; Fan, Kexing

doi:10.1016/j.bbrc.2017.10.009

Cited by 34 publications

(22 citation statements)

References 30 publications

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“…We therefore asked whether delayed adminis- portion of Mmp9-expressing Ly6g + cells was significantly higher in the spleens of control compared with ketorolac-treated mice (Figure 8A). MMP9 is a critical protein that promotes the expansion of Ly6g + myeloid-derived suppressor cells (71). Moreover, upstream regulator analysis (68) of the granulocyte cluster indicated that NF-κB and PI3K were significantly activated in granulocytes from control mice compared with ketorolac-treated mice ( Figure 8B), which is consistent with the suppressive activity of NSAIDs (72).…”

Section: Resultssupporting

confidence: 62%

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Panigrahy¹,

Gartung²,

Yang³

et al. 2019

Journal of Clinical Investigation

110

113

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show abstract

Section: Resultssupporting

confidence: 62%

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Panigrahy¹,

Gartung²,

Yang³

et al. 2019

Journal of Clinical Investigation

110

113

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“…Moreover, MMPs cleave many extracellular proteins including ECM (collagen, proteoglycan, etc. ), matricellular proteins (osteopontin [60], CCN2/CTGF [30]), transmembrane proteins (E-cadherin, pro-HB-EGF), growth factors (latent TGFβ), and an immune checkpoint protein (PD-L1) [61]. Thus, MMP3 and CCN2/CTGF may regulate matricellular balance in the vesicular microenvironment by its moonlighting properties.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were seeded at concentrations of 4.0 × 10 4 per well in a 24-well-plate and then incubated overnight. LuM1-derived EV fraction was added to culture media in a 24-well plate at a concentration of 20 µg/mL, and then cells were cultured for 0, 15,30,60,180,360, and 540 min. Cells were then fixed with 4% paraformaldehyde in PBS for 10 min at each time point after the addition of EVs.…”

Section: Immunocytochemistry and Confocal Laser Scanning Microscopymentioning

confidence: 99%

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Okusha

Eguchi

Tran

et al. 2020

Cancers

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Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.

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“…In contrast, MMPs cleave a number of extracellular proteins including extracellular matrix (ECM: collagen, proteoglycan, etc. ), matricellular proteins (osteopontin [54], CCN2/CTGF [28]), transmembrane proteins (E-cadherin, pro-HB-EGF), growth factors (latent TGFβ), and an immune checkpoint protein (PD-L1) [55]. Thus, CCN2 and MMP3 may regulate matricellular balance in the vesicular microenvironment.…”

Section: Clinical Significance Of Mmp3 Expressionmentioning

confidence: 99%

Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer

Okusha¹,

Eguchi²,

Tran³

et al. 2020

Preprint

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Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

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MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells

Cited by 34 publications

References 30 publications

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer

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