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Upregulation of angiopoietin-like 4 by viral G protein-coupled receptor promotes angiogenesis and vascular permeability in Kaposi’s sarcoma

Upregulation of angiopoietin-like 4 by viral G protein-coupled receptor promotes angiogenesis and... Ma et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A84 http://www.infectagentscancer.com/content/5/S1/A84 MEETING ABSTRACTS Open Access Upregulation of angiopoietin-like 4 by viral G protein-coupled receptor promotes angiogenesis and vascular permeability in Kaposi’s sarcoma 1 1 1 1 1,2 3 1,2* Tao Ma , Bruno C Jham , Jiadi Hu , Eitan R Friedman , John R Basile , Akrit Sodhi , Silvia Montaner th From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010 Acknowledgements Background This work was supported by grant R01CA119911 (National Cancer Institute, Kaposi’s sarcoma (KS) is an enigmatic vascular tumor NIH). We thank Histoserv, Inc., for its assistance in the processing of the thought to be a consequence of dysregulated expression murine tissues. BCJ is a recipient of a predoctoral fellowship from the CNPq- Brazil. of the human herpesvirus-8 (HHV-8 or KSHV)-encoded This article has been published as part of Infectious Agents and Cancer G protein-coupled receptor (vGPCR) [1]. Both human th Volume 5 Supplement 1, 2010: Proceedings of the 12 International and vGPCR experimental KS lesions are characterized Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI). The full contents of the supplement are by prominent angiogenesis and vascular permeability available online at http://www.biomedcentral.com/1750-9378/5?issue=S1. attributed to the paracrine release of angiogenic media- tors, most notably vascular endothelial growth factor Author details Department of Oncology and Diagnostic Sciences, University of Maryland, (VEGF). To date, the relative contribution of these para- Baltimore, MD, USA. Greenebaum Cancer Center, University of Maryland, crine mediators to the angiogenic and exudative pheno- 3 Baltimore, MD, USA. Wilmer Eye Institute, Johns Hopkins School of type of KS lesions remains unclear. Here we show that Medicine, Johns Hopkins University, Baltimore, MD, USA. vGPCR upregulated angiopoietin-like 4 (ANGPTL4) Published: 11 October 2010 (Figure 1A, 1B, 1C) plays a prominent role in promoting the angiogenesis and increasing vascular permeability in References this tumor. Inhibition of ANGPTL4 effectively blocks 1. Moore PS, Chang Y: Kaposi’s sarcoma-associated herpesvirus-encoded oncogenes and oncogenesis. J Natl Cancer Inst Monogr 1998, 23:65-71. vGPCR promotion of angiogenesis and vascular perme- 2. Ganem D: Human herpesvirus 8 and its role in the genesis of Kaposi’s ability in vitro and tumorigenesis in vivo (Figure 1D , sarcoma. Curr Clin Top Infect Dis 1998, 18:237-251. 1E, 1F, 1G , 1H). 3. Montaner S, et al: The Kaposi’s sarcoma-associated herpesvirus G proteincoupled receptor as a therapeutic target for the treatment of Kaposi’s sarcoma. Cancer Res 2006, 66(1):168-174. Conclusion doi:10.1186/1750-9378-5-S1-A84 These observations suggest that ANGPTL4 is a pre- Cite this article as: Ma et al.: Upregulation of angiopoietin-like 4 by viral viously unrecognized target for the treatment of patients G protein-coupled receptor promotes angiogenesis and vascular with KS. As angiogenesis and increased vessel perme- permeability in Kaposi’s sarcoma. Infectious Agents and Cancer 2010 5(Suppl 1):A84. ability are common themes in all solid tumors, these results may have a broad impact on our understanding and treatment of cancer. *Correspondence: smontaner@umaryland.edu Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, MD, USA Full list of author information is available at the end of the article © 2010 Montaner et al; licensee BioMed Central Ltd. Ma et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A84 Page 2 of 2 http://www.infectagentscancer.com/content/5/S1/A84 Figure 1 (A) Analysis of ANGPTL4 mRNA levels (qRT-PCR), cellular ANGPTL4 (WB) and secreted ANGPTL4 (ELISA) of HMEC1 or HMVEC transfected with pCEFL Tet REV TA and pBIG AU5 vGPCR. (B) ANGPTL4 expression in murine vGPCR tumors and human AIDS-KS. An isotype-matched control antibody (Control) or an ANGPTL4 antibody (ANGPTL4) was used. Similar results were found in all murine vGPCR [2] and all human lesions tested [2]. (C) (Control) vGPCR and vGPCR/TK allografts were generated [3]. Treatment of vGPCR/TK tumors with ganciclovir (50 mg/kg) lead to complete loss of all (AU5) vGPCR-expressing cells. Sections were stained with an ANGPTL4 antibody, showing progressive decreased expression. Magnification x 20 (C and D). (D) HMEC1s were transfected with Scrambled (Scrambled si), ANGPTL4 (ANGPTL4 si) or no siRNA and then with pCEFL Tet REV TA and pBIG AU5 vGPCR. Cells were left untreated (Control) or treated with (1 μg/ml) Dox for 24h (vGPCR). Levels of ANGPTL4 in cellular extracts and conditioned media are shown. Overexpression of ANGPTL4 served as control (E) Conditioned media (CM) or hrANGPTL4 (5μg/ml) was used to induce blood vessel development within basement membrane extract (BME)-filled angioreactors (shown in figure) implanted in nude mice (DIVAA assay). Recombinant FGF2, FGF2/VEGF served as controls. (F) Conditioned media (CM) or hrANGPTL4 (5μg/ml) was used to induce migration of HMEC1s, using Boyden-chamber assay. 2.5% serum (FBS) was used as a control. (G) Conditioned media (CM) or hrANGPTL4 (5μg/ml) was used to induce tubule formation of HMVECs in matrigel. hrVEGF (50 ng/ml) served as control. (H) HMEC1s were transfected with Scrambled (Scrambled si), ANGPTL4 (ANGPTL4 si) or no siRNA and then with pCEFL Tet REV TA and pBIG AU5 vGPCR. Cells were left untreated (Control) or treated with (1 μg/ml) Dox for 24h (vGPCR). Conditioned media from these cells (CM) or hrANGPTL4 (5μg/ml) was used to measure FITC–dextran permeability in mature HMVEC monolayers. Treatment (30 min) with VEGF (50 ng/ml) was used as a control. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

