RCAN1 in Thyroid Cancer Progression

描述(申请人提供)：转移性休眠被定义为转移性癌症组织的静止生存能力，但不会侵袭和发展到远处。在甲状腺癌中，肺转移较小的患者通常存活数十年而没有放射学或临床进展，这表明转移部位的进展受到抑制是许多甲状腺癌固有的。由于大多数与甲状腺癌相关的死亡都是由于晚期进行性转移性疾病造成的，因此确定这些癌症逃脱转移休眠的机制是至关重要的。转移抑制因子是肿瘤转移和生长的负性调节因子，可能在转移进展中起“把关”作用。通过询问癌细胞中的KiSS-1/GPr54转移抑制信号级联，我们在体外确定了钙调神经磷酸酶1-4(RCAN1-4)的运动抑制作用；并证明了该蛋白在转移性甲状腺癌组织中缺失。RCAN1-4也被证明在血管内皮生长因子诱导的内皮细胞生长和运动中发挥核心作用。有趣的是，编码所有RCAN1亚型的RCAN1(DSCR1)基因位于21号染色体上，是唐氏综合症(21三体)中过度表达的许多基因之一。最近的研究表明，RCAN1在减少与唐氏综合征相关的实体肿瘤的发病率和进展方面起着关键的作用。在小鼠中，表达了两种RCAN1亚型，它们与两种主要的人类亚型RCAN1-1和RCAN1-4同源。最近的体内研究证实，小鼠中与人RCAN1-4同源的短型RCAN1是肿瘤移植瘤新生血管中的主要诱导亚型，提示它可能在血管内皮生长因子诱导的肿瘤血管生成中具有特殊重要的作用，但该亚型在肿瘤进展中的功能尚未得到直接测试。这一提议的总体假设是，RCAN1-4是一个关键的守门人，通过抑制癌细胞侵袭和抑制内皮细胞对血管内皮生长因子和其他血管生成信号的反应来抑制甲状腺癌的进展。我们将使用各种体内模型来验证这一假说。 公共卫生相关性：项目叙述转移休眠，即转移部位的癌细胞存活而不进展的能力，在甲状腺癌中很常见，因此，这种恶性肿瘤是研究这一重要过程的极好模型。此外，明确转移休眠维持和/或消失的机制有可能为没有有效治疗方法的进行性转移性甲状腺癌患者识别新的生物标志物和治疗靶点。根据初步的实验室和临床数据，我们在目前的提案中假设，RCAN1-4是一种关键的、高度调控的蛋白质，它维持甲状腺癌的转移休眠。

DESCRIPTION (provided by applicant): Metastatic dormancy is defined as the ability of rests of metastatic cancer tissue to survive, but not invade and progress at distant sites. In thyroid cancer, patients with small lung metastases often survive for decades without radiographic or clinical progression, suggesting that restraint of progression at metastatic sites is intrinsic to many thyroid cancers. Because most thyroid cancer- related deaths are due to late-stage progressive metastatic disease, it is crucial to define mechanisms that by which these cancers escape from metastatic dormancy. Metastasis suppressors are negative regulators of cancer metastasis and growth that may serve a "gate-keeping" role in metastatic progression. By interrogating the KiSS-1/GPR54 metastasis inhibitory signaling cascade in cancer cells, we identified a motility-suppressor role for regulator of calcineurin 1-4 (RCAN1-4) in vitro; and demonstrated loss of this protein in metastatic thyroid cancer tissue samples. RCAN1-4 has also been shown to play a central role in VEGF-induced endothelial cell growth and motility. Interestingly, the RCAN1 (DSCR1) gene that encodes all RCAN1 isoforms is located on chromosome 21, and is one of many genes overexpressed in Down's syndrome (trisomy 21). It was recently demonstrated that Rcan1 plays a critical functional role in the reduced solid tumor incidence and progression associated with Down's syndrome. In mouse two Rcan1 isoforms are expressed that are homologous to the two dominant primary human isoforms, RCAN1-1 and RCAN1-4. Recent in vivo studies confirmed that short form of Rcan1 in mouse, which is homologous to human RCAN1-4, is the primary induced isoform in the neovasculature of tumor grafts, suggesting that it may be specifically important in tumor angiogenesis induced by VEGF However the functional role of this isoform on cancer progression has not been directly tested in vivo. The overall hypothesis of this proposal is that RCAN1-4 is a key gate-keeper that restrains thyroid cancer progression by inhibiting cancer cell invasion and by inhibiting endothelial cell response to VEGF and other angiogenic signals. We will use a variety of in vivo models to test this hypothesis. PUBLIC HEALTH RELEVANCE: Project Narrative Metastatic dormancy, or the ability of cancer cells in metastatic sites to survive without progressing, is common in thyroid cancer, thus, this malignancy serves as an excellent model to study this important process. Moreover, defining mechanisms by which metastatic dormancy is maintained and/or lost has potential to identify new biomarkers and therapeutic targets for patients with progressive metastatic thyroid cancer for which there are no effective therapies. Based on preliminary laboratory and clinical data, we hypothesize in the current proposal that RCAN1-4 is a critical and highly regulated protein that maintains metastatic dormancy of thyroid cancer.