Tissue transglutaminase in tumour progression: friend or foe?

Abstract

Basic biological processes in which tissue transglutaminase (TG2, tTG) is thought to be important including apoptosis, cell adhesion and migration, ECM homeostasis and angiogenesis are key stages in the multistage tumour progression cascade. Studies undertaken with primary tumours and experimental models suggest that TG2 expression and activity in the tumour body and surrounding matrix generally decreases with tumour progression, favouring matrix destabilisation, but supporting angiogenesis and tumour invasion. In contrast, in the secondary metastatic tumour TG2 is often highly expressed whereby its potential roles in cell survival both at the intra- and extracellular level become important. In the following review the underlying molecular basis for the selection of these different phenotypes in tumour types and the anomaly for the requirement of TG2 is discussed in relation to the complex events of tumour progression.

The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26

“…They are also consistent with the observation of increased tumour growth and progression of the B16 melanoma (F1and F6) in a mouse TG2 knockout model (Di Giacomo et al 2009;Jones et al 2006). Taking on board the proposed physiological functions for TG2 Griffin et al 2002) and those proposed for its roles in cancer progression (Kotsakis and Griffin 2007;Mehta 2009;Verma and Mehta 2007a), our next step was to Western blotting using specific antibodies as described in the ''Materials and methods''. The membranes were re-probed for a-tubulin detection as a standard for equal loading.…”

“…Given these multifunctional roles of TG2, it is not surprising that reports have been contradictory as to whether TG2 is inhibitory to, or required for tumour progression (Grigoriev et al 2001;Hand et al 1988; Kotsakis and Griffin 2007;Verderio et al 1999). In recent studies, we demonstrated that the crosslinking activity of TG2 leading to ECM deposition and the inhibition of angiogenesis was sufficient for tumour growth blockade following intratumour injection of active TG2 into mice bearing CT26 colon carcinoma tumours (Jones et al 2006).…”

“…The multifunctional enzyme tissue transglutaminase (TG2), which has important roles in cell adhesion and migration, cell survival/death, matrix deposition and angiogenesis, has been the focus of numerous studies in cancer biology (Kotsakis and Griffin 2007;Lentini et al 2004). TG2 is the most ubiquitous member of the transglutaminase family which crosslink proteins through a Ca 2?…”

RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

“…We also illustrated how this compensation mechanism is particularly important for cell survival during situations involving matrix remodeling (e.g. wounding and scarring, angiogenesis, and tumor metastasis), where high levels of TG2 and RGD peptides are released during the matrix remodeling process (23)(24)(25).…”

Transglutaminase 2, a double face enzyme

“…We will now examine separately each of these instances, because it must be considered that these contrasting effects might be related by one side to the intrinsic different actions of Tgase2 as a signaling and a protein crosslinking enzyme, by the other to the toxic potential of transglutaminase itself, as well as to the reactive defense response by surrounding healthy tissues. These considerations are central for understanding the opposing effects of Tgase2 in disease pathogenesis as underlined for instance in the case of tumor biology (Kotsakis and Griffin 2007), as authors wonder whether Tgase is "friend or foe".…”