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

作者：Lopes Bastos Bruno; Jin Liang; Ruge Fiona; Owen Sioned; Sanders Andrew; Cogle Christopher; Chester John; Jiang Wen G; Cai Jun^*

来源：Oncotarget, 2017, 8(49): 85024-85039.

DOI：10.18632/oncotarget.18781

• IFN gamma
• IDO1
• TSP1
• endothelial cells
• breast invasive ductal carcinoma

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 gamma 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 gamma/IDO1/TSP1 axis in microvascular nichedominated dormancy of breast invasive ductal carcinoma with a solid foundation for further investigation of therapeutic and prognostic relevance.

• 出版日期2017-10-17