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

Bruno Lopes-Bastos, Liang Jin, Fiona Ruge, Sioned Owen, Andrew Sanders, Christopher Cogle, John Chester, Wen G. Jiang, Jun Cai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 languageEnglish
Pages (from-to)85024-85039
Number of pages16
JournalOncotarget
Volume8
Issue number49
DOIs
Publication statusPublished - 17 Oct 2017
Externally publishedYes

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

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