Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis
Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis
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DOI：
10.1158/0008-5472.can-03-3235
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发表时间：
2004-06-15
期刊：
影响因子：
11.2
通讯作者：
Matsuura, N
中科院分区：
文献类型：
--
作者：
Shintani, Y;Higashiyama, S;Matsuura, N
“解整合素和金属蛋白酶”(ADAM) 家族有助于调节细胞-细胞和细胞-基质相互作用，这是恶性肿瘤的关键决定因素。为了确定转移与 ADAM 蛋白之间的关系，我们比较了高度转移至脑或骨的 EBC-1 肺癌细胞系亚系中 ADAM9、-10、-12、-15 和 -17 的 mRNA 水平。高度脑转移亚系中的 ADAM9 mRNA 水平显着高于亲本或高度骨转移亚系。为了阐明 ADAM9 在脑转移中的作用，我们用全长 ADAM9 表达载体稳定转染 A549 和 EBC-1 细胞。与模拟转染子相比，ADAM9 过表达导致神经生长因子反应的侵袭能力增加、与脑组织的粘附增加以及整合素 α3 和 β1 亚基的表达增加。抗-β1单克隆抗体的施用减弱了侵袭和粘附活性的增加。向小鼠静脉注射 ADAM9 过表达的 A549 细胞，导致大脑中出现微转移灶，肺部出现多个转移集落。相比之下，给小鼠注射亲代和模拟转染的 A549 细胞会导致肺部肿瘤，但没有脑转移。这些结果表明，ADAM9过表达通过调节其他粘附分子和改变对生长因子的敏感性来增强非小细胞肺癌细胞的细胞粘附和侵袭，从而促进脑转移能力。
The "a disintegrin and metalloprotease" (ADAM) family contributes to regulation of the cell-cell and cell-matrix interactions that are critical determinants of malignancy. To determine the relationship between metastasis and ADAM proteins, we compared the mRNA levels of ADAM9, -10, -12, -15, and -17 in sublines of an EBC-1 lung cancer cell line that were highly metastatic to either brain or bone. ADAM9 mRNA levels were significantly higher in highly brain-metastatic sublines than in the parent or highly bone-metastatic sublines. To elucidate the role of ADAM9 in brain metastasis, we stably transfected A549 and EBC-1 cells with a full-length ADAM9 expression vector. Compared with mock-transfectants, ADAM9 overexpression resulted in increased invasive capacity in response to nerve growth factor, increased adhesion to brain tissue, and increased expression of integrin alpha3 and beta1 subunits. Administration of the anti-beta1 monoclonal antibody attenuated this increase in invasive and adhesive activity. Intravenous administration of ADAM9-overexpressing A549 cells to mice resulted in micrometastatic foci in the brain and multiple metastatic colonies in the lungs. In contrast, administration of parent and mock-transfected A549 cells to mice resulted in lung tumors without brain metastasis. These results suggest that ADAM9 overexpression enhances cell adhesion and invasion of non-small cell lung cancer cells via modulation of other adhesion molecules and changes in sensitivity to growth factors, thereby promoting metastatic capacity to the brain.