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

Saleh, Mary; Davis, Ian D.; Wilks, Andrew F.

doi:10.1002/(sici)1097-0215(19970807)72:4<664::aid-ijc19>3.0.co;2-b

Cited by 50 publications

(38 citation statements)

References 27 publications

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“…16,17 A specific anti-angiogenic action was demonstrated in C6 glioblastomas 18 and our results in 9L tumors confirm this observation. However, in the presence of dex, when immune responses are weakened while the anti-angiogenic action is maintained, the intracranial growth of the tumor increases, supporting the notion that the immune system is playing a major role in the therapeutic action of IL-4.…”

Section: Dexamethasone Inhibits Il-4 Action On Gliomas S Benedetti Et Alsupporting

confidence: 85%

Dexamethasone inhibits the anti-tumor effect of interleukin 4 on rat experimental gliomas

et al. 2003

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Retroviral-mediated gene transfer of the IL-4 gene into experimental gliomas can cause tumor rejection, supporting the clinical use of this form of gene therapy for glioblastomas (GBM). In a clinical setting, the administration of dexamethasone (dex) is a standard procedure for GBM patients. This led us to examine the effects of dex on IL-4 gene therapy. We injected intracranially Fischer 344 rats with phosphatebuffered saline, 9L gliosarcoma cells mixed with E86.L4SN 200 cells (retroviral producer cells, RPC, transducing IL-4 cDNA) and 9L cells mixed with PA317.STK.SBA cells (control RPC expressing the HSV-tk gene). The rats from each group were treated with 0, 50, 100 or 250 mg dex/ kg/day released by osmotic pumps implanted subcutaneously. While 80-100% of rats receiving 9L cells mixed with IL-4 RPC and not treated by dex survived for at least 2 months following tumor injection, only 50% and 17% of rats receiving 50 or 100 mg/kg/day of dex, respectively, reached this time point. These results indicate that dex significantly diminished the anti-tumor effect of IL-4. Thus, in a clinical setting, IL-4 gene transfer should be performed when low levels of dex are administered or in the absence of dex. Gene Therapy (2003) 10, 188-192. doi:10.1038/sj.gt.3301863 Keywords: IL-4; glioma; dexamethasone Glucocorticosteroids (GC) play an important role in the management of malignant brain tumors, either primary or secondary and perioperatively in brain surgery. 1 Dexamethasone (dex) is the GC given in the majority of neuro-oncologic patients, at an empirically chosen dosage of 4 mg qid. Dex has a dramatic effect on symptoms in patients with brain tumors by decreasing the blood-tumor barrier permeability and the regional cerebral blood volume. 2 Furthermore, dex may decrease brain-tumor-associated edema by counteracting the action of VEGF. 3 Steroid medications, including dex, also have immunosuppressive functions. Studies based on flow cytometry to quantify the extent of inflammatory cell infiltration in the immunogenic rat C6 glioma model showed that a 7-day course of dex (100 mg/kg/day) resulted in a greater than 50% inhibition of microglia and lymphocyte (but not macrophage) infiltration into tumors. 4 Dex may specifically inhibit the action of IL-4 by decreasing the expression of the IL-4 receptor alpha. 5 These findings should be considered when experimental immunotherapeutic strategies are evaluated for clinical application. We and others previously found that viral-mediated transfer of the interleukin-4 (IL-4) gene may significantly inhibit the growth of C6, 9L and GL261 experimental gliomas. [6][7][8][9][10][11] In these experiments IL-4 gene transfer was associated with tumor infiltration by inflammatory cells and particularly T-lymphocytes and macrophages. Thus, in view of future clinical trials based on IL-4 gene transfer in gliomas we have evaluated the effects of dex administration on IL-4 gene therapy of 9L malignant gliomas.In experiment A, we tested the effects of 250 mg/kg/ day of dex administered for ...

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Section: Dexamethasone Inhibits Il-4 Action On Gliomas S Benedetti Et Alsupporting

confidence: 85%

Dexamethasone inhibits the anti-tumor effect of interleukin 4 on rat experimental gliomas

et al. 2003

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“…Rat C6 glioma cells are used as an established model for malignant glioma and rapidly form highly vascularised cerebral tumors. 8,9,21 Our results show that endogenous endostatin is biologically active, has an antiproliferative effect on endothelial cells in vitro and can reduce the tumor growth rate in vivo, which is associated with an inhibition of angiogenesis.…”

mentioning

confidence: 67%

“…PECAM and factor VIII-related 840 antigens detect vascular endothelial cells in tumours as previously described. 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%

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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“…In vitro, IL-4 inhibited the migration of cultured bovine and human microvascular cells and suppressed the formation of tube-like structure by human umbilical vein endothelial cells (HUVEC) induced by vascular endothelial growth factor (VEGF) and bFGF (26). Moreover, Saleh et al observed that IL-4-induced inhibition of C6 rat glioma was accompanied by reduced levels of vascularization (27,28). Practically, multiple factors, including innate immune cells, T lymphocytes and angiostasis may contribute to tumor rejection mediated by exogenous IL-4.…”

Section: The Mechanism Of Exogenous Il-4-induced Tumor Rejectionmentioning

confidence: 99%