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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.


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Biochemical and functional properties of metastatic 4T1 and non-invasive EMT6 murine tumours.(a) Luciferase-expressing 4T1 and EMT6 murine mammary tumour cells generate same size tumours in syngeneic BALB/c mice. Scale bar, 1 cm. (b–d) 4T1 tumour-bearing animals develop spontaneous pulmonary metastasis and show early pulmonary infiltration and enlarged spleen compared to the EMT6 tumour-bearing animals. Scale bar, 100 μm (lung sections); and 1 cm (gross organ pictures). (e,f) 4T1 tumour cells produce higher levels of inflammatory cytokines compared to the non-metastatic EMT6 or 67NR as assessed by cytokine antibody array. (g) Mouse transcriptome analyses of 4T1 and EMT6 tumours grown in BALB/c mice reveal 781 differentially expressed genes. (h) Top common genes that are upregulated in both EMT6 and 4T1 tumours. (i) Select genes (implicated in metastatic process) that are distinctly upregulated in 4T1 tumour compared to the EMT6 are. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.
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f1: Biochemical and functional properties of metastatic 4T1 and non-invasive EMT6 murine tumours.(a) Luciferase-expressing 4T1 and EMT6 murine mammary tumour cells generate same size tumours in syngeneic BALB/c mice. Scale bar, 1 cm. (b–d) 4T1 tumour-bearing animals develop spontaneous pulmonary metastasis and show early pulmonary infiltration and enlarged spleen compared to the EMT6 tumour-bearing animals. Scale bar, 100 μm (lung sections); and 1 cm (gross organ pictures). (e,f) 4T1 tumour cells produce higher levels of inflammatory cytokines compared to the non-metastatic EMT6 or 67NR as assessed by cytokine antibody array. (g) Mouse transcriptome analyses of 4T1 and EMT6 tumours grown in BALB/c mice reveal 781 differentially expressed genes. (h) Top common genes that are upregulated in both EMT6 and 4T1 tumours. (i) Select genes (implicated in metastatic process) that are distinctly upregulated in 4T1 tumour compared to the EMT6 are. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.

Mentions: To investigate the role of immune system in the metastatic process, we used the metastatic (4T1) and less invasive (EMT6) murine mammary cell lines in a syngeneic (BALB/c) mouse xenograft model. Murine 4T1 cells were originally isolated from a spontaneous mammary tumour in the BALB/c strain and have been reported as metastatic and also exhibit the characteristics of human basal/triple-negative breast cancer (TNBC) subtype14. In contrast, the EMT6 and 67NR murine cell lines have been shown to be less invasive1516. We first verified the tumorigenic and metastatic ability of EMT6 and 4T1 tumours, when 50,000 cells from both lines were injected into the mammary fat pads of, they produced similarly sized tumours within 8 weeks (Fig. 1a). The 4T1 tumours, however, showed pulmonary infiltrates as early as 1 week post implantation and developed spontaneous metastases by 5 weeks in 100% of animals (Fig. 1b), which also displayed enlarged spleens size and weight (Fig. 1c,d).


Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade
Biochemical and functional properties of metastatic 4T1 and non-invasive EMT6 murine tumours.(a) Luciferase-expressing 4T1 and EMT6 murine mammary tumour cells generate same size tumours in syngeneic BALB/c mice. Scale bar, 1 cm. (b–d) 4T1 tumour-bearing animals develop spontaneous pulmonary metastasis and show early pulmonary infiltration and enlarged spleen compared to the EMT6 tumour-bearing animals. Scale bar, 100 μm (lung sections); and 1 cm (gross organ pictures). (e,f) 4T1 tumour cells produce higher levels of inflammatory cytokines compared to the non-metastatic EMT6 or 67NR as assessed by cytokine antibody array. (g) Mouse transcriptome analyses of 4T1 and EMT6 tumours grown in BALB/c mice reveal 781 differentially expressed genes. (h) Top common genes that are upregulated in both EMT6 and 4T1 tumours. (i) Select genes (implicated in metastatic process) that are distinctly upregulated in 4T1 tumour compared to the EMT6 are. 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

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getmorefigures.php?uid=PMC5384228&req=5

f1: Biochemical and functional properties of metastatic 4T1 and non-invasive EMT6 murine tumours.(a) Luciferase-expressing 4T1 and EMT6 murine mammary tumour cells generate same size tumours in syngeneic BALB/c mice. Scale bar, 1 cm. (b–d) 4T1 tumour-bearing animals develop spontaneous pulmonary metastasis and show early pulmonary infiltration and enlarged spleen compared to the EMT6 tumour-bearing animals. Scale bar, 100 μm (lung sections); and 1 cm (gross organ pictures). (e,f) 4T1 tumour cells produce higher levels of inflammatory cytokines compared to the non-metastatic EMT6 or 67NR as assessed by cytokine antibody array. (g) Mouse transcriptome analyses of 4T1 and EMT6 tumours grown in BALB/c mice reveal 781 differentially expressed genes. (h) Top common genes that are upregulated in both EMT6 and 4T1 tumours. (i) Select genes (implicated in metastatic process) that are distinctly upregulated in 4T1 tumour compared to the EMT6 are. Results are presented as mean±s.d. (n=3). *P<0.05, **P<0.005, unpaired t-test.
Mentions: To investigate the role of immune system in the metastatic process, we used the metastatic (4T1) and less invasive (EMT6) murine mammary cell lines in a syngeneic (BALB/c) mouse xenograft model. Murine 4T1 cells were originally isolated from a spontaneous mammary tumour in the BALB/c strain and have been reported as metastatic and also exhibit the characteristics of human basal/triple-negative breast cancer (TNBC) subtype14. In contrast, the EMT6 and 67NR murine cell lines have been shown to be less invasive1516. We first verified the tumorigenic and metastatic ability of EMT6 and 4T1 tumours, when 50,000 cells from both lines were injected into the mammary fat pads of, they produced similarly sized tumours within 8 weeks (Fig. 1a). The 4T1 tumours, however, showed pulmonary infiltrates as early as 1 week post implantation and developed spontaneous metastases by 5 weeks in 100% of animals (Fig. 1b), which also displayed enlarged spleens size and weight (Fig. 1c,d).

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