Upregulation of angiopoietin-like 4 by viral G protein-coupled receptor promotes angiogenesis and vascular permeability in Kaposi’s sarcoma

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Springer Journals
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Copyright © 2010 by Montaner et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
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10.1186/1750-9378-5-S1-A84
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Abstract

Ma et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A84 http://www.infectagentscancer.com/content/5/S1/A84 MEETING ABSTRACTS Open Access Upregulation of angiopoietin-like 4 by viral G protein-coupled receptor promotes angiogenesis and vascular permeability in Kaposi’s sarcoma 1 1 1 1 1,2 3 1,2* Tao Ma , Bruno C Jham , Jiadi Hu , Eitan R Friedman , John R Basile , Akrit Sodhi , Silvia Montaner th From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010 Acknowledgements Background This work was supported by grant R01CA119911 (National Cancer Institute, Kaposi’s sarcoma (KS) is an enigmatic vascular tumor NIH). We thank Histoserv, Inc., for its assistance in the processing of the thought to be a consequence of dysregulated expression murine tissues. BCJ is a recipient of a predoctoral fellowship from the CNPq- Brazil. of the human herpesvirus-8 (HHV-8 or KSHV)-encoded This article has been published as part of Infectious Agents and Cancer G protein-coupled receptor (vGPCR) [1]. Both human th Volume 5 Supplement 1, 2010: Proceedings of the 12 International and vGPCR experimental KS lesions are characterized Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI). The full contents of the supplement are by prominent angiogenesis and vascular permeability available online at http://www.biomedcentral.com/1750-9378/5?issue=S1. attributed to the paracrine release of angiogenic media- tors, most notably vascular endothelial growth factor Author details Department of Oncology and Diagnostic Sciences, University of Maryland, (VEGF). To date, the relative contribution of these para- Baltimore, MD, USA. Greenebaum Cancer Center, University of Maryland, crine mediators to the angiogenic and exudative pheno- 3 Baltimore, MD, USA. Wilmer Eye Institute, Johns Hopkins School of type of KS lesions remains unclear. Here we show that Medicine, Johns Hopkins University, Baltimore, MD, USA. vGPCR upregulated angiopoietin-like 4 (ANGPTL4) Published: 11 October 2010 (Figure 1A, 1B, 1C) plays a prominent role in promoting the angiogenesis and increasing vascular permeability in References this tumor. Inhibition of ANGPTL4 effectively blocks 1. Moore PS, Chang Y: Kaposi’s sarcoma-associated herpesvirus-encoded oncogenes and oncogenesis. J Natl Cancer Inst Monogr 1998, 23:65-71. vGPCR promotion of angiogenesis and vascular perme- 2. Ganem D: Human herpesvirus 8 and its role in the genesis of Kaposi’s ability in vitro and tumorigenesis in vivo (Figure 1D , sarcoma. Curr Clin Top Infect Dis 1998, 18:237-251. 1E, 1F, 1G , 1H). 