Profound but dysfunctional lymphanglogenesis via vascular endothelial growth factor ligands from CD11b+ macrophages in advanced ovarian cancer
Profound but dysfunctional lymphanglogenesis via vascular endothelial growth factor ligands from CD11b+ macrophages in advanced ovarian cancer
复制标题
DOI：
10.1158/0008-5472.can-07-2572
复制
发表时间：
2008-02-15
期刊：
影响因子：
11.2
通讯作者：
Koh, Gou Young
中科院分区：
文献类型：
--
作者：
Jeon, Bong-Hyan;Jang, Cholsoon;Koh, Gou Young
严重腹水是晚期卵巢癌（OVCA）的标志，但造成腹膜血管渗漏和淋巴引流不平衡的潜在机制尚不清楚。在这里，我们鉴定和表征了OVCA小鼠的腹膜淋巴管，OVCA是通过将人OVCA细胞植入胸腺裸鼠而产生的模型。OVCA小鼠表现出大量淋巴管生成和淋巴重塑，CD11b(+)/LYVE-1（+）巨噬细胞大量浸润，肠系膜和膈弥散性癌病变，乳糜腹水形成进行性。功能分析显示横膈膜中异常丰富的淋巴管在腹膜液引流中不具有导电性。此外，从肠道吸收的脂质从异常的肠系膜淋巴管泄漏出来。我们的研究结果表明，来自CD11b（+）巨噬细胞的血管内皮生长因子(VEGF)-C、VEGF- d和VEGF- a负责产生ovca诱导的功能失调淋巴管生成，尽管其他细胞类型有助于增加腹水形成。因此，分别用可溶性VEGF受体-3和VEGF- trap联合阻断VEGF- c /D和VEGF- a信号，可显著抑制乳糜腹水的形成。这些发现为改善晚期OVCA患者乳糜腹水形成提供了额外的治疗靶点。
Severe ascites is a hallmark of advanced ovarian cancer (OVCA), yet the underlying mechanism that creates an imbalance between peritoneal vascular leakage and lymphatic drainage is unknown. Here, we identified and characterized peritoneal lymphatic vessels in OVCA mice, a model generated by implantation of human OVCA cells into athymic nude mice. The OVCA mice displayed substantial lymphangiogenesis and lymphatic remodeling, massive infiltration of CD11b(+)/LYVE-1(+) macrophages and disseminated carcinomatosis in the mesentery and diaphragm, and progressive chylous ascites formation. Functional assays indicated that the abnormally abundant lymphatic vessels in the diaphragm were not conductive in peritoneal fluid drainage. Moreover, lipid absorbed from the gut leaked out from the aberrant mesenteric lymphatic vessels. Our results indicate that vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF-A from CD11b(+) macrophages are responsible for producing OVCA-induced dysfunctional lymphangiogenesis, although other cell types contribute to the increased ascites formation. Accordingly, the combined blockade of VEGF-C/D and VEGF-A signaling with soluble VEGF receptor-3 and VEGF-Trap, respectively, markedly inhibited chylous ascites formation. These findings provide additional therapeutic targets to ameliorate chylous ascites formation in patients with advanced OVCA.