On the Cells of Origin of Radiogenic Thyroid Cancer: New Studies Based on an Old Idea<xref ref-type="fn" rid="fn1">*</xref><xref ref-type="fn" rid="fn2">+</xref>

Abstract

We have presented evidence that the functional thyroid follicles (follicular units, FU) which are formed in grafts of monodispersed rat thyroid cells, and hence the thyroid tumors which later develop in such grafts, are clonal in origin. Transplantation assays indicate that the clonogens comprise "1% of the cells in monodispersed suspensions of normal thyroid tissue. Carcinogenesis studies show that neoplastic initiation of thyroid c]onogens by radiation is a common event. Promotion-progression to cancer from radiation initiated clonogens has, however, been shown to be inversely related to the total grafted thyroid cell number, i.e. more tumors develop per irradiated clonogen in grafts of small cell numbers than of large cell numbers. Recent studies have been designed to investigate: a) whether the cell number-dependent inln'bition of promotion-progression is mediated by remote hormonal feed-back, local ceU-ceU interactions, or both; b) the cell population kinetics of the clonoge, l subpopulation during goitrogenesis and goiter involution; and c) the effect of prolonged exposure to high levels of TSH (thyrotropin) on the capacity of the clonogens to give rise to functional FU. The results indicate that local ceU-celi interactions play an important role in the cell number-dependent suppression of neoplastic promotionprogression. They also show that if sufficient thyroid cells are grafted, the thyroid-pituitary axis can be reestablished in thyroidectomized rats fed normal diets. In such animals given iodine deficient diets, the FU that develop in the thyroid grafts shift theft secretory pattern to increase the ratio of T3 (triiodothyronine) to T4 (thyroxine), and thus conserve the t | available iodine.Finally, the clonogenic subpopulation is conserved during both goitrogenesis and goiter involution. When they are transplanted to thyroidectomized recipients, clonogens fxom two types of goiters form FU that are morphologically indistinguishable from those that develop in grafts of normal thyroid clonogens.Furthermore, the secretion of T3 and T4 by such grafts is dependent on the grafted clonogen number, and hence FU formation, and not on the total number of thyroid cells transplanted. We conclude that the thyroid clonogens, the presumptive cancer progenitor cells, have many of the characteristics of stem cells.