Neutralizing vascular endothelial growth factor activity inhibits thyroid cancer growth in vivo

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 Monoclonal Antibody Inhibits Growth of Anaplastic Thyroid Cancer Xenografts in Nude Mice

“…Previous studies using a nonspecific antibody of the same isotype as the VEGF-mAb used in our study had no effect (16). These observations confirm that the abrogation of tumor growth conferred by VEGF-mAb is specific to its anti-VEGF effect.…”

“…Animal weights were significantly greater in the VEGF-mAb-treated group and likely reflect reduced metabolic demand of the smaller tumors in the VEGF-mAb-treated mice. These observations echo the central importance of tumor angiogenesis proposed by Folkman (2) and expand the recent report by Soh et al (16) who used VEGF-mAb to inhibit the growth of moderately differentiated follicular thyroid cancer. To our knowledge this is the first report of the successful use of antiangiogenic therapy against ATC, a tumor resistant to most chemotherapeutic agents.…”

“…We do not have an explanation for this failure, but suspect there may be interference from the transgenic model itself. In the previous report by Soh et al (16), a dermal matrix model was used to assess the effect of VEGF-mAb on new vessel formation. Our model did not include a similar acellular dermal matrix and therefore precludes direct comparison between our studies.…”

Vascular Endothelial Growth Factor Expression in Invasive Papillary Thyroid Carcinoma

“…VEGF is a glycoprotein that exists as at least five isoforms of varying size. In addition to cancer, its expression may be greater in hypoxia, in the presence of high concentrations of nitric oxide, and in activation of the oncogenes RAS and BRAF (1,13,(19)(20)(21)(22)(23)(24)(25)(26).…”

Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro

“…The humanization of anti-VEGF Mab A.4.6.1 was completed in 1997, with the humanized version (rhuMabVEGF, bevacizumab, Avastinä) retaining similar ligand binding affinity to its mouse counterpart, and was capable of binding and neutralizing all human VEGF isoforms [22,24]. When tested in preclinical models, bevacizumab exhibited encouraging efficacy in the inhibition of human tumor cell line growth in nude mice [25][26][27][28]. Subsequently, a safety profile was established in Macaca fascicularis [29].…”