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: 8424585
• 负责人: Jason D. Heaney
• 金额: $ 24.84万
• 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/8424585
• 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; men; mouse model; pluripotency; premature; research study; stem cell population; tumor; tumor initiation; tumorigenesis

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.

项目概要 睾丸生殖细胞肿瘤（TGCT）是儿童和年轻人中最常见的癌症。 TGCT结果 源于原始生殖细胞（PGC）（配子的胚胎前体）发育异常。很少 已在人类中鉴定出参与 PGC 肿瘤转化的因素，因为遗传因素 TGCT 的组成部分很复杂，肿瘤在胚胎发生过程中起始。在 129/Sv 小鼠中，唯一的近交系 具有明显频率的自发TGCT的小鼠品系，肿瘤在胚胎日左右开始 13.5（E13.5）。在同一发育时期，发育中性腺中的局部视黄酸 (RA) 水平 影响生殖细胞对减数分裂或有丝分裂停滞（有丝分裂：减数分裂转换）的承诺。在女性胚胎时期 在性腺中，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发挥作用 进入减数分裂。在雄性胚胎性腺中，RA 被降解，Stra8 表达未被诱导，而生殖细胞（生殖细胞） 成年男性生殖细胞的前体细胞在出生前保持静止状态。异常 RA 信号传导的作用和 Stra8在雄性胚胎性母细胞早分化中的表达及其建立 将研究 TGCT 易感小鼠的肿瘤干细胞群。体外和体内的结合 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 致瘤性测定将用于表征三个具体目标。目标 1. 视黄酸是否异常 信号传导有助于 TGCT 易感性以及胚胎生殖细胞如何暴露于 RA？目标 2. 是否 Stra8 在胚胎性母细胞分化和 TGCT 易感性中的功能？目标 3. 子群体是否 胚胎生殖母细胞具有TGCT干细胞的功能吗？这些测试将揭示生殖细胞的独特方面 生物学和TGCT肿瘤发生的关系，可能为人类TGCT的诊断和治疗提供新的靶点。