Physiological and therapeutic roles of tissue transglutaminase in tumour growth and angiogenesis.

Kotsakis, P, 2005. Physiological and therapeutic roles of tissue transglutaminase in tumour growth and angiogenesis. PhD, Nottingham Trent University.

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Abstract

This study provides evidence for the potency of the protein crosslinking enzyme tissue transglutaminase (TG2) as a novel inhibitor of tumour growth and angiogenesis. When B16-F1 melanoma cells were injected into TG2 wild-type and knock-out mice a delay in tumour growth rates was observed only in the former. Immunohistochemistry of tumours extracted from TG2 wild-type mice revealed lack of TG2 expression within the tumour body, but increased deposition at the host-tumour interface suggesting that the enzyme is expressed by stromal cells as a host response against tumour development. Conversely, in a syngeneic model, CT26 colon carcinoma tumours demonstrated marked reduction in growth and in certain instances regression following intratumour injection of gplTG2. Application of gplTG2 into CT26 cultures ruled out any cytotoxic, pro-apoptotic, or anti-proliferative effect. Instead, immunohistochemistry of regressing tumours revealed the presence of fibrotic-like tissue rich in applied TG2, collagen and the ?(y-glutamy1)lysine isopeptide bond. Cross-linking of collagen artificial matrices by TG2 was also shown to reduce the invasive capacity of CT26 tumour cells in an in vitro experimental setting of chemotaxis. Relevant to angiogenesis, an observed increase in migration of TG2 knockout mouse aortic endothelial cells in matrigel suggested that the expression of the enzyme is not needed during neovascularisation. Using in vitro co-culture and ex vivo aortic models of angiogenesis, repeated application of active TG2 was shown to suppress capillary tube formation without causing cellular toxicity. The applied TG2 led to ECM accumulation, and sequestration of transforming growth factor-?1 into the ECM. Single cell studies demonstrated that TG2-induced matrix accumulation was facilitated by a decreased rate of matrix turnover and an increased resistance of cross-linked matrix to MMP-1. The importance of the transamidating function of TG2 in the blockade of tumour growth was verified when CT26 transfected for stable expression of inactive TG2 constructs failed to elicit tumour regression as opposed to CT26 expressing the active TG2. Both CT26 clones exhibited increased attachment but reduced migration in surfaces coated with fibronectin. Intratumour injection of TG2 creates a reinforced ECM barrier at the tumour/stroma interface that may provide a novel antiangiogenic strategy for use in solid tumour containment.

Item Type:	Thesis
Creators:	Kotsakis, P.
Date:	2005
ISBN:	9781369316476
Identifiers:	Number Type PQ10183446 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Jeremy Silvester
Date Added:	25 Sep 2020 15:19
Last Modified:	08 Sep 2023 13:04
URI:	https://irep.ntu.ac.uk/id/eprint/40963

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