Yabushita Hiromitsu, Shimazu Mitsuma, Noguchi Mari, Kishida Tameko, Narumiya Hisao, Sawaguchi Keizo, Noguchi Masayoshi
Department of Obstetrics and Gynecology, Aichi Medical University, School of Medicine, Nagakute-cho, Aichi-gun, Japan.
Oncol Rep. 2003 Jan-Feb;10(1):89-95.
The role of vascular endothelial growth factor (VEGF) during peritoneal dissemination of ovarian carcinoma and the association with tumor microvessel density (MVD) and matrix metalloproteinase (MMP) activity was investigated. To this end, MVD, tumor tissue and ascitic fluid levels of VEGF, and MMP activity of ascitic fluid were examined in patients with ovarian cancer and benign ovarian tumor. The effect of ascites on cell growth, cell invasion activity and angiogenesis was investigated in vitro. Ascitic fluid and tumor tissue samples were obtained from 15 patients with benign ovarian tumor and 24 patients with ovarian carcinoma. Tissue extract and ascitic fluid levels of VEGF were measured using enzyme immunoassay. Tumor microvessels were detected immunohistochemically. MMP activity was measured by gelatin zymography. For the in vitro experiment, the SKOV-3 human ovarian carcinoma cell line was utilized. Cell growth was examined using MTT-assay, cell invasion activity was measured by Matrigel in vitro invasion assay, and neovascularization was assessed using an angiogenesis kit. VEGF levels in tissue extract and ascitic fluid, MVD, expression of active form MMP-2 in ascitic fluid and ascites volume were higher in ovarian cancer patients than in benign ovarian tumor patients. In addition, these were elevated in stage III and IV diseases compared to stage I and II diseases in ovarian cancer patients. MVD and expression of active form MMP-2 in ascitic fluid were closely correlated with VEGF level in tissue extracts, and MVD and ascites volume were closely correlated with VEGF level in ascitic fluid. Cell invasive activity and angiogenesis activity increased when cells were exposed to ascites. These increases were apparent when exposed to ascites obtained from ovarian cancer patients and were related to VEGF concentrations of ascitic fluid and expression of active form MMP-2 in ascitic fluid. The increased VEGF secreted from tumor cells is suggested to enhance tumor growth through angiogenesis, to produce ascites and to elevate ascitic VEGF concentrations and expression of active form MMP-2. The progression of peritoneal involvement may be induced by elevated VEGF and expression of active form MMP-2, followed by increased VEGF in the primary tumor. Control of VEGF in the primary tumor may become an effective strategy against peritoneal dissemination of ovarian carcinoma.
研究了血管内皮生长因子（VEGF）在卵巢癌腹膜播散中的作用及其与肿瘤微血管密度（MVD）和基质金属蛋白酶（MMP）活性的关系。为此，检测了卵巢癌患者和卵巢良性肿瘤患者的MVD、肿瘤组织及腹水VEGF水平以及腹水MMP活性。体外研究了腹水对细胞生长、细胞侵袭活性和血管生成的影响。从15例卵巢良性肿瘤患者和24例卵巢癌患者获取腹水和肿瘤组织样本。采用酶免疫法检测组织提取物和腹水中VEGF水平。免疫组化检测肿瘤微血管。明胶酶谱法检测MMP活性。体外实验采用SKOV-3人卵巢癌细胞系。用MTT法检测细胞生长，用基质胶体外侵袭实验检测细胞侵袭活性，用血管生成试剂盒评估血管生成。卵巢癌患者组织提取物和腹水中的VEGF水平、MVD、腹水中活性形式MMP-2的表达及腹水量均高于卵巢良性肿瘤患者。此外，与卵巢癌患者的Ⅰ期和Ⅱ期疾病相比，Ⅲ期和Ⅳ期疾病中的这些指标升高。腹水中MVD和活性形式MMP-2的表达与组织提取物中VEGF水平密切相关，MVD和腹水量与腹水中VEGF水平密切相关。细胞暴露于腹水时，细胞侵袭活性和血管生成活性增加。当暴露于卵巢癌患者的腹水时，这些增加很明显，并且与腹水中VEGF浓度和腹水中活性形式MMP-2的表达有关。肿瘤细胞分泌的VEGF增加被认为通过血管生成促进肿瘤生长、产生腹水并提高腹水VEGF浓度和活性形式MMP-2的表达。VEGF和活性形式MMP-2表达升高可能诱导腹膜受累进展，随后原发性肿瘤中VEGF增加。控制原发性肿瘤中的VEGF可能成为对抗卵巢癌腹膜播散的有效策略。
