Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2.

ABSTRACT: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages. TRAIL-R suppression in tumor cells impaired CCL2 production and diminished both lung MDSC presence and tumor growth. In accordance, the receptor of CCL2, CCR2, is required to facilitate increased MDSC presence and tumor growth. Finally, TRAIL and CCL2 are co-regulated with MDSC/M2 markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes accumulation of tumor-supportive immune cells in the cancer microenvironment, thereby revealing a tumor-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology.

SUBMITTER: Hartwig T

PROVIDER: S-EPMC5316415 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Integrin α3β1 on Tumor Keratinocytes Is Essential to Maintain Tumor Growth and Promotes a Tumor-Supportive Keratinocyte Secretome.

Project description:The development of integrin-targeted cancer therapies is hindered by incomplete understanding of integrin function in tumor cells and the tumor microenvironment. Previous studies showed that mice with epidermis-specific deletion of the α3 integrin subunit fail to form skin tumors during two-step chemical tumorigenesis, indicating a protumorigenic role for integrin α3β1. Here, we generated mice with tamoxifen-inducible, epidermis-specific α3 knockout to determine the role of α3β1 in the maintenance of established tumor cells and/or the associated stroma. Genetic ablation of α3 in established skin tumors caused their rapid regression, indicating that α3β1 is essential to maintain tumor growth. Although reduced proliferation and increased apoptosis were observed in α3β1-deficient tumor cells, these changes followed a robust increase in stromal apoptosis. Furthermore, macrophages and fibulin-2 levels were reduced in stroma following α3 deletion from tumor cells. Mass spectrometric analysis of conditioned medium from immortalized keratinocytes showed that α3β1 regulates a substantial fraction of the keratinocyte secretome, including fibulin-2 and macrophage CSF1; RNA in situ hybridization showed that expression of these two genes was reduced in tumor keratinocytes in vivo. Our findings identify α3β1 as a regulator of the keratinocyte secretome and skin tumor microenvironment and as a potential therapeutic target.

| S-EPMC7680721 | biostudies-literature

NKAP alters tumor immune microenvironment and promotes glioma growth via Notch1 signaling.

Project description:BackgroundGlioma is one of the most aggressive malignant brain tumors which is characterized with highly infiltrative growth and poor prognosis. NKAP (NF-?B activating protein) is a widely expressed 415-amino acid nuclear protein that is overexpressed by gliomas, but its function in glioma was still unknown.MethodsCCK8 and EDU assay was used to examine the cell viability in vitro, and the xenograft models in nude mice were established to explore the roles of NAKP in vivo. The expressions of NKAP, Notch1 and SDF-1 were analyzed by immunofluorescence analysis. The expression of NKAP and Notch1 in glioma and normal human brain samples were analyzed by immunohistochemical analysis. In addition, CHIP, Gene chip, western blot, flow cytometry, immunofluorescence, ELISA and luciferase assay were used to investigate the internal connection between NKAP and Notch1.ResultsHere we showed that overexpression of NKAP in gliomas could promote tumor growth by contributing to a Notch1-dependent immune-suppressive tumor microenvironment. Downregulation of NKAP in gliomas had abrogated tumor growth and invasion in vitro and in vivo. Interestingly, compared to the control group, inhibiting NKAP set up obstacles to tumor-associated macrophage (TAM) polarization and recruitment by decreasing the secretion of SDF-1 and M-CSF. To identify the potential mechanisms involved, we performed RNA sequencing analysis and found that Notch1 appeared to positively correlate with the expression of NKAP. Furthermore, we proved that NKAP performed its function via directly binding to Notch1 promoter and trans-activating it. Notch1 inhibition could alleviate NKAP's gliomagenesis effects.Conclusionthese observations suggest that NKAP promotes glioma growth by TAM chemoattraction through upregulation of Notch1 and this finding introduces the potential utility of NKAP inhibitors for glioma therapy.

| S-EPMC6612223 | biostudies-literature

Heparan sulfate promotes TRAIL-induced tumor cell apoptosis.

Project description:TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity ( K D = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.

| S-EPMC10402122 | biostudies-literature

Heparan sulfate promotes TRAIL-induced tumor cell apoptosis.

Project description:TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report, we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (KD = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL, and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.

| S-EPMC10945736 | biostudies-literature

GLUT1 Regulates the Tumor Immune Microenvironment and Promotes Tumor Metastasis in Pancreatic Adenocarcinoma via ncRNA-mediated Network.

Project description:Pancreatic adenocarcinoma (PAAD) is a digestive tumor with extremely high malignancy. Previous studies have reported that Glucose transporter 1 (GLUT1) contributes to the aggressive tumor progression in various cancer types and indicates an unfavorable prognosis. However, the function of GLUT1 in PAAD remains largely unclear. Through pan-cancer analysis of GLUT1 expression, GLUT1 expression was significantly higher in several cancer types including PAAD. Survival analysis based on the GLUT1 expression showed that GLUT1 could serve as a predictor of poor prognosis. We further predicted and screened the candidate non-coding RNAs (ncRNAs) upstream of the GLUT1 mRNA through correlation analysis, and found that the CASC19/miR-140-5p axis contributing to the regulation of GLUT1 expression. Our study suggested a link exists between GLUT1 expression and selected immunity-related indicators. Subsequent analysis revealed overexpression of GLUT1 in pancreatic cancer specimens and patients with highly expressed GLUT1 expression had worse prognosis. Based on the significantly different expression of GLUT1, the possibility that GLUT1 participated in tumor progression was identified. Using online public databases, genes co-expressed with GLUT1 were screened and enriched to metastasis-related pathways by enrichment analysis. Additionally, functional assays verified that GLUT1 could function in the metastatic process of PAAD cancer cells. Therefore, we proposed that GLUT1 might serve as a role in tumor immunity and tumor metastasis, and was expected to be a prognostic factor in PAAD.

| S-EPMC9174867 | biostudies-literature

IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma.

