Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment

Abstract

Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.

Keywords: clinical significance; glioma progression; gliomagenesis; matricellular protein; neurogenesis; tenascin C.

Figure 1

Schematic illustration of the domain structure of TNC.

Figure 2

Potential positive feedback mechanism in gliomas between TNC expression and NOTCH pathway. TNC binds to integrin α2β1 on the glioma cell and upregulates JAG1 expression which interacts with its receptor NOTCH. The interaction results in the release of intracellular domain that translocates to the nucleus to affect NOTCH-dependent transcription by binding to RBPJκ. Moreover, the human TNC promoter contains an RBPJκ-responsive element. Thus, the activation of NOTCH signaling increases TNC expression.

Figure 3

The roles of TNC in glioma neovascularization. On the one hand, TNC blocks YAP signaling and endothelial cell behavior through direct contact. On the other hand, TNC induces ephrin-B2 and a pro-angiogenic secretome in glioblastoma cells. In addition, TNC activates AKT/MMP2/MMP9 axis and further promotes vasculogenic mimicry in glioma. Moreover, TNC-ephrinB2-ephB4 signaling pathway supports GSCs differentiation into endothelial cells. YAP, Yes-associated protein; MMP, matrix metalloproteinase.

Figure 4

The roles of TNC in glioma cell proliferation and migration. For one thing, the role of TNC in glioma cell proliferation is complex. The EGF-like repeats, the FBG region, A2 and some alternatively spliced domains, such as AD1, -AD2 and -C, of TNC as well as integral TNC molecule contribute to the glioma cell proliferation. In contrast, the fragment composed of all FNIII-domains decreases the proliferation of glioma cell. In addition, TNC impairs the adhesive properties of FN, which contributes to glioma cell proliferation. For another thing, TNC promotes glioma cell invasiveness. This molecule not only contributes to the intermediate adhesion that support cell motility, but also promotes “EMT-like” changes. Moreover, TNC also induces matrix destructing enzymes to promote tumor cell migration.

Figure 5

Immunomodulatory role of TNC in neuroinflammation.

Figure 6

A possible relationship between TNC and gliomagenesis. In general, TNC can promote NSC/OPC proliferation, inhibit differentiation and regulate migration. However, TNC is associated with gene instability and cell cycle, and contributes to accumulation of mutations. Then NSC/OPC carrying driver mutations are likely to undergo GSC transformation. Additionally, neovascularization, proliferation, migration and immunosuppressive effects on T cell also provide favorable conditions, which leads to gliomagenesis.