Transforming growth factor-beta promotes epidermal growth factor-induced thyroid cell migration and follicle neoformation in collagen gel separable from cell proliferation.

The regulation of growth and migration of thyroid follicular cells by epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta 1) were studied in primary cultures of porcine thyroid follicles embedded in collagen gel. Cultures were exposed to growth factors and [3H]thymidine (1 microCi/ml) for 3 days and then examined by light microscopic autoradiography. EGF at 1 ng/ml increased the [3H]thymidine labeling index from approximately 1% (control value) to 60% and stimulated fivefold the number of cells invading the collagen matrix. Intermediate responses were seen after treatment with 0.1 ng/ml of EGF. EGF-stimulated [3H]thymidine incorporation was reduced by TGF-beta 1 at concentrations above 0.1 ng/ml. In contrast, TGF-beta 1, which alone only had a minor stimulatory effect on cell motility, markedly promoted the migratory response to EGF (1 ng/ml). Thus, 0.1 ng/ml TGF-beta 1 doubled the fraction of migrating cells without changing the level of [3H]thymidine incorporation. Moreover, cell migration was still fourfold over control values in cultures exposed to 1.0 ng/ml EGF and 1.0 ng/ml TGF-beta 1, despite a strongly inhibited [3H]thymidine labeling. The number of microfollicles located peripherally to the mother follicles was increased synergistically by EGF and TGF-beta 1. The epithelium of mother follicles became grossly discontinuous in regions of intense cell migration induced by EGF and TGF-beta 1 in combination. In conclusion, TGF-beta 1 modulates the response of porcine thyrocytes to EGF in collagen gel cultures by promoting cell migration along with inhibition of [3H]thymidine incorporation. This suggests that EGF stimulates cell motility independent of the mitogenic signal. The persistent loss of epithelial integrity during enhanced cell migration indicates that mechanisms of intercellular adhesiveness are down-regulated by TGF-beta 1 and EGF in cooperation.