Collagen type I expression in experimental anaplastic thyroid carcinoma: regulation and relevance for tumorigenicity.
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-alpha 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-alpha 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-beta 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-beta.
Dahlman
Thèrése
T
Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala, Sweden.
Lammerts
Ellen
E
Bergström
Daniel
D
Franzén
Asa
A
Westermark
Kerstin
K
Heldin
Nils-Erik
NE
Rubin
Kristofer
K
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011347:Procollagen / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D024042:Collagen Type I; D006133:Growth Substances; D011347:Procollagen; D012334:RNA, Neoplasm