Tissue transglutaminase induces Epithelial-Mesenchymal-Transition and the acquisition of stem cell like characteristics in colorectal cancer cells

Ayinde, Oluseyi; Wang, Zejing; Griffin, Martin

doi:10.18632/oncotarget.15370

Cited by 38 publications

(50 citation statements)

References 55 publications

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“…The role of TGF β in EMT 12 , 13 and EndMT 14 has been well-documented. Given the comparable effects of either exogenous TG2 or TGF β 1 that result in the loss of HUVEC tubule formation, we next looked at the effects of TG2 on TGF β 1 signalling.…”

Section: Resultsmentioning

confidence: 99%

“…If progressive, EndMT will eventually lead to the loss of blood vessel formation (capillary rarefaction) and ultimately organ fibrosis and failure. Importantly, TG2 has also been shown to be involved in a similar process called epithelial–mesenchymal transition (EMT) important during cancer progression 13 and in cystic fibrosis, 12 It is therefore not surprising that TG2 is also involved in EndMT.…”

Section: Discussionmentioning

confidence: 99%

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The functional relationship between transglutaminase 2 and transforming growth factor β1 in the regulation of angiogenesis and endothelial–mesenchymal transition

Wang

Perez

Lee³

et al. 2017

Cell Death Dis

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The importance of transglutaminase 2 (TG2) in angiogenesis has been highlighted in recent studies, but other roles of this multi-functional enzyme in endothelial cell (EC) function still remains to be fully elucidated. We previously showed that the extracellular TG2 is involved in maintaining tubule formation in ECs by a mechanism involving matrix-bound vascular endothelial growth factor (VEGF) signalling. Here, by using the ECs and fibroblast co-culture and ECs 3D culture models, we demonstrate a further role for TG2 in both endothelial tubule formation and in tubule loss, which involves its role in the regulation of transforming growth factor β1 (TGFβ1) and Smad signalling. We demonstrate that inhibition of tubule formation by TG2 inhibitors can be restored by add-back of exogenous TGFβ1 at pg/ml levels and show that TG2 −/− mouse ECs are unable to form tubules in 3D culture and display negligible Smad signalling compared to wild-type cells. Loss of tubule formation in the TG2 −/− ECs can be reconstituted by transduction with TG2. We demonstrate that extracellular TG2 also has an important role in TGFβ1-induced transition of ECs into myofibroblast-like cells (endothelial–mesenchymal transition), resulting in loss of EC tubules and tubule formation. Our data also indicate that TG2 may have a role in regulating TGFβ signalling through entrapment of active TGFβ1 into the extracellular matrix. In conclusion, our work demonstrates that TG2 has multi-functional roles in ECs where its ability to fine-tune of TGFβ1 signalling means it can be involved in both endothelial tubule formation and tubule rarefaction.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The functional relationship between transglutaminase 2 and transforming growth factor β1 in the regulation of angiogenesis and endothelial–mesenchymal transition

Wang

Perez

Lee³

et al. 2017

Cell Death Dis

Self Cite

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“…For several tissue-derived cells of heterogeneous origin, grown in an appropriate microenvironment, the spheroid (niche-like)-forming capacity per se is typical of stem/progenitor cells, irrespectively of their normal or neoplastic nature [ 1 , 64 , 104 , 105 ]. This spheroid self-building property can be considered as an EMT-dependent process, mediated by TGF-β and its network signaling.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids

Forte

Chimenti

Rosa

et al. 2017

Cancers

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The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target.

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“…More importantly, the activation of the EMT process is closely related to the normal and maintenance of the dryness of the tumor cells. A large number of experimental studies have confirmed that EMT can induce the transformation of tumor cells into cancer stem cells [ 80 , 81 ]. Overexpression of EMT-associated transcription factors Snail, Twist, or FOXC2 not only enables phenotypic transformation of breast cancer cells but also enhances tumor glomus formation, soft agar clonality, and tumorigenic potential and enables them to obtain CD44high/CD24low (cancerous CSCs and markers for mammary epithelial stem cells) antigen phenotype [ 82 , 83 ].…”

Section: Cancer Stem Cells and Plasticitymentioning

confidence: 99%

Exosomes Regulate the Transformation of Cancer Cells in Cancer Stem Cell Homeostasis

Liao

Zhou

2018

Stem Cells International

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In different biological model systems, exosomes are considered mediators of cell-cell communication between different cell populations. Exosomes, as extracellular vesicles, participate in physiological and pathological processes by transmitting signaling molecules such as proteins, nucleic acids, and lipids. The tumor's microenvironment consists of many types of cells, including cancer stem cells and mesenchymal cells. It is well known that these cells communicate with each other and thereby regulate the progression of the tumor. Recent studies have provided evidence that exosomes mediate the interactions between different types of cells in the tumor microenvironment, providing further insight into how these cells interact through exosome signaling. Cancer stem cells are a small kind of heterogeneous cells that existed in tumor tissues or cancer cell lines. These cells possess a stemness phenotype with a self-renewal ability and multipotential differentiation which was considered the reason for the failure of conventional cancer therapies and tumor recurrence. However, a highly dynamic equilibrium was found between cancer stem cells and cancer cells, and this indicates that cancer stem cells are no more special target and blocking the transformation of cancer stem cells and cancer cells seem to be a more significant therapy strategy. Whether exosomes, as an information transforming carrier between cells, regulated cancer cell transformation in cancer stem cell dynamic equilibrium and targeting exosome signaling attenuated the formation of cancer stem cells and finally cure cancers is worthy of further study.

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Tissue transglutaminase induces Epithelial-Mesenchymal-Transition and the acquisition of stem cell like characteristics in colorectal cancer cells

Cited by 38 publications

References 55 publications

The functional relationship between transglutaminase 2 and transforming growth factor β1 in the regulation of angiogenesis and endothelial–mesenchymal transition

The functional relationship between transglutaminase 2 and transforming growth factor β1 in the regulation of angiogenesis and endothelial–mesenchymal transition

EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids

Exosomes Regulate the Transformation of Cancer Cells in Cancer Stem Cell Homeostasis

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