Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors

Ruzinova, Marianna B.; Schoer, R.; Gerald, William L.; Egan, James E.; Pandolfi, Pier Paolo; Rafii, Shahin; Manova, Katia; Mittal, Vivek; Benezra, Robert

doi:10.1016/s1535-6108(03)00240-x

Cited by 230 publications

(173 citation statements)

References 37 publications

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“…Despite the high Id1 levels achieved by adenoviral gene transfer, we were unable to observe changes of the TSP-1 levels in SW480-ADH cells (data not shown). Consistent with our results, spontaneous tumor formation in Pten þ /À Id1 À/À or Pten þ /À Id1 À/À Id3 þ /À mice has not been linked with modifications of TSP-1 production by the tumor cells (Ruzinova et al, 2003).…”

Section: Id1 and Id2 Genes Are Differentially Expressed In Colon Carcsupporting

confidence: 92%

“…Id factors impinge on the expression levels of key regulators of the angiogenic cascade including av, a6, b3, b4 integrins, hypoxia-inducible factor-1a, matrix metalloprotease-2 and FGF receptor-1 (Ruzinova et al, 2003). In mouse embryonic fibroblasts from Id1 knockout mice, levels of antiangiogenic TSP-1 are increased and consequently the angiogenic balance is shifted towards an inhibitory phenotype (Volpert et al, 2002).…”

Section: Id1 and Id2 Genes Are Differentially Expressed In Colon Carcmentioning

confidence: 99%

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1α,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells

et al. 2005

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1a,25-Dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) has antitumor activity in addition to its classical action on calcium metabolism and bone tissue biology. It is thought to regulate the expression of multiple target genes and thus modulate processes critical for tumor growth and metastases. Here we show that 1a,25(OH) 2 D 3 differentially regulates the expression of Id1 and Id2 genes, members of a family of transcriptional regulators of cell proliferation and differentiation. 1a,25(OH) 2 D 3 induced epithelial differentiation in SW480-ADH human colon carcinoma cell line by promoting expression of the proteins implicated in adherent junction formation, including E-cadherin, and by inhibiting b-catenin transcriptional activity. 1a,25(OH) 2 D 3 activated the human Id1 gene promoter and rapidly induced Id1 RNA and protein. Ectopic overexpression of Id1 was not sufficient to induce E-cadherin, which was critical for the morphological changes induced by 1a,25(OH) 2 D 3 in SW480-ADH cells. Conversely, Id2 transcription rate, RNA and protein levels were decreased by 1a,25(OH) 2 D 3 . Id2 downregulation by 1a,25(OH) 2 D 3 mediated the antiproliferative effect of 1a,25(OH) 2 D 3 on SW480-ADH cells. In addition, we showed that 1a,25(OH) 2 D 3 changed the levels of the inducer of angiogenesis, vascular endothelial growth factor and the potent antiangiogenic factor thrombospondin-1, leading to a balanced change in the angiogenic potential of SW480-ADH human colon carcinoma cells.

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Section: Id1 and Id2 Genes Are Differentially Expressed In Colon Carcsupporting

confidence: 92%

Section: Id1 and Id2 Genes Are Differentially Expressed In Colon Carcmentioning

confidence: 99%

1α,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells

et al. 2005

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“…It will be of interest to determine if such behavior is influenced by the secretion of short-acting factors, such as matrix metalloproteinase 2 (MMP2; ref. 21) or MMP9 (22), known to be under Id1 control. Highly aggressive metastatic breast neoplasms, which are negative for ER and HER-2/neu, present a therapeutic challenge due to their limited treatment options.…”

