|Year : 2022 | Volume
| Issue : 2 | Page : 50-55
The role of collagens in glioma: A narrative review
Yi Wang, Toshiya Ichinose, Mitsutoshi Nakada
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
|Date of Submission||25-Apr-2022|
|Date of Decision||14-May-2022|
|Date of Acceptance||07-Jun-2022|
|Date of Web Publication||26-Jul-2022|
Dr. Mitsutoshi Nakada
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University
Source of Support: None, Conflict of Interest: None
Glioma is the most common brain tumor in the central nervous system and characterized by diffuse invasion into adjacent brain tissue. The extracellular matrix (ECM) is an essential component of the tumor microenvironment and it contributes to tumor progression through close interactions with glioma cells. Accumulated evidence has indicated that collagen levels, which are the most critical components of the ECM, are elevated in gliomas and collagen contributes to glioma progression. In this review, we provide a comprehensive summary of the roles of various collagens in glioma. A better understanding of the interactions of various collagens with glioma cells may provide new therapeutic strategies for gliomas.
Keywords: Collagen receptor, collagen remodeling, collagens, extracellular matrix, glioma
|How to cite this article:|
Wang Y, Ichinose T, Nakada M. The role of collagens in glioma: A narrative review. Glioma 2022;5:50-5
| Introduction|| |
Glioma is the most aggressive brain tumor in the central nervous system and it is characterized by diffuse infiltration into the surrounding brain parenchyma. It accounts for approximately 80% of all primary malignant brain tumors. Invading glioma cells are closely linked with the tumor microenvironment, such as the extracellular matrix (ECM). Glioma cells interact closely with tumor microenvironment components and they contribute to glioma proliferation and invasion. The brain tumor microenvironment is primarily composed of basement membrane components, such as collagens, fibronectin, and vitronectin, as well as hyaluronan, which surrounds the tumor. Elevated collagen levels have recently been implicated in the development of gliomas and are thought to play an important role in glioma progression. Herein, we review the functions of collagens in gliomas [Table 1].
| Retrieval Strategy|| |
A literature review was electronically performed using the PubMed database. The following combinations of keywords were used: collagen and cancer, collagen and glioma, Type I collagen and glioma, Type III collagen and glioma, Type IV collagen and glioma, collagen V and glioma, and collagen VI, VIII, XVI, XVII, and XXVIII and glioma.
| Collagens and Glioma|| |
Collagens form a characteristic triple helix that generally consists of three polypeptide chains with the most common sequences of glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid except for glycine, proline, or hydroxyproline. The polypeptide chains can be either homotrimeric or heterotrimeric in nature and comprise at least one triple-helical collagenous domain that is secreted and accumulated in the ECM and/or a noncollagenous domain that is used as building blocks by other ECM proteins [Figure 1]. So far, 42 different collagen genes have been identified that encode more than 26 distinct collagen types, which are categorized into three main classes: fibril-forming collagens, nonfibril-forming collagens, and fibril-associated collagens.
|Figure 1: Structural organization of collagens. Collagens are characterized by a triple-helical structure composed of three polypeptide chains with repetition Gly-X-Y sequence. N-and C-propeptides are removed by metalloproteinase enzymes and finally converted to collagen|
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Collagen I is the most abundant collagen in the human body. It is synthesized inside the cell as a procollagen and then secreted into the surrounding ECM. It is also found in the extra-parenchymal tissue (e.g., meninges and choroid plexus stroma), blood vessels, and parenchyma of the subependymal layer in the brain. Collagen I has a heterotrimer formed by two identical α1 chains and one α2 chain. It plays an important role in maintaining the structural integrity of tissues. Furthermore, collagen I interacts with a variety of proteins and plays an important role in modulating cellular functions. Growing evidence has shown that collagen I contribute to glioma progression. It is an important niche component for CD133-positive glioblastoma (GBM) stem cells and maintains Glioblastoma stem-like cells (GSC) properties. It can also accelerate cell invasion and enhance tumor formation through the PI3K/Akt signaling pathway. With advances in proteomics, genomics, and metabolomics, gene expression analysis has highlighted the significance of collagens in gliomas. COL1A1 expression is elevated in malignant astrocytomas and is negatively correlated with survival. Downregulation of COL1A1 expression inhibits invasion by decreasing molecule expression that is associated with invasions, such as phosphorylated-signal transducer and the activator of transcription 3. In addition, analysis of the gene expression profile demonstrated that COL1A2 was highly associated with clinical outcomes of patients with glioma. The inhibition of COL1A2 remarkably suppressed the proliferation and invasion of GBM cells through dephosphorylating Akt signaling pathway.
