Administration of active TG2 to two different in vitro angiogenesis assays resulted in the accumulation of a complex extracellular matrix (ECM) leading to the suppression of endothelial tube formation without causing cell death. Matrix accumulation was accompanied by a decreased rate of ECM turnover, with increased resistance to matrix metalloproteinase-1. Intratumor injection of TG2 into mice bearing CT26 colon carcinoma tumors demonstrated a reduction in tumor growth, and in some cases tumor regression. In TG2 knockout mice, tumor progression was increased and survival rate reduced compared to wild-type mice. In wild-type mice, an increased presence of TG2 was detectable in the host tissue around the tumor. Analysis of CT26 tumors injected with TG2 revealed fibrotic-like tissue containing increased collagen, TG2-mediated crosslink and reduced organized vasculature. TG2-mediated modulation of cell behavior via changes in the ECM may provide a new approach to solid tumor therapy.
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 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.
Peripheral blood lymphocytes from 21 patients with aleukaemic stages of mycosis fungoides were studied with monoclonal T cell antibodies. Patients with erythematous eruptions or infiltrated plaques (group I) had a higher percentage of OKT4+ cells than patients with a tumorous stage (group II) or normal subjects (p = 0.05). OKT8+ cells were decreased in group I patients whereas in group II they were usually normal or increased (p < 0.02). These data indicate that with advancing stage of the disease a different pattern of imbalance of T-cell subsets is being established.
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