HOX genes in ovarian neoplasia

描述（由申请人提供）：上皮性卵巢癌（EOC）包括几种表现出不同临床病理特征的肿瘤亚型。我们的总体目标是描绘调控不同亚型EOCs组织发生的分子途径，并确定异常分化在卵巢表面上皮（OSE）细胞转化中的作用。这一奋进是定义新的分子标志物和靶标的关键步骤，这些分子标志物和靶标能够开发用于EOC诊断的更有效的多重方法和靶向特定类型EOC的“设计者”疗法。 EOC被认为是从卵巢表面的单层上皮细胞中产生的。EOC与许多其他类型的上皮肿瘤不同，因为它们的分化模式通常比前体细胞的分化模式更复杂。事实上，EOC的主要亚型的特征在于它们与来自苗勒管的生殖道特化上皮的结构相似。HOX基因控制生长，并决定每个组织在正常发育过程中的独特身份。对小鼠苗勒管发育的研究表明，Abd B样HOX基因hoxa 9、hoxa 10和hoxa 11分别正常调节输卵管、子宫和子宫颈的形态发生。在初步研究中，我们分析了上皮和间质的表达模式的人Abd B样蛋白的EOCs的微阵列，并发现其肿瘤亚型特异性和它们在正常生殖道中的分布之间的惊人的相似之处。我们的初步研究还揭示了HOXB 7和HOXA 7分别在促进OSE细胞的异常增殖和分化中的作用，以及HOXA 9和HOXA 7在肿瘤转化中的作用。 我们推测OSE细胞的转化和EOCs主要亚型的形态发生是通过HOXA 7、HOXB 7和Abd B样HOX基因的异常表达而产生的。在这个计划中，我们将确定这些HOX基因在（1）致瘤性和非致瘤性卵巢上皮细胞沿着特定的苗勒氏细胞样途径分化，（2）OSE细胞的肿瘤转化，和（3）EOCs中上皮-基质相互作用中的作用。因此，这些研究调查两个基本的，但了解甚少的方面EOC组织发生，即，形态异质性的疾病，和异常分化的OSE细胞和肿瘤转化之间的关系。

DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) encompasses several subtypes of tumors that exhibit distinct clinicopathologic features. Our overall goals are to delineate the molecular pathways that regulate the histogenesis of different subtypes of EOCs, and to determine the role of aberrant differentiation in transformation of ovarian surface epithelial (OSE) cells. This endeavor is a critical step to defining novel molecular markers and targets that enable development of more effective multiplexed approaches for EOC diagnosis and "designer" therapeutics that target specific types of EOCs. EOCs are thought to arise from the simple epithelium lining the ovarian surface. EOCs differ from many other types of epithelial tumors in that their differentiation patterns are often more complex than that of the precursor cell. Indeed, the major subtypes of EOCs are characterized by their architectural resemblance to the specialized epithelia of the reproductive tract that derive from the mullerian ducts. HOX genes control growth and determine the unique identity of each tissue during normal development. Studies of mouse mullerian duct development indicate that the Abd B-like HOX genes, hoxa9, hoxa10 and hoxa11, normally regulate morphogenesis of the fallopian tubes, uterus and cervix, respectively. In preliminary studies, we analyzed epithelial and stromal expression patterns of the human Abd B-like proteins in microarrays of EOCs, and found striking parallels between their tumor subtype-specificity and their distribution in the normal reproductive tract. Our preliminary studies also revealed roles for HOXB7 and HOXA7 in promoting aberrant proliferation and differentiation, respectively, of OSE cells, and for HOXA9 and HOXA7 in neoplastic transformation. We hypothesize that transformation of OSE cells and the morphogenesis of the major subtypes of EOCs arise through aberrant expression of HOXA7, HOXB7 and the Abd B-like HOX genes. In this proposal, we will determine the roles of these HOX genes in (1) differentiation of tumorigenic and non-tumorigenic ovarian epithelial cells along specific mullerian-like pathways, (2) neoplastic transformation of OSE cells, and (3) epithelial-stromal interactions in EOCs. These studies therefore investigate two fundamental but poorly understood aspects of EOC histogenesis, namely, the morphologic heterogeneity of the disease, and the relationship between aberrant differentiation of OSE cells and neoplastic transformation.