Collagen III, which is a protein composed of three identical monomers, is a crucial component of the ECM in the brain. Collagen III exists in the basal lamina of the vasculature and glial limitans externa. It has been identified that Schwann cells can synthesize and secrete collagen III. Collagen III was shown to significantly increase the migration and invasion abilities of glioma cells. A review of gene expression in The Cancer Genome Atlas database indicated that COL3A1 is notably increased in gliomas and is related to the grade of glioma., COL3A1 regulated by GATA6 activates the angiogenesis process and participates in the recurrence of low-grade glioma by affecting the response to interferon Type II and metabolism of propanoate.
Collagen IV is primarily found in the basal lamina. It is the main component of collagen in the brain and exists in the basement membrane that surrounds vascular endothelial cells. Six different genes encode collagen IV chains and they are designated as COL4A1–COL4A6. Glioma cells can synthesize several types of collagens, such as collagen Types I and IV. In addition, normal brain tissues surrounding the glioma contribute to the synthesis of collagen IV. Accordingly, collagen IV was found to be highly expressed in astrocytomas and it was shown to be present in the basement membrane that lines the vessel walls. Physical compaction, the process by which glioma cells gather together and then compress and cause changes in cell shapes and sizes, can increase collagen IV expression and upregulate angiogenic factors expression, which ultimately contributes to GBM progression. Previous reports have demonstrated that COL4A1 has vital functions in the complex pathomechanisms of many types of malignant tumors. Based on the gene expression profile analysis mentioned previously, COL4A1 expression was reported to be elevated at both the mRNA and protein levels in glioma cells. Furthermore, it was associated with short overall survival of patients with gliomas. The inhibition of COL4A1 expression suppressed the ability of glioma cells to proliferate and migrate. COL4A1 is known to be a marker of poor prognosis in glioma.
Collagen V is a form of fibrillar collagen. It has a triple-helical domain comprised of sequences of glycine-proline-X and glycine-X-hydroxyproline. It is encoded by COL5A1 and contributes to the regulation of the fiber diameter and assembly of collagen fibers. Collagen V can act as a surrogate ligand for the calcitonin receptor (computed tomography CT receptor), which is expressed by both malignant glioma cells and GSCs and can be a potential therapeutic target against glioma. With a better understanding of the functions of collagen V, it was determined that the expression of COL5A1 significantly increased with increases in glioma grades, and COL5A1 inhibition suppressed the abilities of glioma cells to proliferate and migrate and enhanced the temozolomide sensitivity of glioma cells. COL5A1 is also the main gene associated with mesenchymal subtype markers in glioma cells., It contributes to the mesenchymal phenotype transition induced by high nicotinamide adenine dinucleotide phosphate oxidase 2 levels.
Collagen VI is unique in the collagen superfamily and is primarily associated with ECM proteins. It can form a unique network of linked microfilaments that provides stability and structural support in ECM., It is made up of three α chains, i.e., α1, α2, and one of the following α3, α4, α5, and α6. It is encoded by different genes, which have been designated as COL6A1–COL6A6. Collagen VI plays a vital role in numerous cell types, such as chondrocytes, neurons, myocytes, and cardiomyocytes., A comprehensive understanding of the genetic origins and molecular drivers of GBM has created more tailored and targeted treatment strategies. COL6A1 expression levels can be associated with glioma grades, i.e., lower malignant grade astrocytomas exhibit low COL6A1 expression, whereas higher malignant grade gliomas display high expression of COL6A1. COL6A1 is also a biomarker of outcomes. Overexpression of COL6A1 has been correlated with poor prognoses. Furthermore, COL6A1 has been identified as an important gene in antivascular endothelial growth factor therapy and is considered to be a new potential target for the treatment of GBM.
