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Fibrosis in solid malignancies plays a significant role in tumor pathophysiology. Potential mechanisms for collagen type I deposition in anaplastic thyroid carcinoma (ATC) were investigated using 6 characterized ATC cell lines. Three of these cell lines, which produced collagen type I, had, as a group, a poor tumorigenicity when inoculated in athymic mice. This group of cells generated tumors in 4 of 24 injected animals (17%). Pro-␣1(I) collagen mRNA-expressing carcinoma and stromal cells were interdispersed in the tumors generated by these ATC cells. By contrast, the 3 noncollagen-producing ATC cell lines were all tumorigenic with a tumor take of 60% in the whole group. In the latter tumors, pro-␣1(I) collagen mRNA-expressing cells were confined to the stromal compartment, well delineated from carcinoma cell islets. To study the influence of ATC cells on collagen type I synthesis by fibroblasts, we used AG 1518 diploid human fibroblasts cultured on poly-(2-hydroxyethyl methacrylate) (poly[HEMA])-coated plates. This culture condition allows the study of the effect of collagen mRNA translation in the regulation of collagen type I synthesis. Conditioned media from the 6 ATC cell lines did not influence collagen synthesis. The ATC cell line KAT-4 stimulated fibroblast synthesis of collagen type I when the two cell types were cocultured on poly[HEMA]-coated substrates. Specific inhibitors of PDGF and TGF-␤ reduced the KAT 4 carcinoma cell-induced stimulation of collagen type I synthesis. Our data suggest that collagen type I production by carcinoma cells correlates negatively with tumorigenicity and that the formation of a well-defined stroma is of importance for tumor growth. Furthermore, our data suggest that tumor cells are able to stimulate collagen mRNA translation in stromal fibroblasts in direct cell-cell contact by, at least in part, transferring PDGF or TGF-␤.

The mechanisms involved in stromal reactions and fibrosis in solid malignant tumours are incompletely understood. In the present study, collagen type I production was investigated in tissues and cell lines derived from human undifferentiated (anaplastic) thyroid carcinomas, a highly aggressive, often fibrotic malignancy with mesenchymal phenotype. In situ hybridization showed the expression of pro-alpha1(I) collagen mRNA throughout the stromal part of the tumours. However, immunofluorescence staining using an anti-pro-collagen type I antibody revealed the synthesis of pro-collagen type I protein mainly in stromal cells juxtaposed to nests of tumour cells. In one out of five tissue samples from human undifferentiated thyroid carcinomas, pro-alpha1(I) collagen mRNA expression was also found in a small number of tumour cells. Several well-characterized cell lines established from undifferentiated thyroid carcinomas, two from tumours included in the present study, expressed both pro-alpha1(I) collagen and prolyl 4-hydroxylase mRNA, and three of these cell lines also synthesized native triple-helical collagen type I. Taken together, these data suggest that stromal fibroblasts are the main producers of collagen type I in anaplastic thyroid tumours. The carcinoma cells seem to play a regulatory role, stimulating the synthesis of collagen type I protein in the surrounding stroma by increasing pro-alpha1(I) collagen mRNA translation. However, collagen type I production by the carcinoma cells might also contribute to the marked desmoplasia commonly seen in these tumours.

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