Antiangiogenic activity of endostatin inhibits c6 glioma growth

Abstract

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...

Antitumor effect of endostatin overexpressed in C6 glioma cells is associated with the down-regulation of VEGF

“…Therefore, our genetic modification of rat glioblastoma C6 cells that stably released endostatin provided local delivery, eliminated variations in biological distribution, allowing us to directly evaluate in vivo biological efficacy of endostatin. In this study, our data are in line with other experimental studies in which endostatin suppress tumor growth (19,20,(22)(23)(24).…”

Effects of the C-terminal of endostatin on the tumorigenic potential of H22 cells

“…In a previous study by Peroulis et al (28), C6 glioma cells transfected with endostatin by the cationic liposome-mediated method were subcutaneously inoculated into rats. The expression of endostatin detected by RT-PCR and western blot analysis was low and the tumor inhibitory effect was not significant.…”

Effects of endostatin production on oncogenicity and metastatic activity of HPV16-transformed mouse cells: Role of interleukin 1α

“…Where GTS are used, there is no danger of denaturation, such as is involved in the preparation of recombinant ES, and, since successfully transfected cells maintain ES production over long periods of time, there should not be a need for frequent administration of the drug. Gene-modified tumor cells constitutively expressing ES have been studied, but rarely (15,16). The oncogenicity of such cells has been reduced and progression of micrometastases to macroscopic disease has been prevented; however, to the best of our knowledge, their biology has not yet been investigated in much detail.…”