This study investigates the expression of thrombospondin-1 in papillary carcinoma of the thyroid and the role of Met-HGF interaction in TSP-1 regulation. In tissue sections, immunostaining for TSP-1 was associated with the fibrous tumour stroma, and showed areas of marked intensity adjacent to the basal membrane of tumour cells. Investigation of TSP-1 RNA expression showed that, in 10 of 14 cases, TSP-1 mRNA levels were significantly lower in tumour tissue (20-100% reduction; mean = 55% +/- 20; p = 0.001) than in the corresponding normal thyroid. Since it has been reported that HGF can downregulate the expression of TSP-1 mRNA, TSP-1 mRNA levels were measured in 7 primary cultures, established from thyroid papillary carcinomas (TPC), and in 1 TPC cell line prior to, or after, stimulation with HGF. A marked decrease in TSP-1 mRNA levels was observed after HGF stimulation in 6/7 primary cultures (60-100% decrease (mean = 79 +/- 15%; p = 0.006) and in the TPC cell line; moreover, the decrease in TSP-1 mRNA in cell extracts was associated with a decrease in TSP-1 protein in culture supernatants. The HGF activity was dose dependent and the downregulation lasted for at least 48 h after stimulation. The high-level expression of Met protein, the high-affinity receptor for HGF, in most cases of papillary carcinoma of the thyroid is consistent with the possibility that HGF-Met interaction plays a crucial role in regulating the expression of TSP-1 in this tumour type.