Berger C L, de Bustros A, Roos B A, Leong S S, Mendelsohn G, Gesell M S, Baylin S B
J Clin Endocrinol Metab. 1984 Aug;59(2):338-43. doi: 10.1210/jcem-59-2-338.
We used an unique model, human medullary thyroid carcinoma (MTC) in culture (the TT line), to study features of neuroendocrine-related biochemistry in relationship to growth, differentiation, and tumor progression. Tumor tissues from patients with virulent MTC contain a very heterogeneous distribution of cells staining for calcitonin (CT) and have a high ratio of intracellular L-dopa decarboxylase activity (DDC) to CT. We found, in a culture line of MTC derived from a patient with virulent disease, that the degree of the inverse relationship between DDC and CT and the heterogeneous cellular distribution of CT probably relate to the rate of cellular growth and the biochemical set of individual cell clones. During exponential growth of the parent TT cell line, intracellular DDC and CT varied. DDC increased by 70% and CT decreased by 40%. Single time-point measurements in 54 cell clones or highly enriched cell populations revealed a more dramatic variability for CT (15-fold) than for DDC (5-fold). During growth of the clones having the highest and lowest CT measurements, respectively, inverse dynamics between DDC and CT were again found. However, each clone maintained a distinct range of CT during the entire growth curve, with a 2- to 4-fold difference in CT between the two clones throughout. In the low producing CT clone, ratios between DDC and CT rose to greater than 1.0 during growth, a very high value found before this study only in MTC tissues from patients with virulent disease. Immunohistochemical staining for CT of parent cells and clones grown on embryonic chick skin revealed increased cellular heterogeneity for CT distribution during growth. The TT line provides a powerful tool to study neuroendocrine related biochemical events in relationship to growth, differentiation, and tumor progression in MTC. Our in vitro findings in the TT line well explain observations made previously in patients. We conclude that: (1) DDC, a neural property of MTC, is an early differentiation marker as compared to CT and that the differentiation status of MTC cells varies inversely with cell growth rate; and (2) in patients with MTC, the virulence of the tumor probably varies inversely with differentiation status. The inverse ratio of DDC to CT is probably determined in MTC by the proportion of rapidly growing cells and numbers of cell clones which have a poor ability for maturation.
我们使用了一种独特的模型，即培养中的人甲状腺髓样癌（MTC）（TT细胞系），来研究神经内分泌相关生物化学特征与生长、分化及肿瘤进展之间的关系。侵袭性MTC患者的肿瘤组织中，降钙素（CT）染色细胞分布非常不均一，且细胞内L-多巴脱羧酶活性（DDC）与CT的比值很高。我们发现，在源自一名侵袭性疾病患者的MTC培养细胞系中，DDC与CT之间的负相关程度以及CT的细胞异质性分布可能与细胞生长速率和单个细胞克隆的生化特性有关。在亲代TT细胞系指数生长期间，细胞内DDC和CT发生变化。DDC增加70%，CT减少40%。对54个细胞克隆或高度富集的细胞群体进行的单时间点测量显示，CT的变异性（15倍）比DDC（5倍）更为显著。在CT测量值最高和最低的克隆生长过程中，再次发现了DDC与CT之间的反向动态变化。然而，每个克隆在整个生长曲线中都保持着独特的CT范围，两个克隆之间的CT差异在整个过程中为2至4倍。在低CT产生克隆中，生长期间DDC与CT的比值升至大于1.0，这是本研究之前仅在侵袭性疾病患者的MTC组织中发现的非常高的值。对在胚胎鸡皮肤上生长的亲代细胞和克隆进行CT免疫组化染色显示，生长期间CT分布的细胞异质性增加。TT细胞系为研究MTC中与生长、分化及肿瘤进展相关的神经内分泌相关生化事件提供了一个强大的工具。我们在TT细胞系中的体外研究结果很好地解释了先前在患者中所做的观察。我们得出结论：（1）DDC作为MTC的一种神经特性，与CT相比是一种早期分化标志物，且MTC细胞的分化状态与细胞生长速率呈负相关；（2）在MTC患者中，肿瘤的侵袭性可能与分化状态呈负相关。MTC中DDC与CT的反比可能由快速生长细胞的比例和成熟能力较差的细胞克隆数量决定。
