Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth

Jones, Richard A.; Kotsakis, P.; Johnson, Timothy S.; Chau, David; Ali, Selman A.; Melino, Gerry; Griffin, Martin

doi:10.1038/sj.cdd.4401816

Cited by 125 publications

(122 citation statements)

References 36 publications

(55 reference statements)

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“…Because TG2 has been demonstrated to suppress tumor growth, metastasis, and angiogenesis in animal models of colon cancer and melanoma (36,37), our findings highlight TG2 as a potential drug development target for the treatment of cancers overexpressing Myc oncoproteins. Furthermore, our findings provide support for the use of HDAC inhibitor therapy in cancer types overexpressing Myc oncoproteins and suggest that therapies that augment the expression or function of TG2 may have a synergistic therapeutic effect on cancer when combined with HDAC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis

Liu

Tee

Porro

et al. 2007

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

114

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Histone deacetylase (HDAC) inhibitors reactivate tumor suppressor gene transcription; induce cancer cell differentiation, growth arrest, and programmed cell death; and are among the most promising new classes of anticancer drugs. Myc oncoproteins can block cell differentiation and promote cell proliferation and malignant transformation, in some cases by modulating target gene transcription. Here, we show that tissue transglutaminase (TG2) was commonly reactivated by HDAC inhibitors in neuroblastoma and breast cancer cells but not normal cells and contributed to HDAC inhibitor-induced growth arrest. TG2 was the gene most significantly repressed by N-Myc in neuroblastoma cells in a cDNA microarray analysis and was commonly repressed by N-Myc in neuroblastoma cells and c-Myc in breast cancer cells. Repression of TG2 expression by N-Myc in neuroblastoma cells was necessary for the inhibitory effect of N-Myc on neuroblastoma cell differentiation. Dual step cross-linking chromatin immunoprecipitation and protein coimmunoprecipitation assays showed that N-Myc acted as a transrepressor by recruiting the HDAC1 protein to an Sp1-binding site in the TG2 core promoter in a manner distinct from it's action as a transactivator at E-Box binding sites. HDAC inhibitor treatment blocked the N-Myc-mediated HDAC1 recruitment and TG2 repression in vitro . In neuroblastoma-bearing N-Myc transgenic mice, HDAC inhibitor treatment induced TG2 expression and demonstrated marked antitumor activity in vivo . Taken together, our data indicate the critical roles of HDAC1 and TG2 in Myc-induced oncogenesis and have significant implications for the use of HDAC inhibitor therapy in Myc-driven oncogenesis.

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Section: Discussionmentioning

confidence: 99%

Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis

Liu

Tee

Porro

et al. 2007

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

114

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“…40 Although ECs are a rich source of TG2, 41 the presence of TG2 produced by the HFF-1 might be one of the reasons for the observed inhibition of EC assembly into capillary-like structures, as it has already been described that the addition of exogenous TG2 blocks angiogenesis in vitro. 42 In the present work, HUVECs were found to express TG2 when cultured alone for 7, 14, and 21 days (data not shown). However, expression of TG2 was not observed when formation of capillary-like structures occurred, namely in cocultures of HUVEC/HDF (data not shown), which corroborates the fact that the presence of TG2 produced by HFF-1 fibroblasts might be an inhibitor of the formation of capillary-like structures.…”

Section: Ecm Production By the Different Cellsmentioning

confidence: 80%

Fibroblast-Endothelial Partners for Vascularization Strategies in Tissue Engineering

Costa‐Almeida

Gómez-Lázaro

Ramalho

et al. 2015

Tissue Engineering Part A

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Cell-based approaches have emerged as a promising therapy to achieve successful vascularization in tissue engineering. Since fibroblasts activation and migration is required for physiological events relying on angiogenesis, we hypothesize herein that different fibroblasts exhibit distinct capacity to promote capillary-like structures assembly, by mature and progenitor endothelial cells (ECs). Outgrowth endothelial cells (OECs) were isolated from human umbilical cord blood samples and characterized by immunofluorescence and imaging flow cytometry for endothelial markers. Coculture systems were established using either human umbilical vein ECs (HUVECs) or OECs with fibroblasts, being evaluated at 7, 14, and 21 days of culture. Two types of human dermal fibroblasts (HDF) were used, namely neonatal human foreskin fibroblasts-1 (HFF-1) and juvenile HDF. OECs expressed EC markers and formed capillary-like structures. HFF-1 exhibited higher expression of transglutaminase-2, while HDF exhibited a higher expression of a-smooth muscle actin (a-SMA) and podoplanin, which were not observed for HFF-1. Formation of capillary-like structures was only observed in cocultures with HDF and not with HFF-1. No significant differences were found between HDF and OECs or HUVECs cocultures. These findings suggest that HDF is a preferential cell source for promoting vascularization, either using mature or progenitor ECs, probably due to their higher expression of a-SMA and podoplanin, and increased synthesis of extracellular matrix. This work opens new research possibilities regarding the use of specific fibroblast populations cocultured with ECs, as efficient partners for vascular development in regenerative medicine strategies.

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“…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). A recent report showed that exogenous TG2 inhibited angiogenesis and tumor growth, and tumor growth in TG2 knockout mice was enhanced (36). These results implicate TG2, like GPR56, as a suppressor of tumor growth.…”

Section: Gpr56 Is a Gpcr Implicated In Multiple Biologicalmentioning

confidence: 86%

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.

249

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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Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth

Cited by 125 publications

References 36 publications

Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis

Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis

Fibroblast-Endothelial Partners for Vascularization Strategies in Tissue Engineering

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

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