Understanding the tumour micro-environment communication network from an NOS2/COX2 perspective

Abstract

Recent findings suggest that co-expression of NOS2 and COX2 is a strong prognostic indicator in triple-negative breast cancer patients. These two key inflammation-associated enzymes are responsible for the biosynthesis of NO and PGE2 , respectively, and can exert their effect in both an autocrine and paracrine manner. Impairment of their physiological regulation leads to critical changes in both intra-tumoural and intercellular communication with the immune system and their adaptation to the hypoxic tumour micro-environment. Recent studies have also established a key role of NOS2-COX2 in causing metabolic shift. This review provides an extensive overview of the role of NO and PGE2 in shaping communication between the tumour micro-environment composed of tumour and immune cells that in turn favours tumour progression and metastasis. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.

Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1

Increased levels of NO and PGE2 drives tumour growth and its vascularization. PGE2 effects are mediated by EP1–EP4 receptors, while NOS1 and NOS3 produce physiological levels of NO, and NOS2 is important in pathophysiological function. In tumour biology, co‐expression of NOS2–COX2 is associated with poor patient survival. In basal A‐like cells, TRAF2 is activated in a TNF‐α dependent manner, while in the more aggressive mesenchymal‐like cells, ERS was the main activator of COX2 even though TNF‐α‐mediated pathway is also accessible. NO and PGE2 also lead to tumour vascularization and angiogenesis.

Figure 2

Leukocyte profiling in ER− patient samples. The RNA‐Seq leukocyte subset data for the TCGA PanCancer Atlas ER− samples were downloaded from the cBioPortal.org, and the predefined leukocyte signature markers' information was downloaded from the cibersort.stanford.edu. Data on differentially expressed leukocyte markers, generated from RNA‐Seq, were uploaded to the CIBERSORT and processed against the LM22, a predefined leukocyte marker subset. The relative percentage for each leukocyte subtype were presented as (A) stacked bar chart, and (B) the table represents cell types from the signature genes files and columns that represent deconvolution results of each mixture sample. All results are reported as relative fractions normalized to 100% across all cell subsets.

Figure 3

NOS2–COX2‐mediated signalling in TAMs. LDI, low‐dose irradiation; CpG ODN, CpG oligodeoxynucleotide.

Figure 4

Tumour cells interact with MDSCs to mediate an immunosuppressive TME with NO and PGE2 as the key players.

Figure 5

Differentiation of naïve CD4+ T‐cells to different subtypes in the presence of NO and PGE2 in the TME. NO shows a concentration‐dependent role in T‐cell‐mediated tumour response, while PGE2 plays a mainly immunosuppressive role, in the TME.