Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology

Abstract

Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which soluble extracellular matrix constituents affect the microenvironment associated with inflammatory and neoplastic diseases.

Keywords: Toll-like receptors; biglycan; decorin; microtubule-associated protein light chain 3; receptor tyrosine kinase; small leucine-rich proteoglycans.

Fig. 1

Decorin exhibits promiscuity in its ability to alter tumorigenesis via regulation of angiogenesis, autophagy, and inflammation. Decorin antagonizes RTKs, such as EGFR and Met, on the tumor cell surface to inhibit angiogenesis via suppression of pro-angiogenic factors, such as VEGFA, as well as induction of anti-angiogenic proteins, such as thrombospondin-1, while simultaneously reducing tumor growth via cell cycle arrest and inhibition of Myc and β-catenin. Signaling through Met also induces mitostatin leading to tumor cell mitophagy. Interaction between decorin and VEGFR2 in endothelial cells results in autophagic induction vis-à-vis the canonical intermediates, Beclin 1 and LC3 as well as with the novel autophagic regulator, Peg3. In inflammatory cells, decorin signals through TLR2/4 to induce pro-inflammatory mediators, which reduces tumor growth.

Fig. 2

Dual role of biglycan in the control of inflammation and tumorigenesis. Soluble biglycan triggers mRNA expression of pro-inflammatory cytokines and chemokines Il1β, Cxcl1, Cxcl2, and Ccl2 in macrophages in a TLR2/4- and MyD88-dependent manner, while it selectively stimulates the expression of Ccl5 through TLR4 and TRIF. By clustering TLR2/4 and the P2X₇ soluble biglycan induces the NLRP3-inflammasome, activating caspase-1 and releasing mature IL-1β. Moreover, biglycan directly mediates the expression of Nox2 mRNA via TLR4/TRIF and the activation of NOX2 in a TLR4/MyD88-dependent manner, thereby attenuating the expression of the pro-inflammatory cytokine IL-1β. In contrast, by engaging TLR2, soluble biglycan triggers the expression of HSP70, which binds to NOX2, and consequently impairs the inhibitory function of NOX2 on biglycan-mediated IL-1β expression and maturation.

Fig. 3

Biglycan induces tumorigenesis via HIF-2α stabilization and Epo expression. Soluble biglycan binds to the TLR2 in the kidney and/or in the liver and induces the stabilization of HIF-2α produced in liver, kidneys and tumor-associated macrophages (purple). HIF-2α subsequently induces the expression of erythropoietin (Epo). Epo is than released into the circulation, where it may stimulate tumor angiogenesis, cell growth and cell migration, as well as tumor lymphangiogenesis, thus inducing tumorigenesis.