Collagen VIII is a protein that consists of two α1 chains and one α2 chain, which are encoded by COL8A1 and COL8A2, respectively. Collagen VIII is a significant component of Descemet's membrane and it participates in the interactions among cells and the matrix by regulating various cellular functions, including proliferation, adhesion, and migration., Collagen VIII reportedly has higher expression in glioma cells than in nonneoplastic brain tissues. The expression of COL8A2, a subunit of collagen VIII, was found to be upregulated in GBM tissues. Higher expression of COL8A2 was correlated with reduced overall survival of patients with GBM. This has been associated with the malignant development of GBM by inducing the epithelial-mesenchymal transition.
Collagen XVI is a type of fibril-associated collagen encoded by COL16A1 and it has interrupted triple helices. It is thought to maintain the integrity of the ECM. Collagen XVI has higher expression in gliomas compared to nonneoplastic brain tissue. Fluorescent immunostaining confirmed that collagen XVI existed in tumor cells as well as in tumor vessels underlying collagen IV. In line with this finding, glioma cell lines were shown to express and secrete collagen XVI in vitro. The downregulation of collagen XVI significantly reduced the ability of glioma to invade cells and reduced tumor cell adhesion.
Collagen XVII is a transmembrane protein. It plays an important role in maintaining the linkage of intra- and extracellular structural elements that are related to epidermal adhesion. Collagen XVII consists of three α1 chains encoded by the gene COL17A1. Collagen XVII was shown to be upregulated in GBM. Further investigation indicated that a new PTEN-COL17A1 fusion gene along with COL17A1 in GBM increased tumor invasiveness by upregulating matrix metalloproteinase (MMP)-9 expression. Of note, COL17A1 is a potentially useful prognostic biomarker and therapeutic target for GBM.
Collagen XXVIII is the most recently discovered type of collagen and it has been minimally investigated until now. According to the information in The Cancer Genome Atlas database, the crucial prognostic value of COL28A1 in GBM potentially has a role in the progression of GBM.
| Collagen Receptors in Gliomas|| |
Collagen is known to have three primary functions in brain tumors. First, collagen can serve as a reservoir for matricellular proteins, proteoglycans, and various growth factors. Second, collagen is a ligand that activates transduction signaling pathways that are responsible for tumor cell proliferation, differentiation, invasion, and migration. Third, collagen provides cells with potential adhesion sites. It should be noted that collagen-binding receptors mediate these collagen functions. The first category of binding receptors is integrins, which are transmembrane receptors made up of obligate heterodimers of α and β subunits. The α subunit of α1 β1, α2 β1, α10 β1, and α11 β1 integrins has a specific domain, which is identified as a collagen-binding site. They constitute a subset of the integrin family that recognizes a specific amino acid sequence, i.e., GFOGER, in collagens. The binding of integrins to collagen leads to conformational changes that cause the separation of the cytoplasmic tails in the α and β subunits, which exposes the protein binding sites and results in more activation of downstream signaling. Discoidin domain receptors (DDRs) are a family of tyrosine kinase receptors whose autophosphorylation is mediated by collagens. DDRs have recently been found to be a novel modulator to activate collagen-binding integrins. In a previous report, the expression of DDR1 was increased in glioma tissues and high DDR1 expression was negatively associated with the survival of GBM patients. Inhibition of DDR1 expression significantly suppressed glioma cell growth and tissue invasion. Endo180, which is encoded by the MRC2 gene, is another collagen-binding receptor. It is a type-1 membrane protein that belongs to the macrophage mannose receptor protein family. The extracellular part of endo180 comprises a single cysteine-rich domain, a single fibronectin type II domain, and a series of C-type lectin-like domains. Endo180 primarily mediates endocytosis and the degradation of collagen. Endo180 was shown to increase in GBM tissues and promote glioma invasion through the collagen matrix. G protein-coupled receptor 56 (GPR56) is a protein encoded by the ADGRG1 gene and is characterized by an extended extracellular region. It plays an important role in cell-to-cell and cell-to-ECM interactions. GPR56 contributes to the regulation of cortical development and lamination through binding to collagen III. GPR56 inhibits mesenchymal differentiation and radioresistance in GBM.
