HOX genes in ovarian neoplasia

描述(申请人提供)：上皮性卵巢癌(EOC)包括几种亚型的肿瘤，表现出不同的临床病理特征。我们的总体目标是描述调控不同亚型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。这一努力是确定新的分子标志物和靶点的关键一步，这些标记物和靶点能够为EOC诊断和针对特定类型EOC的“设计”疗法开发更有效的多重方法。 EOCs被认为是由卵巢表面衬里的简单上皮形成的。EOCs与许多其他类型的上皮性肿瘤的不同之处在于，它们的分化模式往往比前体细胞更复杂。事实上，EOCs的主要亚型的特征是它们的结构类似于源自苗勒管的生殖道的特化上皮。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hoxa9、hoxa10和hoxa11分别正常调控输卵管、子宫和宫颈的形态发生。在初步研究中，我们分析了人ABD B样蛋白在EOCs微阵列中的上皮和间质表达模式，发现它们的肿瘤亚型特异性与它们在正常生殖道中的分布有惊人的相似之处。我们的初步研究还揭示了HOXB7和HOXA7分别促进OSE细胞的异常增殖和分化，以及HOXA9和HOXA7在肿瘤转化中的作用。 我们推测OSE细胞的转化和主要EOCs亚型的形态发生是通过HOXA7、HOXB7和ABD B样HOX基因的异常表达而产生的。在这项研究中，我们将确定这些HOX基因在(1)致癌和非致瘤卵巢上皮细胞沿着特定的穆勒式途径分化，(2)OSE细胞的肿瘤性转化，以及(3)EOCs中的上皮-间质相互作用中的作用。因此，这些研究探讨了卵巢上皮性癌组织发生的两个基本但知之甚少的方面，即疾病的形态异质性以及OSE细胞的异常分化与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.