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Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade

View Article: PubMed Central - PubMed

ABSTRACT

It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced ‘metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.

No MeSH data available.


NOS2 production by MDSCs induce EMT/CSC phenotype.(a) NOS2 induction by DPTA increased the expression of indicated cytokines and Vimentin in dose-dependent manner. (b) Inhibition of NOS2 by 1,400 W partially reduced the mMDSC-induced expression of IL1, IL6, TGFb and Vimentin. (c) NOS2 dependent pStat1 and pStat3 activation and EMT markers were confirmed by western blotting. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.
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f5: NOS2 production by MDSCs induce EMT/CSC phenotype.(a) NOS2 induction by DPTA increased the expression of indicated cytokines and Vimentin in dose-dependent manner. (b) Inhibition of NOS2 by 1,400 W partially reduced the mMDSC-induced expression of IL1, IL6, TGFb and Vimentin. (c) NOS2 dependent pStat1 and pStat3 activation and EMT markers were confirmed by western blotting. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.

Mentions: We next sought to determine whether elevated NOS2 levels induce EMT/CSC phenotype in tumour cells. Treatment of EMT6 cells with NOS2 donor, DPTA induced the expressions of indicated genes; IL1A, IL6, TGFB1 and VIM in dose-dependent manner as determined by qPCR analyses (Fig. 5a). In line with these findings, NOS2 inhibitor, 1400 W was able to suppress the mMDSC-induced transcription of these genes (Fig. 5b). Expectedly, NOS2 activation by DPTA induced the activation of pStat1 and pStat3 signalling pathways and protein levels of EMT markers, vimentin and twist, while the NOS2 inhibitor, 1,400 W suppressed the activation of the latter pathways and EMT markers (Fig. 5c). To assess the functional consequences of NOS2 mediated induction of EMT-related genes, we performed in vitro tumour invasion assay in presence and absence of NOS2 donor, DPTA. Treatment of tumour cells with DPTA resulted in increased tumour cell invasion, however, blockade of NOS2 by 1400 W suppressed the mMDSC mediated tumour cell invasion (Supplementary Fig. 5a,b). Consistently, NOS2 activation also expanded the CSC population, while NOS2 blockade reduced the mMDSC-induced CSC population (Supplementary Fig. 5c,d). Together, these data suggest that mMDSCs may exert their effects on tumour cells via inducing NOS2 production.


Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade
NOS2 production by MDSCs induce EMT/CSC phenotype.(a) NOS2 induction by DPTA increased the expression of indicated cytokines and Vimentin in dose-dependent manner. (b) Inhibition of NOS2 by 1,400 W partially reduced the mMDSC-induced expression of IL1, IL6, TGFb and Vimentin. (c) NOS2 dependent pStat1 and pStat3 activation and EMT markers were confirmed by western blotting. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384228&req=5

f5: NOS2 production by MDSCs induce EMT/CSC phenotype.(a) NOS2 induction by DPTA increased the expression of indicated cytokines and Vimentin in dose-dependent manner. (b) Inhibition of NOS2 by 1,400 W partially reduced the mMDSC-induced expression of IL1, IL6, TGFb and Vimentin. (c) NOS2 dependent pStat1 and pStat3 activation and EMT markers were confirmed by western blotting. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.
Mentions: We next sought to determine whether elevated NOS2 levels induce EMT/CSC phenotype in tumour cells. Treatment of EMT6 cells with NOS2 donor, DPTA induced the expressions of indicated genes; IL1A, IL6, TGFB1 and VIM in dose-dependent manner as determined by qPCR analyses (Fig. 5a). In line with these findings, NOS2 inhibitor, 1400 W was able to suppress the mMDSC-induced transcription of these genes (Fig. 5b). Expectedly, NOS2 activation by DPTA induced the activation of pStat1 and pStat3 signalling pathways and protein levels of EMT markers, vimentin and twist, while the NOS2 inhibitor, 1,400 W suppressed the activation of the latter pathways and EMT markers (Fig. 5c). To assess the functional consequences of NOS2 mediated induction of EMT-related genes, we performed in vitro tumour invasion assay in presence and absence of NOS2 donor, DPTA. Treatment of tumour cells with DPTA resulted in increased tumour cell invasion, however, blockade of NOS2 by 1400 W suppressed the mMDSC mediated tumour cell invasion (Supplementary Fig. 5a,b). Consistently, NOS2 activation also expanded the CSC population, while NOS2 blockade reduced the mMDSC-induced CSC population (Supplementary Fig. 5c,d). Together, these data suggest that mMDSCs may exert their effects on tumour cells via inducing NOS2 production.

View Article: PubMed Central - PubMed

ABSTRACT

It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced &lsquo;metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.

No MeSH data available.