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

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

doi:10.18632/oncotarget.18781

Bruno Lopes-Bastos, Liang Jin + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.18781

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Journal: Oncotarget	Publication Date: Jun 28, 2017
Citations: 14	License type: cc-by

Affiliation: Cardiff University, University of Florida

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). 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.

Highlights

Invasive ductal carcinoma (IDC) is an aggressive form of breast cancer and the most common cancer in women worldwide [1]
We examined the effects of endothelial cells (ECs) in the induction of dormancy in invasive ductal carcinoma (IDC) cells through flow cytometric analysis of the cell cycle of the MDA-MB-231, MDA-MB-436 and MCF10A
The both MDA-MB-231 and MDA-MB-436 cells co-cultured with ECs had a high percentage of cells in the G0/G1 phase and a significantly low level in the G2/M phase in compared with control, whereas MCF-10A did not exhibit a difference between co-culture and single culture (Figure 1C)

Summary

Introduction

Invasive ductal carcinoma (IDC) is an aggressive form of breast cancer and the most common cancer in women worldwide [1]. Interactions between tumour cells and stromal cells (such as tumour vascular endothelial cells) determine the extent of tumour growth [2]. IDC recurrence probably is mainly due to tumour dormancy rather than the re-growth of the residual cancers in patients [5, 6, 7]. Thrombospondin 1 (TSP1), a large matrix glycoprotein, is the most abundant potent endogenous www.impactjournals.com/oncotarget inhibitory component in the stable microvascular niche via mediating cell-to-cell and cell-to-matrix interactions. Lower levels of TSP1 expression frequently observed at the advance front of invasive breast cancer are significantly correlated with metastasis in tumour progression [10]. Vascular endothelial cells (ECs) are responsible for the majority of TSP1 secreted into the tumour stroma [11]

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