Regulation of Ovarian Carcinoma Proteinases

卵巢癌蛋白酶的调节

• 批准号: 8216505
• 负责人: Mary Sharon Stack
• 金额: $ 6.02万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8216505
• 关键词: Address; Adhesions; Biological Assay; Cancer Etiology; Cause of Death; Cell Survival; Cell-Matrix Junction; Cells; Cessation of life; Collagen; Competence; Complement; Cytoplasmic Tail; Data; Development; Diagnosis; Disease; Dissociation; E-Cadherin; Epithelial; Epithelial ovarian cancer; Event; Funding; Gene Expression; Gene Targeting; Genetic Transcription; Goals; Greater sac of peritoneum; Gynecologic; In Vitro; Integrin Binding; Integrins; Life; Link; MMP14 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Matrix Metalloproteinases; Mediating; Membrane; Mesenchymal; Metastatic Lesion; Metastatic to; Modeling; Modification; Molecular; Mutation; Neoplasm Metastasis; Ovarian Carcinoma; Pathway interactions; Peptide Hydrolases; Peritoneal; Phosphorylation; Phosphotransferases; Population; Post-Translational Protein Processing; Post-Translational Regulation; Primary Neoplasm; Proliferating; Proteins; Proteolysis; Regulation; Research Design; Resistance; Role; Secondary Lesion; Signal Transduction; Solid Neoplasm; Suspension substance; Suspensions; Therapeutic; Woman; chemotherapy; collagenase; design; improved; in vitro Assay; in vivo; inhibitor/antagonist; integrin-linked kinase; interstitial; intraperitoneal therapy; mimetics; model development; mortality; mutant; neoplastic cell; novel; public health relevance; research study; success; tumor progression

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. PUBLIC HEALTH RELEVANCE: Development of models that accurately reflect the metastatic competence of epithelial ovarian cancer (EOC) represents a remarkable scientific challenge, because the EOC metastatic mechanism involves a novel shedding of multi-cellular aggregates (MCAs) into a cavity (peritoneal cavity) as anchorage-independent, chemotherapy-resistant spheroids. In this unique niche, molecular events that occur during the transition from free-floating MCA to life-threatening peritoneally anchored metastatic lesion are poorly understood. Understanding this transition will enable novel means of targeting intraperitoneal therapies to appropriate multicellular populations.

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15500人死亡。大多数妇女被诊断为播散性转移性疾病；因此，在过去的30年里，由肠炎引起的死亡率并没有明显下降。EOC通过原发肿瘤的单细胞和多细胞聚集体（MCAs）脱落转移，这些肿瘤在悬浮液中存活，粘附在腹膜内（ip），局部侵入富含胶原的间质间皮基质，并增殖以固定继发病变。调节EOC转移成功和控制从自由漂浮细胞向危及生命的腹膜锚定转移灶转移的因素尚不清楚。先前资助期的研究强调了整合素介导的与ip胶原的粘附在膜系结胶原酶MT1-MMP （MMP-14）的表达和功能中的作用。这些机制研究为细胞质尾部磷酸化在MT1-MMP膜动力学调节中的功能提供了令人兴奋的新数据，发现了MT1-MMP在细胞粘附片MCA形成中的作用，鉴定了一组参与转移的基因产物，这些基因产物受整合素信号传导调节，并证明了E-cadherin动力学和¿-catenin调节的转录在整合素参与的下游被调节。在目前的提案中，我们将继续解决粘附和蛋白水解之间的功能联系调节卵巢癌转移的假设。Aim 1的研究将评估MT1-MMP细胞质尾部的翻译后调控如何有助于转移成功，使用一组体外和体内试验来机制模拟EOC ip转移中的关键事件。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Aim 2中进行评估。Aim 3中提出的实验将研究整合素对¿-catenin靶基因和上皮/间质转化的调控。EOC ip播散不同于大多数其他实体肿瘤的血源性转移，因此提出了一套独特的治疗挑战。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来抑制ip扩散，从而提高数以千计的EOC女性患者的生存率是必要的。