H. K. Cushing Laboratory of Experimental Medicine and the Department of Surgery of Western Reserve University, Cleveland.
J Exp Med. 1916 Oct 1;24(4):345-59. doi: 10.1084/jem.24.4.345.
It seems evident from the foregoing experiments that the so called tumors (adenomata) of the thyroid possess the property of taking up iodine and metabolizing it into the active combination in the same way that the non-tumorous thyroid tissue does, although not so readily nor to the same degree, and the action on tadpoles of feeding desiccated tumorous thyroid tissue does not differ qualitatively from feeding desiccated non-tumorous thyroid tissue. The action in either case depends upon the iodine (active iodine) content, and in the case of the adenomata bears no constant relation to the state of their growth or differentiation. Examination of Tables II and III shows that in the main this is true. There are, however, certain discrepancies as to time of death, appearance of first forelegs, degree of emaciation, and rate of growth in certain dishes of the series, the action being not quite parallel to the iodine content. Some of these discrepancies may be explained in part by accidents of feeding, slight differences in size, age) and susceptibility of the different tadpoles receiving the same thyroid, and also by the variations in the amount of thyroid consumed by the different individuals in the same dish. Lenhart has shown that the action of the same thyroid varies with the quantity fed. Another important factor which has to be considered is the condition of the iodine itself. It was suspected at the time of these experiments that the iodine might be present in an active and an inactive form, but no satisfactory proof of this assumption, at the beginning of these experiments, was at hand. Support of this point has been afforded by the work of Kendall on the isolation of the active principle of thyroid and the separation of the iodine into two fractions. Since the completion of our experiments Marine has demonstrated by means of perfusion experiments in vivo and in vitro that iodine is rapidly taken up by the thyroid cells, and though the iodine increase in the perfused lobe may be 1,000 per cent in 2 hours as compared with the control lobe, yet the action on tadpoles is no greater. It then becomes an important question to determine the time required by the thyroid to take up inorganic iodine and manufacture it into the active thyroid principle. It is known that iodine is rapidly taken up by the thyroid, and in man the iodine content of the thyroid is subject to greater variations than in animals on account of the prevalent therapeutic use of iodine and the iodides in goiter and other conditions; even the iodine used in preparing patients for operations would increase the iodine content of the thyroid in a short time, so that one might expect such variations in the action of a given thyroid preparation fed to tadpoles as appear in these experiments. In this connection it is interesting to note (Table II) that Thyroid 20 with 4.31 mg. of iodine was only slightly more active than No. 5 with 1.31 mg. of iodine. Two possibilities have to be considered here. First, No. 20 may have active iodine slightly greater than 1.31 mg. and the balance present as inactive iodine. Second, No. 5 with 1.31 mg. of iodine might represent the maximum possible effect under the conditions of the experiment and a larger quantity of active thyroid iodine could produce no greater effect. Of course with the lower iodine contents the variations in effects might well come within the limits of errors of observation. Also the percentage error would be greater in the iodine determinations, accidents of feeding, etc. Our conclusions as to the effect of feeding desiccated thyroid to tadpoles agree in general with those of Lenhart. The action of the thyroid depends not upon a specific stimulus to differentiation but upon a stimulation of metabolism in general in proportion to the active iodine and the quantity consumed. High iodine contents produce rapid emaciation, at the same time resulting in differentiation even in tadpoles dying in 8 to 12 days. Low iodine contents result in differentiation at an earlier period than the controls. Tadpoles fed on thyroid with practically no iodine grow better than the controls, in this instance the thyroid acting simply as a food. Finally, the interest that the results of these experiments may have in connection with the question of function in tumor tissue should be pointed out. To those who hold that tumor lacks the capacity for physiological function, the adenomata of the thyroid could not be consistently regarded as tumors. To those who hold physiological function as a possible property of tumor tissue, the adenomata might be regarded as tumors. Future studies might warrant a recognition of different grades or degrees of tumor. On this basis the fetal adenoma (very little differentiation) might represent a higher degree of tumor than the diffuse colloid or simple adenomatous thyroid in which the adenomatous nodules are present to a great extent throughout the whole gland and are well differentiated. It is certain that there are all grades and degrees of growth and differentiation in the life history of fetal adenomata of the thyroid, from the pure fetal, undifferentiated adenoma with little or no iodine to the simple or colloid adenoma, well differentiated and with varying amounts of iodine approaching that of normal thyroid.
