Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling.

Lorena Carmona-Rodríguez,Santos Mañes,Paula Martín-González,Mónica Franch,Diego Martínez-Rey,Lydia Sorokin,Emilia Mira

doi:10.3390/cancers14051226

Lorena Carmona-Rodríguez, Santos Mañes + Show 5 more

Open Access

https://doi.org/10.3390/cancers14051226

Copy DOI

Abstract

Simple SummaryTumor-infiltrating lymphocytes determine cancer prognosis and the response to immunotherapy. The balance of laminin-α4/laminin-α5 isoforms in the endothelial basement membrane plays an instructive function in regulating the diapedesis of immune cells under inflammatory conditions. Previous studies showed that the extracellular superoxide dismutase (SOD)3 induces laminin-α4, which is associated with improved disease-free survival of colorectal cancer patients. The aim of our study was to determine whether SOD3 also affects the expression of laminin-α5 in the tumor vasculature. The results showed that SOD3 differentially regulates laminin-α4 and laminin-α5 in the tumor endothelium. SOD3 promoted notable transcriptomic changes in tumor-stimulated endothelial cells, including the inhibition of the nuclear factor kappa B (NF-κB) pathway, an inductor of laminin α5 transcription. Therefore, high SOD3 levels in the tumor vasculature shifted the laminin α4/α5 balance towards the laminin-α4high/laminin-α5low phenotype, which is permissive for T cell diapedesis into tumors and explains the improved cancer immune surveillance associated to high SOD3 levels.The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced intratumor T cell infiltration in primary human cancers. We show now that SOD3 overexpression in neoplastic and endothelial cells (ECs) reduces laminin α5 in tumor blood vessels. SOD3 represses the laminin α5 gene (LAMA5), but LAMA5 expression is not changed in SOD1-overexpressing cells. Transcriptomic analyses revealed SOD3 overexpression to change the transcription of 1682 genes in ECs, with the canonical and non-canonical NF-κB pathways as the major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as NF-κB-driven promoter activity in ECs stimulated with tumor necrosis factor (TNF)-α, an NF-κB signaling inducer. SOD3 inhibited the phosphorylation and degradation of IκBα (nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor alpha), an NF-κB inhibitor. Finally, TNF-α was found to be a transcriptional activator of LAMA5 but not of LAMA4; LAMA5 induction was prevented by SOD3. In conclusion, SOD3 is a major regulator of laminin balance in the basement membrane of tumor ECs, with potential implications for immune cell infiltration into tumors.

Highlights

Solid tumors are usually irrigated by an immature and dysfunctional vascular network.The hierarchical branching organization and the features associated with arterioles, capillaries and venules are not seen in a tumor’s vasculature
superoxide dismutase-3 (SOD3) overexpression in tumor and endothelial cells was associated with an improved response to the adoptive transfer of tumor-specific CD8+ T cells, suggesting that SOD3 provides a permissive signal for tumor infiltration by these cells [32]
These tumor samples were analyzed by immunofluorescence to see whether SOD3 affects laminin α5 expression in the tumor vasculature

Summary

Introduction

Solid tumors are usually irrigated by an immature and dysfunctional vascular network.The hierarchical branching organization and the features associated with arterioles, capillaries and venules are not seen in a tumor’s vasculature. Tumor cells adapt and survive under these stressful conditions, and use this abnormal vascular network to create a shield that protects them from the immune system and therapeutic agents. VEGF-A triggers the proliferation, migration and sprouting of endothelial cells (ECs), and greatly increases tumor vessel permeability by weakening vascular endothelial (VE)-cadherin-mediated EC junctions and interfering with pericyteEC interactions [7,8]. Many of these proangiogenic factors are induced by inflammatory mediators, such as tumor necrosis factor (TNF)-α, acting on tumor and stromal cells via the nuclear factor kappa B (NF-κB) pathway [9].

Objectives

Methods

Results

Conclusion