The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants

Abstract

The extracellular matrix (ECM) dynamics in tumour tissue are deregulated compared to the ECM in healthy tissue along with disorganized architecture and irregular behaviour of the residing cells. Nitric oxide (NO) as a pleiotropic molecule exerts different effects on the components of the ECM driving or inhibiting augmented angiogenesis and tumour progression and tumour cell proliferation and metastasis. These effects rely on the concentration of NO within the tumour tissue, the nature of the surrounding microenvironment and the sensitivity of resident cells to NO. In this review article, we summarize the recent findings on the correlation between the levels of NO and the ECM components towards the modulation of tumour angiogenesis in different types of cancers. These are discussed principally in the context of how NO modulates the expression of ECM proteins resulting in either the promotion or inhibition of tumour growth via tumour angiogenesis. Furthermore, the regulatory effects of individual ECM components on the expression of the NO synthase enzymes and NO production were reviewed. These findings support the current efforts for developing effective therapeutics for cancers.

Keywords: extracellular matrix; metastasis; nitric oxide; nitric oxide Extr tumour angiogenesis.

Figure 1.. Composition of tumour tissue and how NO is generated and interacts with its constituents.

The tissue consists mainly of cancer cells, tumour-associated macrophages, cancer-associated fibroblasts, and endothelial cells lining the blood vessels through which these cells get their nutrients, and the tumour cells can metastasize. Nitric oxide (NO) is produced from these cells via different isoforms of NO synthase and works as a signalling molecule for activating various transduction pathways. The extracellular matrix (ECM) of tumour tissue is produced by the resident cells and generally consists of three main categories of proteins: (1) structural proteins: such as collagen, fibronectin, hyaluronan, laminin and elastin; (2) matricellular proteins: such as thrombospondin, osteopontin, periostin and SPARC proteins; (3) MMPs and tissue inhibitors of metalloproteinases (TIMPs). There are mutual interactions between NO, the ECM components and cells for modulating the tumour growth, angiogenesis and metastasis.

Figure 2.. The synthetic pathway of NO in ECs, inducers, inhibitors, the roles played and the effects of different components of the ECM.

The exogenous κ-elastin enhances the mRNA expression of eNOS in the ECs [73], and tropoelastin improves the protein expression for NO production, which is inhibited by L-NAME [74]. The TSP-1-mediated inhibition of NO synthesis and downstream effects is through two main mechanisms: (1) The high concentrations of TSP-1 and its peptide mimetics, ABT-510, via interaction with CD-36, inhibit the translocation of myristate to the cytoplasm, thus inhibit the membrane translocation of the Src responsible the activation of eNOS and generation of NO [68,70]. (2) At low concentration, and via its binding to CD47, TSP-1 inhibits the NO-mediated activation of sGC, cGMP generation from Guanosine triphosphate (GTP), and activation of cGMP-dependent protein kinase (cGK-1) responsible for the enhanced cell proliferation, angiogenesis and metastasis [71,72]. The exogenous NO at a concentration of 1 µM only can decrease the protein expression of TSP-1 in the ECs, while activates sGC [67]. The scheme was created in Biorender.com.

Figure 3.. The stimulated expression of eNOS and NO synthesis in endothelial cells under shear stress and the effects of different components of the ECM.

The mRNA and protein expression of eNOS is stimulated under the influence of shear stress leading to enhanced NO production, which is promoted in the presence of exogenous laminin [98,99]. The treatment of the arteries with active hyaluronidase as well as heparanse III cause inhibition of the flow-induced NO-production [100]. The scheme was created in Biorender.com.