Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

Abstract

Cancer is a multifaceted and complex pathology characterized by uncontrolled cell proliferation and decreased apoptosis. Most cancers are recognized by an inflammatory environment rich in a myriad of factors produced by immune infiltrate cells that induce host cells to differentiate and to produce a matrix that is more favorable to tumor cells' survival and metastasis. As a result, the extracellular matrix (ECM) is changed in terms of macromolecules content, degrading enzymes, and proteins. Altered ECM components, derived from remodeling processes, interact with a variety of surface receptors triggering intracellular signaling that, in turn, cancer cells exploit to their own benefit. This review aims to present the role of different aspects of ECM components in the tumor microenvironment. Particularly, we highlight the effect of pro- and inflammatory factors on ECM degrading enzymes, such as metalloproteases, and in a more detailed manner on hyaluronan metabolism and the signaling pathways triggered by the binding of hyaluronan with its receptors. In addition, we sought to explore the role of extracellular chaperones, especially of clusterin which is one of the most prominent in the extracellular space, in proteostasis and signaling transduction in the tumor microenvironment. Although the described tumor microenvironment components have different biological roles, they may engage common signaling pathways that favor tumor growth and metastasis.

Keywords: clusterin; extracellular chaperones; extracellular matrix remodeling; hyaluronan; inflammation; matrix metalloproteases; tumor microenvironment.

Figure 1

Brief overview of cell signaling mediators in cancer cell–stroma cell communication and ECM remodeling. Tumor cells produce cytokines, chemokines, NF-κB, and TGFβ, that “activate” stromal progenitors, such as fibroblasts, into CAFs and produce, in turn, cytokines and TGFβ, influencing tumor cell functions. TGFβ upregulation in cancer cells provokes an increment in LOX, which in turn affects ECM remodeling by changing the collagen organization and provoking ECM stiffness that induces the mechanical activation of latent TGFβ. An increased amount of cytokines by tumor cells induces MMPs activation that contributes to ECM remodeling and sustains tumor progress.

Figure 2

Overview of HA metabolism and interaction with membrane receptors. Synthesis of HA by HAS2, the main synthetic enzyme in cancer cells, is increased by inflammatory agents, such as TNFα, via the NF-κB signaling pathway. Induction of HAS2 also occurs due to various growth factors and the secreted protein c10orf118 in a not yet fully described mechanism. Pharmacological agents, such as 4-MU, inhibit HA synthesis and downregulate HAS2. A binding to HYAL2 and CD44 and endocytosis lead to the degradation of HMWHA; HYAL2 cuts HMWHA into fragments (LMWHA) at the plasma membrane which, in turn, are internalized into the cell via endocytosis and further degraded by HYAL1 in lysosomes. The produced sugars, GlcNAc and GlcA, may be recycled in cell energy metabolism, i.e., glycolysis, or control HAS2-AS1 expression via NF-κB. HAS2-AS1 is also regulated by hypoxia via HIF-1α. Tumor cells are secreted in tumor microenvironment extracellular vesicles that contain HA, HAS3, and CD44 that can be captured by target cells. The HA of the tumor microenvironment can bind to different cell membrane receptors. The HA–TLR-4 complex signals the NF-κB pathway, supporting cell proliferation, whereas HA-CD44 and HA-RHAMM interact with either TGFβRI and PDGFR, promoting EMT and cell survival and metastasis.

Figure 3

(A) CLU mediates clearance of misfolded proteins through the chaperone- and receptor-mediated extracellular protein degradation (CRED) pathway. CLU binds a misfolded protein and then interacts with the HS chains membrane PGs by electrostatic interactions (I); the CLU–client protein-receptor is endocytosed (II) and delivered to the lysosome (III) for intracellular degradation (IV). (B) Intracellular signaling pathways triggered by CLU after surface receptors binding. CLU inhibits the TAK1– NF-κB signaling axis triggered by inflammatory cytokines. CLU facilitates eHSP90 binding to LRP1, enhancing the activation of ERK, AKT, and NF-κB and promoting EMT. Finally, CLU binds LRP2 and promotes cell survival through PI3K/AKT activation.