The expression of antisense vascular endothelial growth factor (VEGF) sequences inhibits intracranial C6 glioma growth in vivo by suppressing tumour angiogenesis

Saleh, Mary; Vasilopoulos, K.; Stylli, S S; Kaye, Andrew H.; Wilks, Andrew F.

doi:10.1016/s0967-5868(96)90035-1

Cited by 9 publications

(7 citation statements)

References 19 publications

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“…The reduced vascularisation of the C6 Endo -E6 tumors was not sufficient to completely suppress tumor growth, nor lead to an increased tumor necrosis as would be expected in response to an inadequate blood supply. 9,10 We do not believe that the absence of complete tumor growth inhibition observed is due to reduced endostatin expression in the C6-transfected cell lines. We have attempted to use commercially available antibodies to mouse endostatin for immunohistochemical analysis on our frozen tumor sections.…”

Section: Discussionmentioning

confidence: 94%

“…21,24 Vascular density was calculated by counting the number of vessels in 10 random standard fields (0.55 ϫ 0.4 mm) in 5 sections/tumor. 25 Intracranial tumor volumes were calculated from haematoxylin-and eosin-stained brain sections as previously described 10,25 as length ϫ width ϫ depth (mm 3 ) Ϯ standard error.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…9,10 (ii) All of the E6 subcutaneous tumors in mice began growing from day 20 and had rapidly increased in volume by day 22 postimplantation. If endostatin expression was to stop in the tumor cells, we would not expect such a synchronized initiation of tumor growth but rather have some tumors grow whilst others remain dormant for longer periods of time (even an additional 2 days).…”

Section: Endostatin Inhibits C6 Tumor Angiogenesismentioning

confidence: 99%

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Antiangiogenic activity of endostatin inhibits c6 glioma growth

Peroulis

Jonas

Saleh

2001

Intl Journal of Cancer

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Angiogenesis is a vital component of the development and progression of many human solid tumors. Glioblastoma multiforme is one of the most highly vascularised class of solid tumors. Thus, we have investigated the potential antitumourigenic activity of endostatin, an angiogenic inhibitor, in the rat C6 glioma model. We have engineered C6 cells that endogenously express mouse endostatin in order to assess the growth of C6 tumors in vivo when endostatin is constitutively expressed. Endostatin secreted by stably transfected C6 cells is biologically active as shown by its inhibition (26%) of bFGF-stimulated proliferation of BAECs in culture. The subcutaneous implantation of endostatin-C6 cells in athymic (nu/nu) mice resulted in a reduced tumor growth rate (90% inhibition) compared to control cell lines throughout the duration of our experiments. Tumor inhibition was associated with a 50% reduction in the number of vessels, which were also smaller in morphology. However, endostatin-C6 tumors were no more necrotic than control tumors. The implantation of endostatin-C6 cells into immunocompetent Wistar rat brains also resulted in reduced tumor volumes (71% inhibition) compared to controls. Tumor cells were sparsely localised along the injection tract but had not formed discrete tumors. Despite the inhibitory response mediated by endostatin on C6 growth, complete tumor inhibition or dormancy was not observed in either the athymic or immunocompetent tumor models. These findings demonstrate that the endogenous expression of endostatin by C6 glioma cells results in a reduced tumor growth rate in vivo that is associated with an inhibition of tumor angiogenesis. Our data suggest that endostatin should be developed as an adjuvant gene therapy for the effective treatment of gliomas. © 2002 Wiley-Liss, Inc. Key words: endostatin; glioma; angiogenesis; inhibitionAngiogenesis is the sprouting of capillaries from preexisting blood vessels by the proliferation, differentiation and migration of endothelial cells. 1 This physiologic process is tightly regulated and involves a delicate balance between proangiogenic and antiangiogenic factors. 2 Angiogenesis is a fundamental aspect of many physiologic processes such as embryogenesis, wound healing and corpus luteum formation. 3 An imbalance of the angiogenic process contributes to the development of a number of disorders such as diabetic retinopathy 4 and chronic arthritis. 5 It is now well established that the requirement of angiogenesis is a vital component in the development, progression and metastasis of many human solid tumors. 6 -10 The growth and progression of solid tumors beyond 2 mm 3 is dependent on the recruitment of angiogenic vessels and an expansion of the tumor vasculature. 3,11 Investigations have focused on defining the different stimulators and inhibitors of angiogenesis that are required for tumor growth and metastases. By understanding the roles and interactions of these factors and their regulation, effective antiangiogenic therapies may be developed. Studies h...

