Understanding the role of the kynurenine pathway in human breast cancer immunobiology

Abstract

Breast cancer (BrCa) is the leading cause of cancer related death in women. While current diagnostic modalities provide opportunities for early medical intervention, significant proportions of breast tumours escape treatment and metastasize. Gaining increasing recognition as a factor in tumour metastasis is the local immuno-surveillance environment. Following identification of the role played by the enzyme indoleamine dioxygenase 1 (IDO1) in mediating maternal foetal tolerance, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key metabolic pathway contributing to immune escape. In inflammatory conditions activation of the KP leads to the production of several immune-modulating metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, picolinic acid and quinolinic acid. KP over-activation was first described in BrCa patients in the early 1960s. More evidence has since emerged to suggest that the IDO1 is elevated in advanced BrCa patients and is associated with poor prognosis. Further, IDO1 positive breast tumours have a positive correlation with the density of immune suppressive Foxp3+ T regulatory cells and lymph node metastasis. The analysis of clinical microarray data in invasive BrCa compared to normal tissue showed, using two microarray databank (cBioportal and TCGA), that 86.3% and 91.4% BrCa patients have altered KP enzyme expression respectively. Collectively, these data highlight the key roles played by KP activation in BrCa, particularly in basal BrCa subtypes where expression of most KP enzymes was altered. Accordingly, the use of KP enzyme inhibitors in addition to standard chemotherapy regimens may present a viable therapeutic approach.

Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice

“…Using the well-differentiated MCF7 human mammary breast cancer cell line which is estrogen receptor-positive and which displays a limited subpopulation of basal stem-like cells with tumor-initiating properties (Filmore & Kuperwasser, 2008), similar to Wnt1-Tg mammary tumors, we show that serum-derived Kyn, but not 2-OHG, a metabolite also associated with poor breast cancer prognosis (Terunuma et al , 2014), can recapitulate the HFDO serum effects on reducing apoptosis and increasing mammosphere-formation. Increased levels of Kyn relative to Trp have been recently reported to correlate with disease progression in lung cancer through its immunosuppressive effects (Suzuki et al , 2010) and to avert immune surveillance in several cancer types including breast cancer (Heng et al , 2015). Our collective results suggest a novel mechanism (altered Trp catabolism) and a specific target population (basal stem cell-like subpopulation) that are subject to maternal metabolic dysregulations which can influence early chemotherapeutic response of mammary tumors of progeny.…”

Quinolinic acid induces neuritogenesis in SH‐SY5Y neuroblastoma cells independently of NMDA receptor activation

“…Glutamate signalling and its dysregulation have been implicated in the development and progression of several types of cancer such as glioblastoma, lung cancer, melanoma and breast cancer (Sagan et al ., ; Heng et al ., ). This opens up the possibility that other endogenous ligands at glutamate receptors, such as the NMDA receptor agonist quinolinic acid (QA) (Stone & Perkins, ; Stone & Darlington, ) and the antagonist kynurenic acid (Perkins & Stone, ; Stone et al ., ), both metabolites of the kynurenine pathway for the oxidation of tryptophan, could also be involved in the regulation of tumour development.…”

“…On the other hand, glutamate receptor antagonists such as Mk‐801 and kynurenic acid inhibit growth, DNA synthesis, proliferation and migration of colon adenocarcinoma (Walczak et al ., ), renal carcinoma cells (Walczak et al ., ), Caki‐2 and T98G cells (Walczak et al ., , b). Inhibition of the first enzyme in the kynurenine pathway, indoleamine‐2,3‐dioxygenase (IDO‐1) has become a target for anti‐cancer strategies as this enzyme and its kynurenine‐derived products regulate T cell suppression and promote cancer cell immune evasion and tolerance (Opitz et al ., ; Prendergast, ; Adams et al ., ; Bessede et al ., ; Pucetti et al ., ; Heng et al ., ). In the light of this previous information it was of interest to determine the effects of quinolinic acid, as the component of the kynurenine pathway with agonist activity on NMDA receptors, to establish whether it could affect neurite growth from cells with a neuronal phenotype (differentiation induced by retinoic acid) or those left undifferentiated.…”

Monoaminergic and Kynurenergic Characterization of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Cerebrospinal Fluid and Serum

“…Due to its implication in (neuro-)inflammation, the kynurenine pathway (KP) has received increasing attention in immune-related diseases such as cancer [20,21], HIV [22], and several neurodegenerative disorders including ALS [23][24][25]. Although few researchers have previously focused on determining the KP in samples derived from patients with ALS, it appears that concentrations of some neuroprotective and neurotoxic metabolites are altered in CSF and serum [23,26].…”