Project description:Amino acid catabolizing enzymes emerged as a crucial mechanism used by tumors to dampen immune responses. The L-phenylalanine oxidase IL-4 induced gene 1 (IL4I1) is expressed by tumor-associated myeloid cells of most solid tumors, including melanoma. We previously provided the only evidence that IL4I1 accelerates tumor growth by limiting the CD8+ T cell mediated immune response, in a mouse model of melanoma cell transplantation. Here, we explored the role of IL4I1 in Ret mice, a spontaneous model of melanoma. We found that IL4I1 was expressed by CD11b+ myeloid cells and that its activity correlated with disease aggressiveness. IL4I1 did not enhance tumor cell proliferation or angiogenesis, but orchestrated the remodeling of the immune compartment within the primary tumor. Indeed, the inactivation of IL4I1 limited the recruitment of polymorphonuclear myeloid-derived suppressor cells and enhanced the infiltration by Th1 and cytotoxic T cells, thus delaying tumor development and metastatic dissemination. Accordingly, human primary melanomas that were poorly infiltrated by IL4I1+ cells exhibited a higher density of CD8+ T cells. Collectively, our findings strengthen the rationale for therapeutic targeting of IL4I1 as one of the key immune regulators.

| S-EPMC5384381 | biostudies-literature

TRAIL-induced cancer secretome

Project description:To comprehensively determine which factors are secreted by cancer cells upon TRAIL stimulation, we conducted an unbiased mass spectrometric analysis of TRAIL’s secretome in resistant A549 cells.

2017-12-19 | PXD005664 | Pride

Roles of CCL2-CCR2 Axis in the Tumor Microenvironment.

Project description:Chemokines are a small family of cytokines that were first discovered as chemotactic factors in leukocytes during inflammation, and reports on the relationship between chemokines and cancer progression have recently been increasing. The CCL2-CCR2 axis is one of the major chemokine signaling pathways, and has various functions in tumor progression, such as increasing tumor cell proliferation and invasiveness, and creating a tumor microenvironment through increased angiogenesis and recruitment of immunosuppressive cells. This review discusses the roles of the CCL2-CCR2 axis and the tumor microenvironment in cancer progression and their future roles in cancer therapy.

| S-EPMC8395188 | biostudies-literature

Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation.

Project description:Circadian disruption negatively affects physiology, posing a global health threat that manifests in proliferative, metabolic, and immune diseases, among others. Because outputs of the circadian clock regulate daily fluctuations in the immune response, we determined whether circadian disruption results in tumor-associated immune cell remodeling, facilitating tumor growth. Our findings show that tumor growth rate increased and latency decreased under circadian disruption conditions compared to normal light-dark (LD) schedules in a murine melanoma model. Circadian disruption induced the loss or inversion of daily patterns of M1 (proinflammatory) and M2 (anti-inflammatory) macrophages and cytokine levels in spleen and tumor tissues. Circadian disruption also induced (i) deregulation of rhythmic expression of clock genes and (ii) of cyclin genes in the liver, (iii) increased CcnA2 levels in the tumor, and (iv) dampened expression of the cell cycle inhibitor p21WAF/CIP1 , all of which contribute to a proliferative phenotype.

| S-EPMC7556830 | biostudies-literature

Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression.

Project description:The antitumor immune response is a critical defense system that eliminates malignant cells. The failure of the system results in immune escape and proceeds to tumor growth. We have previously showed that estrogen receptor-binding fragment-associated antigen 9 (EBAG9) is a relevant cancer biomarker and facilities immune escape of cancers from the immune surveillance. EBAG9 in cancer cells suppresses T-cell infiltration into tumor in vivo, whereas that in host immune cells functions as a limiter for T-cell cytotoxicity. Considering that EBAG9 plays immune suppressive roles in both tumor and microenvironment, we here questioned whether EBAG9 is a transferable protein from cancer to surrounding T cells and affects antitumor immune response. In this study, we showed that spontaneous development of prostate cancer was repressed in a model of Ebag9 knockout mice crossed with transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. We identified TM9SF1 as a collaborative EBAG9 interactor, which regulates epithelial-mesenchymal transition (EMT) in cancer cells. Notably, extracellular vesicles (EVs) from EBAG9-overexpressing prostate cancer cells have a potential to facilitate immune escape of tumors by inhibiting T-cell cytotoxicity and modulating immune-related gene expression in T cells. Furthermore, we showed that a neutralizing antibody for EBAG9 could rescue the EV-mediated immune suppression by recovering T-cell cytotoxicity. In addition to its autocrine functions in cancer cells, EBAG9 could behave as a new class of immune checkpoint that suppresses tumor immunity in a secretory manner. We propose that EBAG9-targeting cancer treatment could be alternative therapeutic options for advanced diseases, particularly for those with EBAG9 overexpression.

| S-EPMC5833691 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data