The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

Tempest, Robert; Guarnerio, Sonia; Maani, Rawan; Cooper, Jamie; Peake, Nicholas

doi:10.3390/cancers13112788

Cited by 20 publications

(27 citation statements)

References 270 publications

(335 reference statements)

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“…It is therefore conceivable that TG2 plays differential, and in some cases tissue-specific functions [ 60 ], in both normal and pathologic conditions. In tumors, including BrCa [ 1 ], TG2 is frequently expressed at higher levels than it is in normal tissues and is involved in the maintenance of cancer stem cells, in sensitivity to therapy, in vascularization, and in spreading by metastasis [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

The Motility and Mesenchymal Features of Breast Cancer Cells Correlate with the Levels and Intracellular Localization of Transglutaminase Type 2

Bianchi

Brugnoli

Grassilli

et al. 2021

Cells

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We have investigated motility in breast cancer cell lines in association with the expression of Transglutaminase type 2 (TG2) as well as upon the administration of Doxorubicin (Dox), an active cytotoxic agent that is employed in chemotherapy. The exposure of MCF-7 cells to the drug increased TG2 levels, triggering epithelial–mesenchymal transition (EMT), thereby supporting cell motility. The effects of Dox on the movement of MCF-7 cells were counteracted by treatment with NC9, a TG2 inhibitor, which induced morphological changes and also reduced the migration of MDA-MB-231 cells exhibiting high levels of TG2. The physical association of TG2 with the cytoskeletal component vimentin appeared pivotal both in drug-treated MCF-7 and in MDA-MB-231 cells and seemed to be independent of the catalytic activity of TG2. NC9 altered the subcellular distribution of TG2 and, consequently, the co-localization of TG2 with vimentin. Furthermore, NC9 induced a nuclear accumulation of TG2 as a prelude to TG2-dependent gene expression modifications. Since enzyme activity can affect both motility and nuclear functions, targeting of this protein could represent a method to improve therapeutic interventions in breast tumors, particularly those to control progression and to limit drug resistance.

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Section: Discussionmentioning

confidence: 99%

The Motility and Mesenchymal Features of Breast Cancer Cells Correlate with the Levels and Intracellular Localization of Transglutaminase Type 2

Bianchi

Brugnoli

Grassilli

et al. 2021

Cells

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“…Stiffness of the ECM scaffold can be increased by biochemical crosslinking of its molecules to form supramolecular complexes [ 455 ]. Thus, in addition to increased deposition of collagen I, the TME and the metastatic niche are enriched in lysyl-oxidases (LOXs) and LOX-like proteins (LOXL), which crosslink collagen molecules via oxidatively derived lysyl side chains [ 456 , 457 ]. Additionally, transglutaminase activity in the TME increases ECM rigidity [ 457 ].…”

Section: Mmps and Tme: More Than A Hit-and-run Relationmentioning

confidence: 99%

“…Several clinical studies with ECM-normalizing drugs and drugs that target mechanotransduction with a possible effect on MMP-14 function are currently underway [ 498 , 499 ]. Targeting transglutaminase or lysyl oxidase with therapeutics could be options to fight cancer by reversing the biomechanical stiffening of the TME [ 456 , 457 ].…”

Section: Translational Perspectives: Mmps and Invadopodia Are Worthwhile Targets For Inhibiting Cancer Progressionmentioning

confidence: 99%

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

Niland

Riscanevo

Eble

2021

IJMS

152

107

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Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell–matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.

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“…Given the wide pattern of TG2 expression, including fibroblasts, endothelium, and immune cells, it is important to consider whether its secretion in the TME or its expression in stromal cells alters cancer initiation and/or progression [ 104 ]. Within the TME, TG2 has been shown to modulate multiple biological and biomechanical processes, impacting tumor progression and metastasis ( Figure 3 ) [ 105 ].…”

Section: Tg2 In the Extracellular Matrix In Cancermentioning

confidence: 99%

The Outside-In Journey of Tissue Transglutaminase in Cancer

Sima

Matei

Condello

2022

Cells

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Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca2+-dependent protein crosslinks and hydrolyzes guanosine 5′-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca2+ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca2+ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2’s unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential for cellular adhesion to the matrix. This mechanism allows TG2 to interact with key matrix proteins and to regulate epithelial to mesenchymal transition and stemness. Here, we highlight the current knowledge on TG2 involvement in cancer, focusing on its roles translating extracellular cues into activation of oncogenic programs. Improved understanding of these mechanisms could lead to new therapeutic strategies targeting this multi-functional protein.

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The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

Cited by 20 publications

References 270 publications

The Motility and Mesenchymal Features of Breast Cancer Cells Correlate with the Levels and Intracellular Localization of Transglutaminase Type 2

The Motility and Mesenchymal Features of Breast Cancer Cells Correlate with the Levels and Intracellular Localization of Transglutaminase Type 2

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

The Outside-In Journey of Tissue Transglutaminase in Cancer

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