Association of breast carcinoma growth with a non-canonical axis of IFNγ/IDO1/TSP1
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Bruno Lopes-Bastos1, Liang Jin1, Fiona Ruge1, Sioned Owen1, Andrew Sanders1, Christopher Cogle2, John Chester3, Wen G. Jiang1 and Jun Cai1
1Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
2School of Medicine, University of Florida, Gainesville, Florida 32610-0278, USA
3Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
Jun Cai, email: caiJ5@cardiff.ac.uk
Keywords: IFNγ, IDO1, TSP1, endothelial cells, breast invasive ductal carcinoma
Received: March 22, 2017 Accepted: May 29, 2017 Published: June 28, 2017
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). IFNγ 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 IFNγ/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.
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