Clearance of normal and tumor-related thyroglobulin from the circulation of rats: Role of the terminal sialic acid residues

Abstract

The transplantable rat thyroid tumor 1-1C2 has been used to study circulating thyroglobulin (TG) related to thyroid cancer. Since tumor 1-1C2 is defective in its ability to incorporate sialic acid into TG, the role of the terminal carbohydrate residues in the clearance of rat TG from the circulation was also studied. Sialic acid was removed from normal TG by treatment with V. cholerae neuraminidase (asialo-TG) and the newly exposed galactose residues were oxidized with galactose oxidase (galox-TG). Native TG, the modified TGs, and tumor TG gave parallel radioimmunoassay displacement curves. These preparations were injected into rats that had been thyroidectomized by surgery and 131I − and subsequently maintained on T 3. The clearance rates were determined by measuring sequential plasma concentrations by radioimmunoassay. The circulating TG in tumor-bearing rats had sedimentation properties characteristic of poorly iodinated TG. At low temperature the sedimentation rate decreased and there was partial dissociation into subunits. The half-life of native TG was 4.4 hr whereas asialo-TG disappeared from the rat circulation 18-fold faster, with a half-life of 15 min. The half-life of TG isolated from the 1-1C2 tumor, 12 min, was also much more rapid than native TG half-life. Compared with asialo-TG and tumor TG, the half-life of galox-TG, 1.5 hr, returned towards normal. Asialofetuin competed with asialo-TG for degradation and prolonged the circulating lifetime of the latter. These results suggest that TG is cleared from the circulation by the same pathway used for fetuin and therefore by the common degradative pathway for glycoproteins. Sialic acid residues protect circulating TG by shielding its galactose residues, which are recognized by the degradative system. The TG of the 1-1C2 tumor behaves like poorly iodinated, sialic-acid-poor TG. The 1-1C2 transplantable tumor should be a useful model for the study of circulating TG related to thyroid cancer.