Yoneda J, Kuniyasu H, Crispens M A, Price J E, Bucana C D, Fidler I J
Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
J Natl Cancer Inst. 1998 Mar 18;90(6):447-54. doi: 10.1093/jnci/90.6.447.
By the time patients are diagnosed with ovarian carcinoma, peritoneal dissemination of the tumor often has occurred. The progressive growth and spread of ovarian carcinoma depend, in part, on the formation of an adequate blood supply. We determined whether the expression of genes that regulate distinct steps in angiogenesis (i.e., the formation of new blood vessels) was associated with the pattern and progressive growth of human ovarian carcinomas implanted in the peritoneal cavity of nude mice.
Five different human ovarian carcinomas were injected individually into the peritoneal cavity of female NCr-nu/nu nude mice. The expression of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), and collagenase type IV (MMP-2 [matrix metalloproteinase-2] and MMP-9) was determined by northern blot analysis, in situ hybridization of messenger RNA, and immunohistochemical analysis. Blood vessel distribution and density, macrophage infiltration pattern, and stromal reaction were determined by immunohistochemical analysis with specific antibodies.
Three of the carcinomas produced both solid lesions and ascitic tumors, whereas the remaining two produced only solid lesions. Two of the carcinomas produced rapidly progressive disease, two produced slow disease, and one produced intermediate disease. The formation of ascites was directly associated with expression of VEGF/ VPF, and survival was inversely associated with expression of IL-8. In rapidly growing tumors, the number of blood vessels was high throughout the lesion; in contrast, in slow-growing tumors, most vessels (and infiltrating macrophages) were located at the periphery.
The expression of various genes that regulate angiogenesis in human ovarian carcinomas is associated with the pattern of the disease and its progression. Therefore, targeting specific genes that regulate angiogenesis could offer new approaches to the treatment of ovarian cancer.
当患者被诊断为卵巢癌时，肿瘤通常已发生腹膜播散。卵巢癌的进展性生长和扩散部分取决于充足血供的形成。我们确定了调控血管生成（即新血管形成）不同步骤的基因表达是否与植入裸鼠腹腔的人卵巢癌的模式和进展性生长相关。
将五种不同的人卵巢癌分别注射到雌性NCr-nu/nu裸鼠的腹腔内。通过Northern印迹分析、信使核糖核酸原位杂交和免疫组织化学分析来确定碱性成纤维细胞生长因子、血管内皮生长因子/血管通透因子（VEGF/VPF）、白细胞介素8（IL-8）和IV型胶原酶（基质金属蛋白酶-2 [MMP-2]和MMP-9）的表达。用特异性抗体通过免疫组织化学分析来确定血管分布和密度、巨噬细胞浸润模式以及基质反应。
三种癌产生实性病变和腹水肿瘤，而其余两种仅产生实性病变。两种癌产生快速进展性疾病，两种产生缓慢进展性疾病，一种产生中等进展性疾病。腹水的形成与VEGF/VPF的表达直接相关，而生存率与IL-8的表达呈负相关。在快速生长的肿瘤中，整个病变区域血管数量较多；相反，在生长缓慢的肿瘤中，大多数血管（和浸润的巨噬细胞）位于周边。
调控人卵巢癌血管生成的各种基因的表达与疾病模式及其进展相关。因此，靶向调控血管生成的特定基因可为卵巢癌的治疗提供新方法。