3. Montaner S, et al: The Kaposi’s sarcoma-associated herpesvirus G proteincoupled receptor as a therapeutic target for the treatment of Kaposi’s sarcoma. Cancer Res 2006, 66(1):168-174. Conclusion doi:10.1186/1750-9378-5-S1-A84 These observations suggest that ANGPTL4 is a pre- Cite this article as: Ma et al.: Upregulation of angiopoietin-like 4 by viral viously unrecognized target for the treatment of patients G protein-coupled receptor promotes angiogenesis and vascular with KS. As angiogenesis and increased vessel perme- permeability in Kaposi’s sarcoma. Infectious Agents and Cancer 2010 5(Suppl 1):A84. ability are common themes in all solid tumors, these results may have a broad impact on our understanding and treatment of cancer. *Correspondence: smontaner@umaryland.edu Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, MD, USA Full list of author information is available at the end of the article © 2010 Montaner et al; licensee BioMed Central Ltd. Ma et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A84 Page 2 of 2 http://www.infectagentscancer.com/content/5/S1/A84 Figure 1 (A) Analysis of ANGPTL4 mRNA levels (qRT-PCR), cellular ANGPTL4 (WB) and secreted ANGPTL4 (ELISA) of HMEC1 or HMVEC transfected with pCEFL Tet REV TA and pBIG AU5 vGPCR. (B) ANGPTL4 expression in murine vGPCR tumors and human AIDS-KS. An isotype-matched control antibody (Control) or an ANGPTL4 antibody (ANGPTL4) was used. Similar results were found in all murine vGPCR [2] and all human lesions tested [2]. (C) (Control) vGPCR and vGPCR/TK allografts were generated [3]. Treatment of vGPCR/TK tumors with ganciclovir (50 mg/kg) lead to complete loss of all (AU5) vGPCR-expressing cells. Sections were stained with an ANGPTL4 antibody, showing progressive decreased expression. Magnification x 20 (C and D). (D) HMEC1s were transfected with Scrambled (Scrambled si), ANGPTL4 (ANGPTL4 si) or no siRNA and then with pCEFL Tet REV TA and pBIG AU5 vGPCR. Cells were left untreated (Control) or treated with (1 μg/ml) Dox for 24h (vGPCR). Levels of ANGPTL4 in cellular extracts and conditioned media are shown. Overexpression of ANGPTL4 served as control (E) Conditioned media (CM) or hrANGPTL4 (5μg/ml) was used to induce blood vessel development within basement membrane extract (BME)-filled angioreactors (shown in figure) implanted in nude mice (DIVAA assay). Recombinant FGF2, FGF2/VEGF served as controls. (F) Conditioned media (CM) or hrANGPTL4 (5μg/ml) was used to induce migration of HMEC1s, using Boyden-chamber assay. 2.5% serum (FBS) was used as a control. (G) Conditioned media (CM) or hrANGPTL4 (5μg/ml) was used to induce tubule formation of HMVECs in matrigel. hrVEGF (50 ng/ml) served as control. (H) HMEC1s were transfected with Scrambled (Scrambled si), ANGPTL4 (ANGPTL4 si) or no siRNA and then with pCEFL Tet REV TA and pBIG AU5 vGPCR. Cells were left untreated (Control) or treated with (1 μg/ml) Dox for 24h (vGPCR). Conditioned media from these cells (CM) or hrANGPTL4 (5μg/ml) was used to measure FITC–dextran permeability in mature HMVEC monolayers. Treatment (30 min) with VEGF (50 ng/ml) was used as a control.

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Infectious Agents and Cancer – Springer Journals

Published: Oct 11, 2010

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