OVARIAN CANCER METASTASIS: Unraveling the biology of the plasminogen activation cascade

卵巢癌转移：揭示纤溶酶原激活级联的生物学原理

• 批准号: nhmrc : 114111
• 负责人: Prof Mark Baker
• 金额: $ 11.33万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/ovarian-cancer-metastasis-activation-cascade/100902
• 关键词: OVARIAN; CANCER; METASTASIS; Unraveling; biology

Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of the biology of ovarian cancer metastasis may lead to new therapies designed to control these processes - as such this would be a major inroad into our fight against this cancer. The aim of this novel research project is to unravel the role that one cell surface system (the plasminogen (Plg) activation cascade) plays in determining the ability of ovarian cancer cells to metastasise and regulate new tumour blood vessel formation. This study addresses the paradoxical observations that this cascade can simultaneously facilitate cancer metastasis whilst concomitantly stopping new blood vessel formation in tumours. Using a number of advanced molecular cell biology methods, the hypothesis we will test is that the capacity of ovarian cancer to metastasise is determined by differential processing of plasminogen subsequent to cell-surface Plg binding. This results in a delicate balance between the generation of cell surface proteases and the release of protein fragments capable of stopping tumour blood vessel growth. Our group is well-equipped to address this hypothesis since we have already shown that: (1) Plg binding and activation is required for cancer cell invasion; (2) Plg binding and activation is elevated on malignant compared to benign cancers (3) Plg unfolds after it binds to cell surfaces or recombinant receptors; and, (4) Plg is easily fragmented to products that inhibit new blood vessel formation after binding to some cancer cells.

卵巢癌每年影响1，200名新澳大利亚人。与研究教育和早期筛查提高了死亡率的乳腺癌相比，卵巢癌的发病率没有改善，自1930年以来死亡率增加了一倍多。卵巢癌几乎没有明显的症状，预后极差-诊断患有卵巢癌的妇女中有71%会死于这种疾病，而乳腺癌的这一比例为21%。任何增加我们对卵巢癌转移生物学的理解的研究都可能导致旨在控制这些过程的新疗法-因此，这将是我们对抗这种癌症的主要进展。这项新研究项目的目的是揭示一种细胞表面系统（纤溶酶原（Plg）激活级联）在决定卵巢癌细胞转移和调节新肿瘤血管形成的能力中所起的作用。这项研究解决了矛盾的观察，即这种级联反应可以同时促进癌症转移，同时阻止肿瘤中新血管的形成。使用一些先进的分子细胞生物学方法，我们将测试的假设是，卵巢癌转移的能力是由纤溶酶原的差异加工后，细胞表面Plg结合。这导致细胞表面蛋白酶的产生和能够阻止肿瘤血管生长的蛋白质片段的释放之间的微妙平衡。我们的研究小组已经准备好解决这一假设，因为我们已经表明：（1）Plg结合和活化是癌细胞侵袭所必需的;（2）与良性癌症相比，恶性癌症的Plg结合和活化升高;（3）Plg在与细胞表面或重组受体结合后展开;和（4）Plg在与某些癌细胞结合后容易断裂成抑制新血管形成的产物。