Pleiotropic Role of Tenascin-C in Central Nervous System Diseases: From Basic to Clinical Applications

Abstract

The extracellular matrix is composed of a variety of macromolecular substances secreted by cells, which form a complex network that supports and connects tissue structures, regulates the morphogenesis of tissues, and maintains the physiological activities of cells. Tenascin-C, a secreted extracellular matrix glycoprotein, is abundantly expressed after exposure to pathological stimuli. It plays an important regulatory role in brain tumors, vascular diseases, and neurodegenerative diseases by mediating inflammatory responses, inducing brain damage, and promoting cell proliferation, migration, and angiogenesis through multiple signaling pathways. Therefore, tenascin-C may become a potential therapeutic target for intracranial diseases. Here, we review and discuss the latest literature regarding tenascin-C, and we comprehensively explain the role and clinical significance of tenascin-C in intracranial diseases.

Keywords: brain injury; inflammatory; intracranial tumor; neurodegenerative diseases; tenascin-C; therapeutic target; vascular diseases.

Figure 1

Molecular structure of tenascin-C; (A) Each subunit, including heptad repeat, epidermal growth factor-like (EGFL) repeats, fibronectin type III (FNIII) domains, and a C-terminal globular fibrinogen-homology domain (B) hexabrachion of the tenascin molecule.

Figure 2

Proposed mechanism of TN-C under physiological and pathological conditions. EGFR, epidermal growth factor receptor; TLR4, Toll-like receptor 4; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; ECM, extracellular matrix; FAK, focal adhesion kinase; PKB, protein kinase B; PKC, protein kinase C; MAPK, mitogen-activated protein kinase.

Figure 3

Regulatory function of TN-C on angiogenesis, proliferation, migration, and invasion of glioma cells. MKK, MAP kinase kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; FAK, focal adhesion kinase; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; LPA, lysophosphatidic acid; LPAR, lysophosphatidic acid receptor; ADAM9, A disintegrin and A metalloproteinase-9; ECM, extracellular matrix.

Figure 4

Proposed mechanism of TN-C in post-SAH brain injury. (A): TN-C induced cerebral vasospasm after SAH via the upregulation of PDGFR-β. (B): TN-C-induced neuronal apoptosis, partly mediated by TLR4/NF-κB/IL-1β pathways. (C): TN-C induces brain edema and BBB disruption following SAH. PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; BBB, blood–brain barrier; MMP, matrix metalloprotein; ZO, zonula occludens; JNK, c-Jun N-terminal kinase; ERK, extracellular regulated protein kinases; PI3k, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; TLR4, Toll-like receptor 4.

Figure 5

Proposed mechanism of TN-C in the pathogenesis of Alzheimer's disease. APP, amyloid precursor protein.