Clifton K H, Domann F E, Groch K M
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
J Radiat Res. 1991 Dec;32 Suppl 2:143-55. doi: 10.1269/jrr.32.supplement2_143.
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 approximately 1% of the cells in monodispersed suspensions of normal thyroid tissue. Carcinogenesis studies show that neoplastic initiation of thyroid clonogens 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 inhibition of promotion-progression is mediated by remote hormonal feed-back, local cell-cell interactions, or both; b) the cell population kinetics of the clonogen 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 cell-cell interactions play an important role in the cell number-dependent suppression of neoplastic promotion-progression. 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 their secretory pattern to increase the ratio of T3 (triiodothyronine) to T4 (thyroxine), and thus conserve the available iodine. Finally, the clonogenic subpopulation is conserved during both goitrogenesis and goiter involution. When they are transplanted to thyroidectomized recipients, clonogens from 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.
我们已提供证据表明，在单分散大鼠甲状腺细胞移植中形成的功能性甲状腺滤泡（滤泡单位，FU），以及随后在此类移植中发生的甲状腺肿瘤，起源于克隆。移植试验表明，克隆原细胞约占正常甲状腺组织单分散悬浮液中细胞的1%。致癌研究表明，辐射引发甲状腺克隆原细胞的肿瘤起始是常见事件。然而，已证明从辐射引发的克隆原细胞促进进展为癌症与移植的甲状腺细胞总数呈负相关；即，在小细胞数移植中，每个受辐射的克隆原细胞比大细胞数移植中产生更多肿瘤。最近的研究旨在调查：a）细胞数量依赖性的促进进展抑制是由远程激素反馈、局部细胞间相互作用还是两者介导；b）甲状腺肿形成和甲状腺肿消退过程中克隆原细胞亚群的细胞群体动力学；c）长期暴露于高水平促甲状腺激素（TSH）对克隆原细胞产生功能性FU能力的影响。结果表明，局部细胞间相互作用在细胞数量依赖性的肿瘤促进进展抑制中起重要作用。研究还表明，如果移植足够数量的甲状腺细胞，在喂食正常饮食的甲状腺切除大鼠中可以重建甲状腺 - 垂体轴。在给予缺碘饮食的此类动物中，甲状腺移植中形成的FU会改变其分泌模式，以增加三碘甲状腺原氨酸（T3）与甲状腺素（T4）的比例，从而保存可用的碘。最后，克隆原细胞亚群在甲状腺肿形成和甲状腺肿消退过程中均得以保留。当将它们移植到甲状腺切除的受体中时，两种类型甲状腺肿的克隆原细胞形成的FU在形态上与正常甲状腺克隆原细胞移植中形成的FU无法区分。此外，此类移植分泌T3和T4取决于移植的克隆原细胞数量，进而取决于FU形成，而非移植的甲状腺细胞总数。我们得出结论，甲状腺克隆原细胞，即假定的癌症祖细胞，具有许多干细胞的特征。