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Section: Discussionmentioning

confidence: 94%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Endostatin Inhibits C6 Tumor Angiogenesismentioning

confidence: 99%

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Antiangiogenic activity of endostatin inhibits c6 glioma growth

Peroulis

Jonas

Saleh

2001

Intl Journal of Cancer

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“…Serial frozen sections (7 m) of subcutaneous tumor or whole brain were stained in the following ways: (1) hematoxylin and eosin for tumor cell volumes and infiltrating granulocytes; (2) indirect immunoperoxidase with the rat anti-mouse PECAM monoclonal antibody (MAB) (PharMingen, San Diego, CA, USA) or mouse anti-rat PECAM MAB (Endogen, Woburn, MA, USA) for vascular endothelial cells in mouse 7,37,42 or rat 43,44 tissue respectively; (3) indirect immunoperoxidase with the mouse anti-rat RT1.B class II MAB (HIS 19; Serotec, Oxford, UK), the mouse anti-rat RT1.A MHC class I MAB (Ox-18; Serotec), the rat anti-mouse IFN-␥ MAB (XMG1-2), the mouse anti-rat CD3 + /TcR MAB (453(MCA)), the mouse anti-rat CD4 + MAB (W3/25), the mouse anti-rat CD8 + MAB (Ox8) or the mouse anti-rat macrophage MAB (ED1) (gifts from P Motram, The University of Melbourne); (4) ␤-galactosidase staining for visualization of RPC and transduced cells. 24 Vascular density was calculated by counting the number of vessels in 10 random standard fields (0.55 × 0.4 mm) in five sections per tumor.…”

Section: Histological Analysis Of Tissuementioning

confidence: 99%

The treatment of established intracranial tumors by in situ retroviral IFN-γ transfer

et al. 2000

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Current treatments for malignant gliomas are still largely ineffective in significantly improving prognosis. We have investigated the efficacy of treating established rat C6 glioma by in situ retroviral delivery of IFN-␥ cDNA. Ecotropic retrovirus packaging cells were transfected with a retroviral vector containing the mouse IFN-␥ gene. The IFN-␥ packaging cells were stereotactically implanted into established intracranial C6 glioma in immunocompetent Wistar rats, resulting in the eradication of these tumors. All IFN-␥-treated rats survived to 92 days after C6 implantation (an arbitrary

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“…Serial frozen sections of 7 µm were cut through the entire tumours. Alternate sections were stained either with haematoxylin and eosin or by indirect immunoperoxidase with the rat anti-mouse PECAM monoclonal antibody (PharMingen, San Diego, CA) as previously described (Saleh et al, 1996b), which detects vascular endothelial cells in the tumours. The sections were counterstained with Harris' haematoxylin.…”

Section: Immunohistochemistrymentioning

confidence: 99%

The paracrine role of tumour-derived mIL-4 on tumour-associated endothelium

1997

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Interleukin-4 (IL-4) has been demonstrated to possess anti-tumourigenic properties in vivo which is initially attributed to the infiltration of eosinophils proposed to occur by IL-4 binding to its receptors on endothelial cells, thereby mediating eosinophil adhesion. We have investigated whether the binding of IL-4 to receptors on endothelial cells could elicit other biological responses which may also play a role in tumour inhibition, such as angiogenesis. We have demonstrated that mouse IL-4 (mIL-4) down-regulates the expression of one of the receptors for VEGF, VEGF-R2, on endothe-lial cells in vitro. By generating stable transfectants of C6 glioma cells that express mIL-4 under a tetracycline-responsive promoter system, we were able to apply tight regulatory control of mIL-4 expression in vivo. Subcutaneous implantation of mIL-4/C6 cell lines in nu/nu mice revealed that tumour growth is inhibited by mIL-4 expression. mIL-4-expressing tumours were demonstrated to have a reduced level of vascularisation compared with controls, in addition to a high degree of eosinophil infiltration. Our results suggest that mIL-4 has bimodal biological roles in potentiating tumour inhibition in athymic mice: the suppression of angiogen-esis and the augmentation of the host local immune response.

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The expression of antisense vascular endothelial growth factor (VEGF) sequences inhibits intracranial C6 glioma growth in vivo by suppressing tumour angiogenesis

Cited by 9 publications

References 19 publications

Antiangiogenic activity of endostatin inhibits c6 glioma growth

Antiangiogenic activity of endostatin inhibits c6 glioma growth

The treatment of established intracranial tumors by in situ retroviral IFN-γ transfer

The paracrine role of tumour-derived mIL-4 on tumour-associated endothelium

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