Interactions between the stroma and thyroid epithelial cells of normal and malignant origin

Sammanfattning: Endocrine and locally produced factors as well as interactions between epithelial cells and the stroma important in the control of growth and function of the thyroid gland. In this study, the effects of, and mechanism(s) for, such cross-talk under some normal and pathological conditions were investigated.In three-dimensional collagen gels, neoformation of thyroid follicles occured as a result of the combined actions of EGF and TGF-β1 on cell-cell and cell-matrix adhesion. This process was independent of cell proliferation. These data demonstrate that cell proliferation and cell migration can be mediated by separate signaling pathways, and that, in the presensce of collagen type I, neoformation of follicles can occur as a result of increased cell migration. The expression of adhesion receptors in benign and malignant human thyroid tissue was studied by immunohistochemistry. Neoexpression of the integrins α2β1 and α6β4, together with a loss of E-cadherin expression was detected in human anaplastic thyroid carcinomas, which indicates an importance of these receptors in tumor growth and invasion. Collagen type I is a major component of the stroma in tumors. The cellular source of the newly formed collagen type I was investigated in anaplastic thyroid carcinoma both in vitro and in vivo. Our data suggest that fibroblasts are the major producers of collagen type I in anaplastic thyroid carcinoma. Tumor cells may add to the formation of this stroma by regulating the translation of pro-α1(I)collagen mRNA in stromal fibroblast. This stimulation seems to be dependent on direct cell-cell contact. In one out of five anaplastic thyroid tumors, expression of pro-α1(I) collagen mRNA by tumor cells was detected; a findings that raises the possibility of a dual role for tumor cells in anaplastic thyroid carcinoma. This is further strengthened by the finding that several well characterized cell lines, derived from human anaplastic thyroidcarcinomas, expressed pro-α1(I) collagen mRNA and prolyl-4-hydroxylase mRNA. Three of these cell lines also synthesized native triple helical collagen type I albeit to a low level compared to fibroblasts. Only 15-20 % of tumor cells in culture participated in the production of collagen type I. Six anaplastic thyroid carcinoma cell lines were injected subcutaneously into C57 b1/6 athymic nude mice. In general, collagen type I producing tumor cells were found to be less tumorigenic than non-prodicing cells. Histopathological studies of mouse tumor tissue revealed two distinct patterns of collagen fiber distribution in the respective groups. In tumors derived from collagen type I producing tumor cells, collagen fibers and tumor cells were dispersed. Non-producing tumor cells generatedtumors with a more organized histology, where collagen fibers, harboring blood vessels, were distributed in between groups of tumor cells. In conclusion, our data are compatible with the notion that changes in cell-cell and cellmatrix interactions mediated by adhesion receptors and modulated by growth factors, are of importance in thyroid follicle neoformation and tumor invasion probably involving the deposition of a stromal component, collagen type I, as could be demonstrated in anaplastic thyroid carcinoma.

  Denna avhandling är EVENTUELLT nedladdningsbar som PDF. Kolla denna länk för att se om den går att ladda ner.