Charles Roch-Philippe, Silva Jillian, Iezza Gioia, Phillips Wayne A, McMahon Martin
Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center; Departments of Cell and Molecular Pharmacology, and
Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center; Departments of Cell and Molecular Pharmacology, and.
Mol Cancer Res. 2014 Jul;12(7):979-86. doi: 10.1158/1541-7786.MCR-14-0158-T. Epub 2014 Apr 25.
Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3'-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAF(V600E), we previously developed a model of PTC. However, as in humans, BRAF(V600E)-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CA(H1047R) is unable to drive transformation on its own, when combined with BRAF(V600E) in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAF(V600E) cooperates with either PIK3CA(H1074R) or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma.
This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma.
甲状腺恶性肿瘤是最常见的内分泌肿瘤类型。在各种组织学亚型中，间变性甲状腺癌（ATC）占所有病例的一部分，但在甲状腺癌相关死亡率中占很大比例。事实上，ATC被认为是侵袭性较强且难以治疗的癌症形式之一。迄今为止，缺乏相关模型系统来严格评估在人类ATC中检测到的标志性基因异常如何导致疾病发病机制。BRAF原癌基因的突变激活在约40%的乳头状甲状腺癌（PTC）和25%的ATC中被检测到。此外，在ATC中，突变的BRAF经常与PI3'-激酶（PIK3CA）的p110催化亚基的功能获得性突变或p53（TP53）或PTEN肿瘤抑制因子的功能丧失性改变同时出现。利用具有BRAF（V600E）条件性、甲状腺细胞特异性表达的小鼠，我们之前建立了一个PTC模型。然而，与人类情况一样，BRAF（V600E）诱导的小鼠PTC生长缓慢，不会导致终末期疾病的快速发展。在这里，我们使用携带PIK3CA条件等位基因的小鼠来证明，虽然突变激活的PIK3CA（H1047R）自身无法驱动转化，但当与甲状腺细胞中的BRAF（V600E）结合时，这会导致小鼠发生致命的ATC。综合来看，这些数据表明BRAF（V600E）与PIK3CA（H1074R）或肿瘤抑制因子PTEN的沉默协同作用，促进间变性甲状腺癌的发展。
这种与基因相关的ATC小鼠模型将成为预防和治疗甲状腺癌的通路靶向治疗临床前测试的宝贵平台。
