Collagen type I expression in experimental anaplastic thyroid carcinoma: Regulation and relevance for tumorigenicity

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Abstract
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‐α1(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‐α1(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‐β 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‐β.
Funding Information
  • Swedish Cancer Foundation
  • Swedish Medical Research Council (11207)
  • GustafV:s 80-årsfond
  • Åke Wiberg Foundation
  • Göran Gustavsson Foundation