In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer
In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer
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DOI：
10.1097/01.cad.0000217424.36961.47
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发表时间：
2006-08-01
影响因子：
2.3
通讯作者：
Kunnimalaiyaan, Muthusamy
中科院分区：
文献类型：
--
作者：
Vaccaro, Abram;Chen, Herbert;Kunnimalaiyaan, Muthusamy
甲状腺髓样癌是一种来源于滤泡旁C细胞的神经内分泌肿瘤，除手术切除外，尚无有效的治疗方法。我们以前已经表明，激活的TT-raf细胞中的raf-1雌二醇抑制肿瘤细胞的生长和降钙素的分泌在体外。TT-raf细胞是含有雌激素诱导型raf-1构建体的人甲状腺髓样癌细胞系。然而，raf-1激活在该细胞系中的体内效应尚未被表征。因此，我们在小鼠皮下异种移植模型中利用TT或TT-raf细胞来研究肿瘤的发展和生长。在患有TT-raf肿瘤的小鼠中，raf-1的激活导致甲状腺髓样癌肿瘤形成的显著减少。然而，对照组的甲状腺髓样癌肿瘤发生率很高。这些数据表明，在该TT-raf异种移植模型中，通过雌二醇处理的raf-1活化抑制了肿瘤发展。此外，为了确定raf-1激活是否也能抑制已建立的肿瘤的生长，在肿瘤形成后植入雌二醇和对照颗粒。与TT-raf对照组相比，接受雌二醇颗粒的TT-raf组肿瘤体积减少了8倍。总之，这些结果表明，在甲状腺髓样癌小鼠模型中raf-1的体内激活不仅导致肿瘤发展的减少，而且还抑制了已建立肿瘤的生长。这些结果表明，激活raf-1/MEK/ERK 1/2信号通路的策略可能是治疗转移性甲状腺髓样癌患者的可行方法。
Apart from surgical resection, there are no effective therapies for medullary thyroid cancer, a neuroendocrine tumor derived from parafollicular C cells. We have previously shown that activation of raf-1 in TT-raf cells by estradiol suppresses tumor cell growth and calcitonin secretion in vitro. TT-raf cells are a human medullary thyroid cancer cell line that contains an estrogen-inducible raf-1 construct. The in-vivo effects of raf-1 activation in this cell line, however, have not been characterized. Therefore, we utilized TT or TT-raf cells in a murine subcutaneous xenograft model to study tumor development and growth. Activation of raf-1, in mice with TT-raf tumors, led to a significant decrease in medullary thyroid cancer tumor formation. Control groups, however, had a high rate of medullary thyroid cancer tumor development. These data indicate that raf-1 activation by estradiol treatment in this TT-raf xenograft model inhibited tumor development. Furthermore, to determine whether raf-1 activation could also inhibit the growth of established tumors, estradiol and control pellets were implanted after tumor development. The TT-raf group that received estradiol pellets showed an 8-fold decrease in tumor volume compared with the TT-raf control group. Taken together, these results suggest that in-vivo activation of raf-1 in a murine model of medullary thyroid cancer not only led to a reduction in tumor development, but also inhibited the growth of established tumors. These results suggest that strategies to activate the raf-1/MEK/ERK1/2 signaling pathway may be a viable approach to treat patients with metastatic medullary thyroid cancer.