Regulation of Ovarian Carcinoma Proteinases

描述（由申请人提供）：上皮性卵巢癌（EOC）是美国女性癌症死亡的第五大原因，也是妇科恶性肿瘤死亡的主要原因，每年造成> 15，500例死亡。 大多数妇女被诊断为播散性转移性疾病;因此，EOC的死亡率在30年内没有明显降低。 EOC通过从原发性肿瘤脱落的单细胞和多细胞聚集体（MCA）转移，所述MCA在悬浮液中存活，在腹膜内（ip）粘附，经历局部侵入富含胶原的间质性间皮基质下并增殖以锚继发性病变。 调节EOC转移成功和控制从自由漂浮细胞到危及生命的腹膜锚定转移病灶的转变的因素尚不清楚。 上一个资助期的研究强调了整合素介导的与ip胶原的粘附在膜系胶原酶MT 1-MMP（MMP-14）的表达和功能中的作用。 这些机制研究产生了关于胞质尾磷酸化在调节MT 1-MMP膜动力学中的功能的令人兴奋的新数据，发现了MT 1-MMP在从细胞-细胞粘附片形成MCA中的作用，鉴定了一组参与转移的基因产物，这些基因产物由整合素信号传导调节，并证明了E-钙粘蛋白动力学和β-连环蛋白调节的转录在整合素接合的下游被调节。 在目前的研究中，我们将继续探讨粘附和蛋白水解之间的功能联系调节卵巢癌转移的假设。 目的1中的研究将使用一组体外和体内测定来评估MT 1-MMP胞质尾区的翻译后调节如何有助于转移成功，所述体外和体内测定用于对EOC ip转移中的关键事件进行机械建模。 粘附介导的整合素连接激酶（ILK）激活在EOC转移中的作用将在目标2中进行评价。 目的3中提出的实验将检查整合素对β-连环蛋白靶基因和上皮/间充质转化的调节。 EOC ip播散与大多数其他实体瘤的血行转移不同，因此提出了一组独特的治疗挑战。 在分子水平上了解EOC肿瘤细胞如何转移对于开发新的治疗方法以抑制IP扩散并从而改善数千名EOC女性的生存是必要的。

DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among US women and the major cause of death from gynecologic malignancy, causing >15,500 mortalities/year. Most women are diagnosed with disseminated metastatic disease; as such the mortality rate from EOC has not been reduced appreciably in 30 years. EOC metastasizes via exfoliation of single cells and multicellular aggregates (MCAs) from the primary tumor that survive in suspension, adhere intra-peritoneally (ip), undergo localized invasion into the interstitial collagen-rich sub-mesothelial matrix and proliferate to anchor secondary lesions. The factors that regulate EOC metastatic success and control the transition from free-floating cells to life-threatening peritoneally anchored metastatic lesion are unknown. Studies in the previous funding period highlighted the role of ¿1 integrin-mediated adhesion to ip collagen in expression and function of the membrane-tethered collagenase MT1-MMP (MMP-14). These mechanistic studies generated exciting new data on the function of cytoplasmic tail phosphorylation in regulation of MT1-MMP membrane dynamics, discovered a role for MT1-MMP in MCA formation from cell-cell adherent sheets, identified a panel of gene products involved in metastasis that are regulated by integrin signaling, and demonstrated that E-cadherin dynamics and ¿-catenin-regulated transcription are modulated downstream of integrin engagement. In the current proposal, we will continue to address the hypothesis that a functional link between adhesion and proteolysis regulates ovarian cancer metastasis. Studies in Aim 1 will evaluate how post-translational regulation of the MT1-MMP cytoplasmic tail contributes to metastatic success using a panel of in vitro and in vivo assays with which to mechanistically model key events in EOC ip metastasis. The role of adhesion-mediated integrin linked kinase (ILK) activation in EOC metastasis will be evaluated in Aim 2. Experiments proposed in Aim 3 will examine integrin regulation of ¿-catenin target genes and epithelial/mesenchymal transition. EOC ip dissemination is distinct from that of most other solid tumors that metastasize hematogenously and thereby presents a distinct set of therapeutic challenges. A molecular level understanding of how EOC tumor cells metastasize is necessary for the development of novel therapies to inhibit ip spread and thereby improve the survival of thousands of women with EOC.