Dataset Information

Association of breast carcinoma growth with a non-canonical axis of IFN?/IDO1/TSP1.

ABSTRACT: Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown. Lower stromal TSP1 levels and positive tumour vascular IDO1 staining seems to associate with poor survive of patients with IDC. IDC cells induced a significantly increase in IDO1 expression in endothelial cells (ECs). IFN? exerts a similar effect on ECs. We hypothesized a tryptophan starvation theory that since tryptophan is essential for the synthesis of TSP1, IDO1 induce a decrease in tryptophan availability and a reduction in TSP1 synthesis in ECs, leading to overcoming the dormancy state of IDC cells and exacerbating conditions such as tumour invasion and metastasis. These findings identify a non-canonical role of IFN?/IDO1/TSP1 axis in microvascular niche-dominated dormancy of breast invasive ductal carcinoma with a solid foundation for further investigation of therapeutic and prognostic relevance.

SUBMITTER: Lopes-Bastos B

PROVIDER: S-EPMC5689591 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Association of breast carcinoma growth with a non-canonical axis of IFNγ/IDO1/TSP1.

Lopes-Bastos Bruno B Jin Liang L Ruge Fiona F Owen Sioned S Sanders Andrew A Cogle Christopher C Chester John J Jiang Wen G WG Cai Jun J

Oncotarget 20170628 49

Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the fi ...[more]

PMID: 29156701

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Project description:Most intracellular pathogens that reside in a vacuole prevent transit of their compartment to lysosomal organelles. Effector mechanisms induced by the pro-inflammatory cytokine Interferon-gamma (IFNγ) can promote the delivery of pathogen-occupied vacuoles to lysosomes for proteolytic degradation and are therefore important for host defense against intracellular pathogens. The bacterial pathogen Coxiella burnetii is unique in that, transport to the lysosome is essential for replication. The bacterium modulates membrane traffic to create a specialized autophagolysosomal compartment called the Coxiella-containing vacuole (CCV). Importantly, IFNγ signaling inhibits intracellular replication of C. burnetii, raising the question of which IFNγ-activated mechanisms restrict replication of a lysosome-adapted pathogen. To address this question, siRNA was used to silence a panel of IFNγ-induced genes in HeLa cells to identify genes required for restriction of C. burnetii intracellular replication. This screen demonstrated that Indoleamine 2,3-dioxygenase 1 (IDO1) contributes to IFNγ-mediated restriction of C. burnetii. IDO1 is an enzyme that catabolizes cellular tryptophan to kynurenine metabolites thereby reducing tryptophan availability in cells. Cells deficient in IDO1 function were more permissive for C. burnetii replication when treated with IFNγ, and supplementing IFNγ-treated cells with tryptophan enhanced intracellular replication. Additionally, ectopic expression of IDO1 in host cells was sufficient to restrict replication of C. burnetii in the absence of IFNγ signaling. Using differentiated THP1 macrophage-like cells it was determined that IFNγ-activation resulted in IDO1 production, and that supplementation of IFNγ-activated THP1 cells with tryptophan enhanced C. burnetii replication. Thus, this study identifies IDO1 production as a key cell-autonomous defense mechanism that limits infection by C. burnetii, which suggests that peptides derived from hydrolysis of proteins in the CCV do not provide an adequate supply of tryptophan for bacterial replication.

Dataset Information

Association of breast carcinoma growth with a non-canonical axis of IFN?/IDO1/TSP1.

Publications

Association of breast carcinoma growth with a non-canonical axis of IFNγ/IDO1/TSP1.

Similar Datasets

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