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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.


Related in: MedlinePlus

Metastatic growth of EMT6-Luci tumour is enhanced by 4T1 tumour-secreted factors that modulate MDSC induction and infiltration.(a–c) EMT6-Luci cells were either IV injected alone or in combination with a condition medium from 4T1 cells that lead to enhanced metastatic growth and induction of MDSC subsets. ***P<0.0005, two-way analysis of variance test (d) EMT6-Luci cells (50k per per injection) were either IV injected into naïve BALB/c mice or into the 4T1-primed mice (in which primary 4T1 tumours resected after 10 days) which resulted in enhanced metastatic growth. (e–g) Flow cytometry sorted tumour-derived mMDSCs (100k) or lung-derived gMDSCs (100k) from 4T1 tumour-bearing mice were co-injected with the 4T1-luci cells (50k per injection) and MDSC subsets injections were repeated 1 week later. (g,h) Animals injected with lung-derived gMDSCs showed accelerated metastatic growth and shortened survival compared to the control or mMDSCs co-injected group. Results are presented as mean±s.d. (5–10 mice in each group).
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f8: Metastatic growth of EMT6-Luci tumour is enhanced by 4T1 tumour-secreted factors that modulate MDSC induction and infiltration.(a–c) EMT6-Luci cells were either IV injected alone or in combination with a condition medium from 4T1 cells that lead to enhanced metastatic growth and induction of MDSC subsets. ***P<0.0005, two-way analysis of variance test (d) EMT6-Luci cells (50k per per injection) were either IV injected into naïve BALB/c mice or into the 4T1-primed mice (in which primary 4T1 tumours resected after 10 days) which resulted in enhanced metastatic growth. (e–g) Flow cytometry sorted tumour-derived mMDSCs (100k) or lung-derived gMDSCs (100k) from 4T1 tumour-bearing mice were co-injected with the 4T1-luci cells (50k per injection) and MDSC subsets injections were repeated 1 week later. (g,h) Animals injected with lung-derived gMDSCs showed accelerated metastatic growth and shortened survival compared to the control or mMDSCs co-injected group. Results are presented as mean±s.d. (5–10 mice in each group).

Mentions: We reasoned whether 4T1 tumour-secreted cytokines might enhance the metastatic ability of less invasive EMT6 tumours in mice. To provide evidence for this, we injected EMT6-Luci cells in BALB/c mice which were injected (intraperitoneally) with conditioned medium (CM) derived from 4T1 cells (Fig. 8a,b) which resulted in enhanced EMT6-Luci lung metastasis compared to control medium injected animals. Enhanced pulmonary metastasis also correlated with the expansion of MDSCs in 4T1 CM injected animals (Fig. 8c). To further corroborate, we generated 4T1-primed mice in which orthotopically injected 4T1 tumours were resected after 10 days and predicted that the 4T1 tumours within 10 days will create a pro-metastasis microenvironment. Therefore, the pro-metastatic microenvironment created by 4T1 tumours will enhance the metastatic ability of EMT6 tumours, which are otherwise non-metastatic. As predicted, the metastatic ability of EMT6-Luci tumours was enhanced in 4T1-primed mice (Fig. 8d, right panel) compared to the injection in naïve mice (Fig. 8d, left panel).


Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade
Metastatic growth of EMT6-Luci tumour is enhanced by 4T1 tumour-secreted factors that modulate MDSC induction and infiltration.(a–c) EMT6-Luci cells were either IV injected alone or in combination with a condition medium from 4T1 cells that lead to enhanced metastatic growth and induction of MDSC subsets. ***P<0.0005, two-way analysis of variance test (d) EMT6-Luci cells (50k per per injection) were either IV injected into naïve BALB/c mice or into the 4T1-primed mice (in which primary 4T1 tumours resected after 10 days) which resulted in enhanced metastatic growth. (e–g) Flow cytometry sorted tumour-derived mMDSCs (100k) or lung-derived gMDSCs (100k) from 4T1 tumour-bearing mice were co-injected with the 4T1-luci cells (50k per injection) and MDSC subsets injections were repeated 1 week later. (g,h) Animals injected with lung-derived gMDSCs showed accelerated metastatic growth and shortened survival compared to the control or mMDSCs co-injected group. Results are presented as mean±s.d. (5–10 mice in each group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5384228&req=5

f8: Metastatic growth of EMT6-Luci tumour is enhanced by 4T1 tumour-secreted factors that modulate MDSC induction and infiltration.(a–c) EMT6-Luci cells were either IV injected alone or in combination with a condition medium from 4T1 cells that lead to enhanced metastatic growth and induction of MDSC subsets. ***P<0.0005, two-way analysis of variance test (d) EMT6-Luci cells (50k per per injection) were either IV injected into naïve BALB/c mice or into the 4T1-primed mice (in which primary 4T1 tumours resected after 10 days) which resulted in enhanced metastatic growth. (e–g) Flow cytometry sorted tumour-derived mMDSCs (100k) or lung-derived gMDSCs (100k) from 4T1 tumour-bearing mice were co-injected with the 4T1-luci cells (50k per injection) and MDSC subsets injections were repeated 1 week later. (g,h) Animals injected with lung-derived gMDSCs showed accelerated metastatic growth and shortened survival compared to the control or mMDSCs co-injected group. Results are presented as mean±s.d. (5–10 mice in each group).
Mentions: We reasoned whether 4T1 tumour-secreted cytokines might enhance the metastatic ability of less invasive EMT6 tumours in mice. To provide evidence for this, we injected EMT6-Luci cells in BALB/c mice which were injected (intraperitoneally) with conditioned medium (CM) derived from 4T1 cells (Fig. 8a,b) which resulted in enhanced EMT6-Luci lung metastasis compared to control medium injected animals. Enhanced pulmonary metastasis also correlated with the expansion of MDSCs in 4T1 CM injected animals (Fig. 8c). To further corroborate, we generated 4T1-primed mice in which orthotopically injected 4T1 tumours were resected after 10 days and predicted that the 4T1 tumours within 10 days will create a pro-metastasis microenvironment. Therefore, the pro-metastatic microenvironment created by 4T1 tumours will enhance the metastatic ability of EMT6 tumours, which are otherwise non-metastatic. As predicted, the metastatic ability of EMT6-Luci tumours was enhanced in 4T1-primed mice (Fig. 8d, right panel) compared to the injection in naïve mice (Fig. 8d, left panel).

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.


Related in: MedlinePlus