Primordial germ cell differentiation and the initiation of testicular cancer

原始生殖细胞分化和睾丸癌的发生

• 批准号: 7893887
• 负责人: Jason D. Heaney
• 金额: $ 8.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-14 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893887
• 关键词: 129/Sv Mouse; Adult; Apoptosis; Biological Assay; Birth; Cell Differentiation process; Cell Proliferation; Cell Separation; Cell physiology; Cellular biology; Child; Complex; Defect; Development; Diagnosis; Diagnostic; Embryo; Embryonic Development; Event; Female; Frequencies; Future; Gene Expression; Genes; Genetic; Germ Cells; Germ Lines; Gonadal structure; Human; In Vitro; Inbred Strains Mice; Incidence; Malignant Neoplasms; Malignant neoplasm of testis; Mediating; Meiosis; Mitotic; Mus; Neoplastic Cell Transformation; Oocytes; Population; Predisposition; Reporter; Research; Role; Signal Transduction; Spermatogonia; Stem Cell Development; Stem cells; Structure of primordial sex cell; Teratoma; Testicular Germ Cell Tumor; Testing; Testis; Time; Transgenes; Tretinoin; Tumor Stem Cells; Tumorigenicity; Work; in vivo; loss of function mutation; male; men; mouse model; pluripotency; premature; public health relevance; research study; stem cell population; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Testicular germ cell tumors (TGCTs) are the most common cancer in children and young men. TGCTs result from anomalies in the development of primordial germ cells (PGC), the embryonic precursors of gametes. Few factors involved in neoplastic transformation of PGCs have been identified in humans because the genetic component of TGCTs is complex and tumors initiate during embryogenesis. In 129/Sv mice, the only inbred strain of mice with an appreciable frequency of spontaneous TGCTs, tumors initiate around embryonic day 13.5 (E13.5). During this same developmental period, local retinoic acid (RA) levels in the developing gonad influences germ cell commitment to meiosis or mitotic arrest (the mitotic:meiotic switch). In female embryonic gonads, RA induces expression of Stra8, which functions in differentiation events required for germ cell entry into meiosis. In male embryonic gonads, RA is degraded, Stra8 expression is not induced, and gonocytes, the precursors of adult male germ cells, remain quiescent until after birth. The role of aberrant RA signaling and Stra8 expression in the premature differentiation of male embryonic gonocytes and the establishment of a tumor stem cell population in TGCT susceptible mice will be investigated. A combination of in vitro and in vivo teratoma formation assays, expression assays, loss-of-function mutations, and pluripotency and tumorigenicity assays will be used to characterize three Specific Aims. Aim 1 - Does aberrant retinoic acid signaling contribute to TGCT susceptibility and how are embryonic gonocytes exposed to RA? Aim 2 - Does Stra8 function in embryonic gonocyte differentiation and TGCT susceptibility? Aim 3 - Does a sub-population of embryonic gonocytes function as TGCT stem cells? These tests will reveal unique aspects of germ cell biology and TGCT tumorigenesis and may provide new targets for diagnosis and treatment of human TGCTs. PUBLIC HEALTH RELEVANCE: Defects in male germ cell development can result in testicular germ cell tumors (TGCTs). TGCTs are the most common cancer in children and young men. Despite considerable work in humans, little is known about the cellular process involved in early TGCT development. The mouse model of TGCTs will help guide potential future studies in humans and provide better diagnostic markers and targets for the identification and treatment of TGCTs.

描述（由申请人提供）：睾丸生殖细胞肿瘤（TGCT）是儿童和年轻男性最常见的癌症。 TGCT是由原始生殖细胞（PGC）（配子的胚胎前体）发育中的异常引起的。由于TGCT的遗传成分是复杂的，并且在胚胎发生过程中启动肿瘤，因此在人类中鉴定出涉及PGC的肿瘤转化的因素很少。在129/SV小鼠中，唯一具有明显自发TGCT频率的小鼠的近交性菌株在胚胎第13.5天（E13.5）附近启动。在同一发育时期，发育中的性腺中局部视黄酸（RA）水平会影响对减数分裂或有丝分裂停滞的生殖细胞承诺（有丝分裂：减数分裂开关）。在雌性胚胎性腺中，RA诱导Stra8的表达，该表达在细胞进入减数分裂所需的分化事件中起作用。在雄性胚胎性腺中，RA被降解，不诱导StrA8表达，而成年男性生殖细胞的前体Gonoctes一直保持静止，直到出生后。将研究将研究异常的RA信号传导和StrA8表达在男性胚胎促分子过早分化中的作用，以及在TGCT易感小鼠中建立肿瘤干细胞群体的作用。体外和体内畸胎瘤形成测定，表达测定，功能丧失突变以及多能性和肿瘤性测定的组合将用于表征三个特定目标。 AIM 1-异常的视黄酸信号传导是否有助于TGCT敏感性？如何暴露于RA的胚胎斑点？ AIM 2 -Stra8在胚胎分化和TGCT敏感性中是否功能？ AIM 3-胚胎性孢子细胞的亚群是否充当TGCT干细胞？这些测试将揭示生殖细胞生物学和TGCT肿瘤发生的独特方面，并可能为人类TGCT的诊断和治疗提供新的靶标。 公共卫生相关性：男性生殖细胞发育的缺陷会导致睾丸生殖细胞肿瘤（TGCT）。 TGCT是儿童和年轻人中最常见的癌症。尽管在人类中有很多工作，但对早期TGCT发育涉及的细胞过程知之甚少。 TGCT的小鼠模型将有助于指导人类的潜在研究，并为TGCT的识别和治疗提供更好的诊断标记和靶标。