从前面的实验中可以明显看出，所谓的甲状腺肿瘤（腺瘤）具有摄取碘并将其代谢为活性结合物的特性，就像非肿瘤性甲状腺组织一样，尽管摄取的速度不如后者快，摄取的程度也不如后者高，而且喂食干燥的肿瘤性甲状腺组织对蝌蚪的作用在质上与喂食干燥的非肿瘤性甲状腺组织没有区别。这种作用取决于碘（活性碘）的含量，在这种情况下，与腺瘤的生长或分化状态没有固定的关系。表二和表三的检查表明，在主要方面情况确实如此。然而，在某些情况下，如死亡时间、第一前肢出现时间、消瘦程度和某些盘中的生长速度，其作用与碘含量不完全平行。这些差异中的一些可能部分归因于喂食、大小、年龄、不同蝌蚪对同一甲状腺的敏感性以及同一盘中不同个体消耗的甲状腺量的差异等偶然因素。伦哈特已经表明，同一甲状腺的作用因所喂食的量而有所不同。另一个需要考虑的重要因素是碘本身的状况。在进行这些实验时，人们怀疑碘可能以活性和非活性两种形式存在，但在实验开始时，没有令人满意的证据支持这一假设。肯德尔关于甲状腺活性成分的分离和碘分为两部分的工作为这一点提供了支持。自我们的实验完成以来，马林通过体内和体外灌注实验证明，碘被甲状腺细胞迅速摄取，尽管在灌注叶中碘的增加可能在 2 小时内比对照叶增加 1000%，但对蝌蚪的作用并没有更大。因此，一个重要的问题是确定甲状腺摄取无机碘并将其制造为活性甲状腺素所需的时间。众所周知，碘被甲状腺迅速摄取，而在人类中，由于甲状腺素在治疗甲状腺肿和其他疾病中的普遍应用，以及碘和碘化物的使用，甲状腺中的碘含量变化更大；即使是用于为手术患者做准备的碘也会在短时间内增加甲状腺中的碘含量，因此人们可能会期望在这些实验中给蝌蚪喂食的特定甲状腺制剂的作用会出现这些实验中出现的变化。在这方面，值得注意的是（表二），含 4.31 毫克碘的甲状腺 20 号制剂的活性仅略高于含 1.31 毫克碘的 5 号制剂。这里有两种可能性需要考虑。第一，20 号制剂可能含有略高于 1.31 毫克的活性碘，其余部分则为非活性碘。第二，5 号制剂含 1.31 毫克碘可能代表在实验条件下可能达到的最大效果，而更多的活性甲状腺碘不会产生更大的效果。当然，对于较低的碘含量，效果的变化很可能在观察误差的范围内。此外，碘含量的测定、喂食等方面的误差也会更大。我们对喂食干燥甲状腺给蝌蚪的影响的结论与伦哈特的结论基本一致。甲状腺的作用不是取决于对分化的特定刺激，而是取决于对新陈代谢的一般刺激，刺激程度与活性碘和消耗的量成正比。高碘含量会导致迅速消瘦，同时即使在 8 到 12 天内死亡的蝌蚪中也会导致分化。低碘含量会导致比对照更早的分化。几乎不含碘的甲状腺喂养的蝌蚪比对照生长得更好，在这种情况下，甲状腺只是作为一种食物。最后，应该指出这些实验结果在肿瘤组织功能问题上可能具有的意义。对于那些认为肿瘤缺乏生理功能的人来说，甲状腺腺瘤不能被一致地视为肿瘤。对于那些认为肿瘤可能具有生理功能的人来说，腺瘤可能被视为肿瘤。未来的研究可能需要认识到不同程度或等级的肿瘤。在此基础上，胎儿腺瘤（分化程度很低）可能比弥散性胶体或单纯腺瘤性甲状腺具有更高的肿瘤程度，后者的腺瘤结节在整个腺体中广泛存在，并且分化良好。可以肯定的是，在胎儿腺瘤的生命史中，存在着所有的生长和分化程度，从纯胎儿、未分化的腺瘤，只有很少或没有碘，到简单或胶体腺瘤，分化良好，碘含量不同，接近正常甲状腺。