Section: Discussionmentioning

confidence: 99%

Reassessment of Id1 Protein Expression in Human Mammary, Prostate, and Bladder Cancers Using a Monospecific Rabbit Monoclonal Anti-Id1 Antibody

et al. 2006

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Id proteins are a class of dominant-negative antagonists of helix-loop-helix transcription factors and have been shown to control differentiation of a variety of cell types in diverse organisms. Although the importance of Id1 in tumor endothelial cells is well established, the expression and role of the Id1 protein in human cancer cells is controversial. To explore this issue, we developed and characterized a highly specific rabbit monoclonal antibody against Id1 to assess its expression in human breast, prostate, and bladder malignancies. Our results show that in usual types of human mammary carcinomas, the Id1 protein is expressed exclusively in the endothelium. Interestingly, we detected nuclear expression of the Id1 protein in the tumor cells in 10 of 45 cases of poorly differentiated and highly aggressive carcinoma with metaplastic morphology. Similarly, only 1 of 30 prostate cancer samples showed Id1-positive tumor cells, whereas in almost all, endothelial cells showed high Id1 expression. Intriguingly, whereas normal prostate glands do not show any Id1 protein expression, basal layer cells of benign prostate glands in proximity to tumors expressed high levels of the Id1 protein.In contrast to the lack of Id1 expression in the usual types of mammary and prostate cancers, the majority of transitional cell bladder tumors showed Id1 protein expression in both tumor and endothelial cells. These results suggest that further refinement of Id1 expression patterns in a variety of tumor types will be necessary to identify and study the functional roles played by Id1 in human neoplastic processes. (Cancer Res 2006; 66(22): 10870-7)

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“…Since ID2 is expressed outside the central nervous system (CNS), it is reasonable that the confinement of the ID1/ID3 knockout defects to the CNS is a result of compensation outside the CNS, indirectly associating ID2 with involvement in angiogenesis (51). Several mechanisms are now emerging by which ID proteins could contribute to angiogenesis, involving transcriptional repression of angiogenesis inhibitors (52) as well as regulation of proangiogenic proteins, all exhibiting decrease upon loss of ID (53). Physiological and tumor angiogenesis is largely dependent on proper VEGF signaling, which is induced by HIF-1 (and HIF-2) and, interestingly, which can be decreased by loss of ID function (25).…”

Section: Discussionmentioning

confidence: 99%

Induction of ID2 Expression by Hypoxia-inducible Factor-1

Löfstedt

Jögi

Sigvardsson

et al. 2004

Journal of Biological Chemistry

118

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ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at ؊725 and ؊1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxiainduced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors.In solid tumors the supply of oxygen and nutrients to some areas is often deprived because of a high rate of cellular proliferation that outpaces the rate of angiogenesis, and structurally abnormal vascularization leading to inadequate intratumoral blood circulation (1). In the resulting hypoxic microenvironment, cancer cells undergo adaptive changes that allow them to survive and even proliferate under hypoxic conditions (2). Mammalian cells, including cancer cells, adapt to hypoxia primarily through a transcriptional response pathway mediated by the hypoxia-inducible factors HIF 1 -1 and HIF-2, which consist of an ␣-subunit (HIF-1␣ or HIF-2␣) and the constitutively expressed transcription factor ARNT/HIF-1␤ (3). At normoxia the ␣-subunit is hydroxylated at critical proline residues by Fe(II)-and O 2 -dependent prolyl hydroxylases (4, 5) and proteasomally degraded via interaction with the von Hippel-Lindau tumor suppressor protein, pVHL (6, 7). In addition to regulation of stability, hydroxylation of an asparagine residue within the ␣-subunit negatively interferes with the function of the transactivation region of HIF under normoxic conditions (8). Hypoxia abrogates both proline and asparagine hydroxylation (4, 8), leading to stable and functional HIFs that can bind regulatory HIF binding sites (HBSs) of target genes involved in maintaining homeostasis, for instance erythropoiet...

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Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors

Cited by 230 publications

References 37 publications

1α,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells

1α,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells

Reassessment of Id1 Protein Expression in Human Mammary, Prostate, and Bladder Cancers Using a Monospecific Rabbit Monoclonal Anti-Id1 Antibody

Induction of ID2 Expression by Hypoxia-inducible Factor-1

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