Alterations in the distribution and activity of transglutaminase during tumour growth and metastasis

Barnes, Richard N.; Bungay, Peter J.; Elliott, B.M.; Walton, Peter L.; Griffin, Martin

doi:10.1093/carcin/6.3.459

Cited by 63 publications

(33 citation statements)

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“…However, in the later stages of tumour progression, following increased selection for the metastatic phenotype, TG2 expression may be important in cell mechanisms facilitating cell survival. In this report, we validate earlier findings (Barnes et al 1985;Hand et al 1988;Jones et al 2006;Knight et al 1990) that reduced TG2 expression is required during tumour growth and progression, and provides a mechanism relating to the importance of the enzyme in matrix synthesis and deposition explaining why this reduction should occur.…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2010

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The multifunctional enzyme tissue transglutaminase (TG2) is reported to both mediate and inhibit tumour progression. To elucidate these different roles of TG2, we established a series of stable-transfected mouse colon carcinoma CT26 cells expressing a catalytically active (wild type) and a transamidating-inactive TG2 (Cys277Ser) mutant. Comparison of the TG2-transfected cells with the empty vector control indicated no differences in cell proliferation, apoptosis and susceptibility to doxorubicin, which correlated with no detectable changes in the activation of the transcription factor NF-jB. TG2-transfected cells showed increased expression of integrin b3, and were more adherent and less migratory on fibronectin than control cells. Direct interaction of TG2 with b3 integrins was demonstrated by immunoprecipitation, suggesting that TG2 acts as a coreceptor for fibronectin with b3 integrins. All cells expressed the same level of TGFb receptors I and II, but only cells transfected with active TG2 had increased levels of TGFb1 and matrix-deposited fibronectin, which could be inhibited by TG2 site-directed inhibitors. Moreover, only cells transfected with active TG2 were capable of inhibiting tumour growth when compared to the empty vector controls. We conclude that in this colon carcinoma model increased levels of active TG2 are unfavourable to tumour growth due to their role in activation of TGFb1 and increased matrix deposition, which in turn favours increased cell adhesion and a lowered migratory and invasive behaviour.

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Section: Discussionsupporting

confidence: 91%

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

et al. 2010

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“…Upon secretion, TG2 is activated by the high level of Ca 2ϩ in the extracellular space and functions as a cross-linking enzyme in the matrix (28). There are numerous reports of downregulation of TG2 in aggressive tumors and metastases (30)(31)(32)(33). Recombinant TG2 applied to rat mammary adenocarcinomas implanted in dorsal skin window chambers produced significant growth delay in the tumors (34), and transfection of TG2 into a highly malignant hamster fibrosarcoma cell line led to significant reduction of tumor incidence (35).…”

Section: Gpr56 Is a Gpcr Implicated In Multiple Biologicalmentioning

confidence: 99%

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

Begum

Hearn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

251

297

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The survival and growth of tumor cells in a foreign environment is considered a rate-limiting step during metastasis. To identify genes that may be essential for this process, we isolated highly metastatic variants from a poorly metastatic human melanoma cell line and performed expression analyses of metastases and primary tumors from these cells. GPR56 is among the genes markedly downregulated in the metastatic variants. We show that overexpression of GPR56 suppresses tumor growth and metastasis, whereas reduced expression of GPR56 enhances tumor progression. Levels of GPR56 do not correlate with growth rate in vitro, suggesting that GPR56 may mediate growth suppression by interaction with a component in the tumor microenvironment in vivo. We show that GPR56 binds specifically to tissue transglutaminase, TG2, a widespread component of tissue and tumor stroma previously implicated as an inhibitor of tumor progression. We discuss the mechanisms whereby GPR56-TG2 interactions may suppress tumor growth and metastasis. (ii) some of the detached cells enter the circulation via blood vessels or lymphatics (intravasation); (iii) a fraction of the cells in the circulation arrest and transmigrate through blood vessels or lymphatics and invade into a distant tissue or organ (extravasation); (iv) some of the invading cells survive and proliferate in the new environment as metastases. To produce any clinically relevant metastases, a tumor cell must complete all these steps.Abundant clinical and experimental data suggest that the survival and growth step (step iv) is a rate-limiting step during metastasis (1, 2). Frequently, tumor cells are able to enter the circulation and settle in many organs but are not able to proliferate or are only able to proliferate in certain organs. Experimental metastasis assays have been developed to study these steps of metastasis. In these assays, a pool of poorly metastatic tumor cells is injected into the circulation of immunodeficient mice and gives rise to metastases at low frequency. Cells in these rare metastases can be selected from the original pool as variants which, through genetic or epigenetic changes, have gained the ability to invade, survive, and grow in a foreign environment. When these cells are isolated and amplified in vitro, they largely maintain their enhanced metastatic potential. Genes involved in metastasis can then be identified by comparing the gene expression profiles between the highly metastatic variants and the poorly metastatic pool through microarray analyses. With this method, RhoC has previously been discovered to play important roles during melanoma metastasis to lung (3), and a five-gene signature has been discovered to be essential for breast cancer metastasis to bone (4).In this article, we report that a member of a newly described family of G protein-coupled receptors (GPCRs), GPR56, contributes to suppression of melanoma metastasis and tumor growth. This suppression is not cell-autonomous, because cells with altered levels of GPR56 grow at similar rates ...

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“…60 TG2 has also been implicated in cancer progression. Its expression and activity levels have often been reported to be downregulated during tumor progression, [62][63][64][65] although there are some reports of up-regulation. 66 The function of TG2 in tumor progression is not understood.…”

Section: Gpr56 and Tg2 Interactions In Metastasismentioning

confidence: 99%

GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

Xu¹,

Hynes²

2007

Cell Cycle

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Metastasis is a complex process that involves multiple levels of cell-cell interaction. Among these interactions, tumor-stroma interactions are being actively investigated. Metastatic cells are hypothesized to show gene expression changes that contribute to their survival and growth at the distant site. Such changes could contribute either to enhancement of growth or to evasion of growth inhibition by the normal tissue environment thus allowing growth as metastases. Our recent report that tumors from highly metastatic melanoma derivatives express low levels of a suppressor of tumor progression, GPR56, is consistent with such a model. GPR56 associates in a complex with Gaq and the tetraspanin protein CD81. We further identified a ligand that interacts with GPR56 in the extracellular matrix (ECM) as TG2, a major crosslinking enzyme in the matrix. TG2 also binds to fibronectin and integrins and affects their cell adhesion functions. TG2 itself has been implicated in suppression of tumor progression; therefore TG2 might serve as a host defense against the invading metastatic cells. The highly metastatic cells may escape from this inhibition by down-regulation of GPR56. Much future work will be needed to test this hypothesis and further our understanding of metastasis in general.

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Alterations in the distribution and activity of transglutaminase during tumour growth and metastasis

Cited by 63 publications

References 0 publications

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

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

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

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