Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma.
Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma.
复制标题
由降钙素/降钙素基因相关肽启动子驱动的 v-Ha-ras 表达：一种新型的甲状腺髓样癌转基因小鼠模型。
作者：
Johnston,D;Hatzis,D;Sunday,ME
v-Ha-ras以前已被证明诱导甲状腺髓样癌（MTC，恶性C细胞肿瘤）细胞系的神经内分泌分化。通过在神经/神经内分泌特异性降钙素/降钙素基因相关肽（CGRP）启动子的控制下表达v-Ha-ras，研究了ras介导的信号传导在体内神经内分泌细胞中的潜在作用。在生殖系插入转基因后，衍生出五个独立的小鼠谱系。五个谱系中的四个一致地表达转基因;在五个谱系中的三个中发现神经内分泌表达为剪接和全长信息。从表型上看，表达rascal的小鼠寿命缩短，主要是由于6个月至1岁之间的MTC发病率高。在没有肿瘤形成的大体证据的情况下，在几只小鼠中证实了C细胞增生。组织学和超微结构分析表明，典型的功能，包括突出的降钙素和致密核心神经分泌型颗粒免疫组化染色的MTC。此外，22个肿瘤中的4个在肿瘤细胞的子集中共表达甲状腺球蛋白（一种非神经内分泌滤泡上皮细胞标记物）和降钙素（一种神经内分泌标记物）。流氓转基因小鼠提供了一个独特的模型，调查的顺序发病机制的MTC，也可能阐明MTC和混合髓滤泡癌之间的关系。
v-Ha-ras has been demonstrated previously to induce neuroendocrine differentiation of medullary thyroid carcinoma (MTC, malignant C cell tumor) cell lines. The potential role of ras mediated signaling in neuroendocrine cells in vivo has been investigated by expressing v-Ha-ras under control of the neural/neuroendocrine specific calcitonin/calcitonin gene-related peptide (CGRP) promoter. Five independent mouse lineages were derived following germ line insertion of the transgene. Four of the five lineages consistently express the transgene; neuroendocrine expression is found in three of the five lineages as both spliced and full length messages. Phenotypically, the mice expressing rascal have shortened lifespans primarily due to the high incidence of MTCs between 6 months to a year of age. C-cell hyperplasia is demonstrated in several mice in the absence of gross evidence of tumor formation. Histopathological and ultrastructural analyses demonstrate typical features of MTCs including prominent immunohistochemical staining for calcitonin and dense-core neurosecretory-type granules. In addition, four of 22 tumors co-express thyroglobulin (a non-neuroendocrine follicular epithelial cell marker) and calcitonin (a neuroendocrine marker) in a subset of the tumor cells. The rascal transgenic mouse provides a unique model for investigating the sequential pathogenesis of MTC and possibly also for elucidating the relationship between MTC and mixed medullary-follicular carcinomas.