环氧合酶-2对乳腺癌淋巴管形成的影响

The effect of cyclooxygenase-2 on lymphangiogenesis in breast cancer

目的探讨环氧合酶-2（COX-2）对人乳腺癌淋巴管形成的影响。方法1998年11月至2002年3月行手术治疗并经病理证实的乳腺癌患者94例，随访83例，失访11例。免疫组织化学方法检测COX-2、血管内皮生长因子-C（VEGF—C）及D2-40在乳腺癌中的表达。逆转录聚合酶链式反应（RT-PCR）和Western印迹法分别检测加入不同浓度COX-2抑制剂尼美舒利后VEGF-CmRNA及蛋白的变化。Western印迹法检测加入外源性前列腺素E2（PGE2）和曲妥珠单抗后VEGF—C蛋白的变化。结果46．8％的乳腺癌组织呈COX-2高表达，51．1％呈VEGF—C高表达。COX-2与VEGF—C（P〈0．01）、淋巴管密度（P=0．032）和淋巴结转移（P＝0．035）呈正相关，与乳腺癌患者的无病生存率（P=0．010）和总生存率（P＝0．040）呈负相关。尼美舒利以剂量依赖性方式下调VEGF-CmRNA及蛋白表达，而PGE2上调其蛋白表达。曲妥珠单抗可显著降低VEGF—C的蛋白表达。结论COX-2可通过上调VEGF—C的表达，促进乳腺癌的淋巴管形成和淋巴结转移，并影响乳腺癌患者的预后。

Objective To study the effect of cyclooxygenase-2 （COX-2） on lymphangiogenasis in breast cancer. Methods By the means of immunohistochemistry, COX-2, vascular endothelial growth factor-C （VEGF-C） and D2-40 were examinated in the tissue samples of primary tumors from 94 patients underwent surgical resections for breast cancer from November 1998 to March 2002. Eighty-three patients were followed-up. The expressions of VEGF-C mRNA and protein were detected by reverse transcription polymerase chain reaction （RT-PCR） and Western blot in MDA-MB-231 cell lines by the treatment of selective COX-2 inhibitor Nimesulide at different doses. The expressions of VEGF-C protein were evaluated in MDA-MB-231 cells treated by PGE2 （ 1μg/ml） and Trastuzumab （ 1 μg/ml）, respectively. Results COX-2 over-expression was observed in 46. 8% of surgical specimens （ 44/94 ）, while VEGF-C over- expression occurred in 51.1% of tumor samples （48/94）. COX-2 was strongly correlated with VEGF-C expression（P 〈 0. 01 ）, microlymphatic vessels （ P = 0. 032 ） and metastatic lymph nodes （ P = 0. 035 ）. Patients with COX-2 positive tumors had a significant shorter survival time than those with negative tumors did, including disease-free survival （ P = 0. 010） and overall survival （ P= 0. 040）. Nimesulide could down- regulate the expressions of VEGF-C mRNA and protein in a does-dependent manner, while PGE2 could up- regulate the expressions. The expression of VEGF-C protein up-regulated by PGE2 treatment was decreased by Trastuzumab. Conclusions COX-2 over-expression can up-regulate the expression of VEGF-C. VEGF-C might promote lymph node metastasis by a lymphangiogenic pathway, then affect the prognosis of the patients with breast cancer.