| Collagen Remodeling in Glioma|| |
A hallmark of cancer is tumor invasion and metastasis to remote regions. Disruption of the ECM surrounding tumor cells is considered the central process that mediates these events and it is not only a vital rate-limiting step in the infiltration of adjacent tissues but also involves crucial modification of the tumor-surrounding microenvironment. Collagens are essential components of the ECM and they undergo constant remodeling. MMPs are metalloproteinases that are responsible for collagen remodeling. MMPs belong to the metzincin superfamily, which are calcium-dependent zinc-containing endopeptidases that have a common domain structure, including the propeptide domain, the catalytic domain, and the hemopexin-like C-terminal domain linked to the catalytic domain by a flexible hinge region. Until recently, only 14 MMPs were identified as capable of degrading different kinds of collagens. MMP-2 and MMP-9 contain three repeats of the fibronectin type II motif and play an important role in cleaving denatured collagen. The N-terminal catalytic domain and the c-terminal hemopexin domain of MMP-1 are associated with collagen binding. MMPs modulate collagen remodeling by collaborating with collagen receptors. DDRs are reported to modulate MMP expression. Two members of the DDR family are DDR1 and DDR2. DDR1a was shown to enhance glioma cell invasion by increasing pro-MMP-2 production. On the other hand, degradation of collagen-binding receptors by MMPs has also been reported for some malignant tumors. For example, MMP-2 can degrade β1 integrin with the release of the β1 I-domain, which reduces tumor cell adhesion and ultimately increases motility and invasiveness in colon cancers. The membrane-anchored collagenases, MT1-, MT2-, and MT3-MMP, can also degrade DDR1 and inhibit collagen-induced DDR1 activation in breast cancer. Thus, in malignant tumors, the interaction between MMPs and collagen receptors may act in an inhibitory manner, resulting in tumor promotion.
| Mechanical Properties of Collagen Matrices in Glioma|| |
Collagen is the main component of the ECM and contributes to ECM stiffness. The mechanical properties of collagens are also involved in regulating glioma cell behavior. Glioma cells were found to migrate rapidly with high ECM stiffness, while glioma cells migrated very little when the ECM stiffness was similar to normal brain tissue. These results indicated that glioma cells can be regulated by the surrounding ECM stiffness. Further studies of Three-dimensional model systems provided more evidence on the mechanical properties of collagen in glioma. Glioma cells exhibited a strong invasion ability with high concentrations of collagen. Furthermore, GBM cells exhibited stronger migration and invasion and exhibited additional morphological changes in response to the high stiffness at the bottom of the collagen gel compared with the GBM cells close to the top position of the collagen gel. Although knowledge of the exact mechanisms behind the contribution of the mechanical properties of collagen to GBM progression is still limited, the importance of collagen-binding receptors is worth further investigation. DDRs were found to be involved in mechanotransduction.
| Limitations|| |
This review is limited by incomplete retrieval of the literature and report bias, which may inadvertently have led to the omission of potentially relevant work.
| Conclusion|| |
In this review, several types of collagens were shown to be aberrantly expressed in gliomas. Collagen is closely correlated with glioma progression and contributes to the modulation of glioma cell proliferation, migration, and invasion. Collagen receptors and remodeling are the underlying factors that contribute to glioma progression [Figure 2]. A better understanding of the functions of collagen in glioma could provide a new strategy for the treatment of glioma. In the future, collagen could be a novel target for glioma therapy.
|Figure 2: Relationship between collagens and their receptors and gliomas. Collagens and their receptors modulate glioma proliferation, invasion, and migration by activating various collagen receptors. MMPs work with collagen receptors to modulate collagen remodeling and increase the invasion ability of glioma cells. DDR: Discoidin domain receptor, ECM: Extracellular matrix, FAK: Focal adhesion kinase, MMP: Matrix metalloproteinase|
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]