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Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth.

ABSTRACT: Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by recombinant adenoviruses in endothelial cells, however, leads to the specific induction of potent feedback inhibitory mechanisms, including strong up-regulation of transcriptional repressors, negative cell cycle check point effectors, proteins with established antiangiogenic activity, and several proapoptotic genes. Sustained EGR-1 expression consistently leads to an antiangiogenic state characterized by an altered responsiveness to VEGF and bFGF and a striking inhibition of sprouting and tubule formation in vitro. Furthermore, EGR-1-expressing viruses potently inhibit cell invasion and vessel formation in the murine Matrigel model and repress tumor growth in a murine fibrosarcoma model. We propose that gene therapy involving sustained EGR-1 expression may constitute a novel therapeutic principle in the treatment of cancer due to the simultaneous induction of multiple pathways of antiangiogenesis, growth arrest, and apoptosis induction in proliferating cells leading to preferential inhibition of angiogenesis and tumor growth.

SUBMITTER: Lucerna M

PROVIDER: S-EPMC2882226 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth.

Lucerna Markus M Pomyje Jiri J Mechtcheriakova Diana D Kadl Alexandra A Gruber Florian F Bilban Martin M Sobanov Yuri Y Schabbauer Gernot G Breuss Johannes J Wagner Oswald O Bischoff Markus M Clauss Matthias M Binder Bernd R BR Hofer Erhard E

Cancer research 20060701 13

Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by recombinant adenoviruses in endothelial cells, however, leads to the specific induction of ...[more]

PMID: 16818645

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Project description:In multiple myeloma (MM), hypoxia-inducible transcription factor-1 (HIF-1) is overexpressed in the MM cells of the hypoxic bone marrow (BM) microenvironment. Herein, we explored in MM cells the in vitro and in vivo effects of persistent HIF-1 inhibition by expression of a lentivirus shRNA pool on proliferation, survival and transcriptional and pro-angiogenic profiles. Among the significantly modulated genes (326 and 361 genes in hypoxic and normoxic condition, respectively), we found that HIF-1 inhibition in the human myeloma cell line JJN3 downregulates the pro-angiogenic molecules VEGF, IL8, IL10, CCL2, CCL5, and MMP9. Interestingly, several pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1. The effect of HIF-1 inhibition was assessed in vivo in NOD/SCID mice both in subcutaneous and intratibial models, indicating in either case a dramatic reduction of weight and volume of the tumor burden as a consequence of HIF-1 knockdown. Moreover, a significant reduction of the number of vessels per field and VEGF immunostaining were observed. Finally, in the intra-tibial experiments, HIF-1 inhibition significantly blocks JJN3-induced bone destruction. Overall, our data indicate that HIF-1 suppression in MM cells significantly blocks MM-induced angiogenesis and reduces both tumor burden and bone destruction in vivo, strongly indicating HIF-1 as an emerging therapeutic target in MM. The transcriptional profiles on JJN3 transduced with shRNA anti-HIF-1 (JJN3-anti-HIF-1), as compared to those infected with the control vector pLKO.1 (JJN3-pLKO.1), have been analyzed either in hypoxic or normoxic conditions. To perform gene expression profiles, total RNA was purified using the RNeasy Total RNA Isolation Kit (Qiagen, Valencia, CA). Preparation of biotin-labeled cRNA, hybridization to GeneChip Human Genome U133 Plus 2.0 Arrays and scanning (GeneChip¨ Scanner 3000 7G, Affymetrix Inc.) were performed according to manufacturer's protocols.

Project description:BackgroundSecreted frizzled-related protein 1 (SFRP1) expression is down-regulated in a multitude of cancers, including breast cancer. Loss of Sfrp1 also exacerbates weight gain as well as inflammation. Additionally, loss of SFRP1 enhances TGF-β signaling and the downstream MAPK pathway. TGF-β has been shown to increase the expression of Early Growth Response 2 (EGR2), a transcription factor implicated in immune function in a wide variety of cell types. The work described here was initiated to determine whether SFRP1 modulation affects TGF-β mediated EGR2 expression in mammary tissues as well as macrophage polarization.MethodsReal-time PCR analysis was performed to examine EGR2 expression in human and murine mammary epithelial cells and tissues in response to SFRP1 modulation. Chemical inhibition was employed to investigate the roles TGF-β and MAPK signaling play in the control of EGR2 expression in response to SFRP1 loss. Primary murine macrophages were isolated from Sfrp1-/- mice and stimulated to become either M1 or M2 macrophages, treated with recombinant SFRP1, and real-time PCR was used to measure the expression of murine specific M1/M2 markers [Egr2 (M2) and Gpr18 (M1)]. Immunohistochemical analysis was used to measure the expression of human specific M1/M2 markers [CD163 (M2) and HLA-DRA (M2)] in response to rSFRP1 treatment in human mammary explant tissue.ResultsKnockdown of SFRP1 expression increases the expression of EGR2 mRNA in human mammary epithelial cells and addition of rSFRP1 decreases the expression of EGR2 when added to explant mammary gland tissues. Chemical inhibition of both TGF-β and MAPK signaling in Sfrp1-/- or knockdown mammary epithelial cells results in decreased expression of EGR2. Stimulated murine macrophages obtained from Sfrp1-/- mice and treated with rSFRP1 exhibit a reduction in Egr2 expression and an increase in Gpr18 mRNA expression. Human mammary explant tissue treated with rSFRP1 decreases CD163 protein expression whereas there was no effect on the expression of HLA-DRA.ConclusionsLoss of SFRP1 likely contributes to tumor progression by altering the expression of a critical transcription factor in both the epithelium and the immune system.

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Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth.

Publications

Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth.

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