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: 8627975
• 负责人: Jason D. Heaney
• 金额: $ 23.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-06 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627975
• 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; Inbreeding; 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; mouse model; pluripotency; premature; research study; stem cell population; tumor; tumor initiation; tumorigenesis; young man

Project Summary 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 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.

项目摘要 睾丸生殖细胞肿瘤（TGCT）是儿童和年轻男性中最常见的癌症。 TGCT结果 来自原始生殖细胞发展（PGC）的异常，是配子的胚胎前体。很少 由于遗传 TGCT的成分是复杂的，在胚胎发生过程中启动肿瘤。在129/SV小鼠中，唯一 小鼠的菌株具有明显的自发性TGCT频率，肿瘤在胚胎日附近启动 13.5（E13.5）。在同一发育时期，发育中的性腺中局部视黄酸（RA）水平 影响生殖细胞对减数分裂或有丝分裂停滞的承诺（有丝分裂：减数分裂开关）。在女性胚胎中 性腺，RA诱导Stra8的表达，该表达在生殖细胞进入所需的分化事件中起作用 进入减数分裂。在雄性胚胎性腺中，RA被降解，stra8表达不会被诱导，并且Gonocytes，The Gonocytes 成年男性生殖细胞的前体一直保持静止，直到出生后。异常RA信号传导和 stra8在雄性胚胎刺激细胞的过早区分中表达和建立 将研究TGCT易感小鼠的肿瘤干细胞种群。体外和体外的组合 体内畸胎瘤形成测定，表达测定，功能丧失突变和多能性和多能性和 肿瘤性测定将用于表征三个特定目标。目标1。异常的视黄酸会 信号传导有助于TGCT敏感性，并且如何暴露于RA的胚胎刺激性？目标2。做 Stra8功能在胚胎性肌细胞分化和TGCT敏感性中？目标3。 胚胎碎石细胞充当TGCT干细胞？这些测试将揭示生殖细胞的独特方面 生物学和TGCT肿瘤发生，并可能为人类TGCT的诊断和治疗提供新的靶标。