Antiangiogenesis therapy of human ovarian cancer

背景：卵巢癌的渐进性生长和扩散部分依赖于足够的血液供应的形成和维持，即血管生成。我们发现，在血管生成过程中调控不同步骤的基因的表达与人卵巢癌细胞移植到裸鼠腹膜内的方式和进行性生长有关：成瘤性与碱性成纤维细胞生长因子(BFGF)的表达有关，腹水的产生与血管内皮生长因子/血管通透性因子(VEGF/VPF)的表达直接相关，而小鼠的进行性生长(和死亡)与白细胞介素8(IL-8)的表达直接相关。总体指导假设和特定目标：目前的结果提出了两个相互依赖的假设：(I)血管生成调节基因在原发性卵巢癌中的表达预测了疾病的类型和临床结果；(Ii)靶向IL-8基因可能促进卵巢癌的生长和血管生成，可能为卵巢癌的治疗提供新的途径。具体目标包括：(1)确定血管生成相关基因在卵巢癌中的表达是否可以预测疾病类型和临床预后；(2)确定IL-8的表达是否对人卵巢癌细胞的进行性生长是必不可少的；(3)确定器官微环境(缺氧、酸中毒)是否可以调节人卵巢癌细胞的IL-8的表达；(4)确定干扰素-β(IFN-β)抑制IL-8的表达是否可以抑制人卵巢癌的血管生成和进行性(腹膜内)生长。意义：这项拟议的研究将为血管生成过程提供新的线索(重点是IL-8的作用)，这对人类卵巢癌的渐进生长至关重要。更好地了解IL-8在人卵巢癌发展过程中的作用以及IL-8的表达是如何调节的，将有助于设计新的治疗方法来下调IL-8的表达，从而抑制肿瘤细胞的生长和血管生成，最初在原位模型中，后来在临床上。

DESCRIPTION: (Applicant's Description) Background: The progressive growth and spread of ovarian carcinoma is dependent in part on the formation and maintenance of adequate blood supply, i.e., angiogenesis. We found that the expression of genes that regulate distinct steps in the process of angiogenesis correlates with the pattern and progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of athymic nude mice: tumorigenicity correlated with expression of basic fibroblast growth factor (bFGF), and the production of ascites was directly correlated with expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), whereas progressive growth (and death of mice) was directly correlated with expression of interleukin-8 (IL-8). Overall Guiding Hypotheses and Specific Aims: The current results suggest two interdependent hypotheses: (I) the expression of angiogenesis-regulating genes in primary human ovarian cancer predicts the pattern of the disease and its clinical outcome; and (II) targeting the IL-8 gene which may enhance ovarian cancer growth and angiogenesis could offer new approaches to the treatment of ovarian cancer. The specific aims include the following: (1) to determine whether the expression of angiogenesis-related genes in primary ovarian cancers predicts disease pattern and clinical outcome; (2) to determine whether the expression of IL-8 is essential for the progressive growth of human ovarian cancer cells; (3) to determine whether the organ microenvironment (hypoxia, acidosis) can regulate the expression of IL-8 in human ovarian cancer cells; and (4) to determine whether inhibition of IL-8 expression by interferon-beta (IFN-beta) can inhibit angiogenesis and progressive (intraperitoneal) growth of human ovarian cancer. Significance: The proposed research will shed new light on the process of angiogenesis (with emphasis on the role of IL-8) which is crucial for the progressive growth of human ovarian cancer. A better understanding of the role of IL-8 in the progression of human ovarian cancer and how IL-8 expression is regulated will allow the design of new therapeutic approaches to downregulate the expression of IL-8 and, hence, inhibit tumor cell growth and angiogenesis initially in orthotopic models and later in the clinic.