No abstract

Background Without angiogenesis, tumours cannot grow larger than a few millimetres in size, the limit of diffusion. Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen and is a major regulator of physiological and pathological angiogenesis. Higher levels of VEGF messenger RNA expression and VEGF production and secretion have been found in FTC-133 cells than normal thyroid cells. Methods To investigate the relationship between VEGF and thyroid tumour angiogenesis and growth, human dermal matrix inoculated with FTC-133 cells was xenografted into nude mice or directly injected subcutaneously. To block the function of VEGF, the neutralizing anti-VEGF monoclonal antibody A.4.6.1 (mAb A.4.6.1) was injected intraperitoneally 100 μg per 0·2 ml twice weekly. As control, an antibody of the same isotype (immunoglobulin G1), directed against the gP120 protein (Ab 5B6), or phosphate-buffered saline (PBS) was used. To evaluate the dermal matrix as a model for angiogenesis studies, rhVEGF was inoculated into the dermal matrix pocket and xenografted into mice. Results In vivo study using the dermal matrix showed that the number of blood vessel ingrowths paralleled the concentration of rhVEGF and was highest at the concentration of 100 ng ml−1. Mice treated with the mAb A.4.6.1 developed fewer blood vessels (mean 7 per high-power field (HPF)) than control mice (18 per HPF in Ab 5B6 and 22 per HPF in PBS) (P < 0·01). The size of tumours between mAb A.4.6.1- and Ab 5B6- or PBS-treated groups showed a significant difference from the second week after the inoculation of FTC-133 cells. The tumours from mice treated with mAb A.4.6.1 were smaller (mean(s.d.) 0·09(0·02) g at 5 weeks) than tumours from mice treated with Ab 5B6 (5·38(1·15) g) or PBS (4·00(0·72) g) (P < 0·001, two-tailed unpaired t test). Conclusion VEGF is produced by thyroid cancer cell line FTC-133 and stimulates angiogenesis and growth of thyroid cancer. More importantly, this stimulation can be blocked by mAb A.4.6.1.

Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, is important in the angiogenesis of glioblastoma. A major difference between pilocytic astrocytoma, a grade I tumor, and the grade II fibrillary astrocytoma is the vascular proliferation, highly vascularized stroma, and great propensity for cyst formation in the former. In order to explore factors regulating such angiogenesis and cyst formation in pilocytic astrocytoma, we examined expression of VEGF and its receptors (KDR and Flt-1) using in situ hybridization. In all 14 cases a high level of VEGF transcripts could be demonstrated. These were found in specific regions, namely, in the tumor cyst wall, in areas of hyaline cystic degeneration, in stellate reticulated astrocytes around microcysts in the biphasic compact and loose areas, and in tumor cells with degenerative pleomorphic multicoated nuclei. KDR and Flt-1 were expressed in the tumor vasculature, with particularly high levels seen in coiled young proliferating vessels, especially those in the cyst wall. Given the known angiogenic and vascular permeability activities of VEGF, we propose that VEGF plays an important role in molding the characteristic morphologic features of this tumor, namely, the formation of cysts, microcystic pattern, hyaline cystic degeneration, hyaline vessels, and vascular proliferation. Mechanisms that block the VEGF pathway could constitute a potential therapeutic strategy for the treatment of this tumor.