High Indoleamine 2,3-Dioxygenase Is Correlated With Microvessel Density and Worse Prognosis in Breast Cancer

Abstract

Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy. IDO has also received more attention because of its non-immune functions including regulating angiogenesis. The purpose of this study was to investigate the effects of IDO on microvessel density (MVD), and to explore its prognostic role in breast cancer. We showed IDO expression was positively correlated with MVD labeled by CD105 (MVD-CD105) rather than MVD labeled by CD31 (MVD-CD31) in breast cancer specimens. Both IDO expression and MVD-CD105 level were associated with initial TNM stage, histological grade, and tumor-draining lymph nodes (TDLNs) metastasis in breast cancer. In the prognostic analysis, TDLNs metastasis, an advanced TNM stage (III) and high histological grade (III) significantly predicted shorter survival in univariate analysis. Concentrating on IDO and MVD, the patients with IDO expression or high MVD level had poorer prognosis compared with no IDO expression [P = 0.047 for progress-free survival (PFS)] and low MVD level (P = 0.019 for OS); the patients with IDO expression and high MVD level had a tendency with shorter overall survival when compared with non IDO expression, low MVD level, or both (P = 0.062 for OS). In multivariate analysis, an advanced TNM stage (III) was significantly associated with shorter 5-year survival rate of PFS (HR: 0.126, 95% CI: 0.024–0.669, P = 0.015). In order to verify the phenomenon of IDO promoting angiogenesis, we contained the study in vitro. We detected the expression of IDO mRNA in breast cancer cell lines and measured the concentration of tryptophan and kynurenine in the supernatants of MCF-7 by high performance liquid chromatography. The ratio of Kyn and trp (kyn/trp) was calculated to estimate IDO-enzyme activity. MCF-7 cells, which produce high level of IDO and metabolize tryptophan, promoted human umbilical vein endothelial cells (HUVEC) proliferation significantly in co-culture system. Meanwhile IDO could upregulate the expression of CD105 in HUVEC, which was downregulated after adding IDO inhibitor, 1-methyl-d-trytophan. These results suggest that IDO could promote angiogenesis in breast cancer, providing a novel, potentially effective molecular or gene therapy target for angiogenesis inhibition in the future.

Targeting the IDO1 pathway in cancer: from bench to bedside

“…Administration of the IDO1 inhibitor epacodostat (INCB024360) in mice with tumors or vascularized metastases significantly reduced neovascularization [ 11 ]. High IDO1 expression positively correlates with microvessel density and poor prognosis in breast cancer patients [ 61 ]. In summary, IDO1-mediated effects on neovascular development and established neovascular networks broaden the potential effectiveness of IDO1 inhibitors in clinical trials and in practice.…”

Cancer-associated hypersialylated MUC1 drives the differentiation of monocytes into macrophages with a pathogenic phenotype

“…It is additionally interesting to note that 14/18 of the upregulated protein-validated factors are associated with poor prognosis or invasion in breast cancers, when measured in serum or tissue; this suggests that cells which secrete these factors would have a negative impact on prognosis 39,41,47,49,54,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] . It is also of interest to note that in these studies 8/14 of these poorly prognostic factors have been seen to derive predominantly from stromal cells.…”

Curdione induces G2/M phage arrest, apoptosis and autophagy via COX2 mediate IDO1 expression through PKCδ/ GSK3β/β-catenin pathway in human uterine leiomyosarcoma

“…IDO1, which plays an important role in promoting the growth of cancers, is over-express in many cancer types and predicts poor outcome [9]. Growing evidence suggest that IDO1 contribute to cancer development [18]. Furthermore, lots of antitumor drugs induced apoptosis and autophagy via declining IDO1 levels in cancers [19,20].…”