Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via IL-22
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE217223 | GEO | 2023/01/10
REPOSITORIES: GEO
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Project description:Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via IL-22
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Project description:Hyaluronan receptor LYVE-1 is expressed by liver sinusoidal endothelial cells (LSEC), lymphatic endothelial cells and specialized macrophages. Besides binding hyaluronan, LYVE-1 mediates adhesion of leukocytes and cancer cells to endothelial cells. Here, we analyzed the impact of LYVE-1 on physiological liver functions and metastasis. Mice with deficiency of Lyve-1 (Lyve-1 KO) were analyzed using histology, immunofluorescence, RNA sequencing, plasma proteomics and flow cytometry. Liver metastasis was studied by intrasplenic/intravenous injection of melanoma (B16F10luc2, WT31) or colorectal carcinoma (MC38) cell lines. Results: Hepatic architecture, liver size, endothelial differentiation and angiocrine functions were unaltered in Lyve-1 KO mice. Hyaluronan plasma levels were significantly increased in Lyve-1-KO mice; besides, plasma proteomics revealed increased carbonic anhydrase-2 and decreased FXIIIA, potential modulators of metastatis. Furthermore, gene expression analysis of LSEC indicated regulation of immunological pathways. Therefore, liver metastasis of a highly and of a weekly immunogenic tumor, i.e. melanoma and colorectal carcinoma (CRC), was analyzed in Lyve-1 KO mice. Hepatic metastasis of B16F10 luc2 and WT31 melanoma cells, but not MC38 CRC cells, was significantly reduced in Lyve-1 KO mice. While short-term adhesion assays with B16F10 luc2 cells in vivo did not show differences between Lyve-1 KO and wild-type mice, increased numbers of resident hepatic CD4+, CD8+ and regulatory T cells were detected in Lyve-1 KO livers. In addition, iron deposition was detected in F4/80+ liver macrophages known to exert pro-inflammatory effects. Conclusions: LYVE-1 deficiency controlled hepatic metastasis in a tumor cell-specific manner reducing hepatic metastasis of melanoma, but not CRC. Anti-tumorigenic effects are likely due to enhancement of the resident hepatic immune microenvironment.
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Project description:Qi2013 - IL-6 and IFN crosstalk model
(non-competitive)
This model
[BIOMD0000000543]
describes the crosstalk between IFN-gamma and IL-6 induced
signalling; it aims to outline mechanisms and factors that may
control the interaction between both signalling pathways,
discussing a role of heterodimer formation in signalling
dysfunction.
To account for the possibility of different IFNR and gp130
binding sites for STAT1 and STAT3, model 1
[BIOMD0000000543]
assumes that there is no competition between STAT1 and STAT3 for
the receptor complexes (includes two extra reactions).
The reverse of this is true in model 2
[BIOMD0000000544]
where it generally is assumed that there is competition between
STAT1 and STAT3 for the receptor complexes.
This model is described in the article:
Elucidating the crosstalk
mechanism between IFN-gamma and IL-6 via mathematical
modelling.
Qi YF, Huang YX, Wang HY, Zhang Y,
Bao YL, Sun LG, Wu Y, Yu CL, Song ZB, Zheng LH, Sun Y, Wang GN,
Li YX.
BMC Bioinformatics 2013; 14: 41
Abstract:
BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6
(IL-6) are multifunctional cytokines that regulate immune
responses, cell proliferation, and tumour development and
progression, which frequently have functionally opposing roles.
The cellular responses to both cytokines are activated via the
Janus kinase/signal transducer and activator of transcription
(JAK/STAT) pathway. During the past 10 years, the crosstalk
mechanism between the IFN-gamma and IL-6 pathways has been
studied widely and several biological hypotheses have been
proposed, but the kinetics and detailed crosstalk mechanism
remain unclear. RESULTS: Using established mathematical models
and new experimental observations of the crosstalk between the
IFN-gamma and IL-6 pathways, we constructed a new crosstalk
model that considers three possible crosstalk levels: (1) the
competition between STAT1 and STAT3 for common receptor docking
sites; (2) the mutual negative regulation between SOCS1 and
SOCS3; and (3) the negative regulatory effects of the formation
of STAT1/3 heterodimers. A number of simulations were tested to
explore the consequences of cross-regulation between the two
pathways. The simulation results agreed well with the
experimental data, thereby demonstrating the effectiveness and
correctness of the model. CONCLUSION: In this study, we
developed a crosstalk model of the IFN-gamma and IL-6 pathways
to theoretically investigate their cross-regulation mechanism.
The simulation experiments showed the importance of the three
crosstalk levels between the two pathways. In particular, the
unbalanced competition between STAT1 and STAT3 for IFNR and
gp130 led to preferential activation of IFN-gamma and IL-6,
while at the same time the formation of STAT1/3 heterodimers
enhanced preferential signal transduction by sequestering a
fraction of the activated STATs. The model provided a good
explanation of the experimental observations and provided
insights that may inform further research to facilitate a
better understanding of the cross-regulation mechanism between
the two pathways.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000543.
To cite BioModels Database, please use:
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To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
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2024-09-02 | BIOMD0000000543 | BioModels