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 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.
Original language | English |
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Pages (from-to) | 85024-85039 |
Number of pages | 16 |
Journal | Oncotarget |
Volume | 8 |
Issue number | 49 |
DOIs | |
Publication status | Published - 17 Oct 2017 |
Externally published | Yes |
Keywords
- IFN gamma
- IDO1
- TSP1
- endothelial cells
- breast invasive ductal carcinoma
- INTERFERON-GAMMA
- INDOLEAMINE 2,3-DIOXYGENASE
- TUMOR DORMANCY
- ENDOTHELIAL-CELLS
- MELANOMA-CELLS
- OVARIAN-CANCER
- THROMBOSPONDIN-1
- EXPRESSION
- TRYPTOPHAN
- RESISTANCE