Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis
Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis
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DOI：
10.1158/0008-5472.can-06-0183
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Kuwano, Michihiko
中科院分区：
文献类型：
--
作者：
Maruyama, Yuichiro;Ono, Mayumi;Kuwano, Michihiko
Cap43是一种镍和钙诱导基因，也被称为N-myc下游调节基因1(A7DRG1)、DRG-1和rit42。另据报道，Cap43过表达可抑制某些恶性肿瘤的转移，但其确切作用尚不清楚。在本研究中，我们探讨了Cap43是如何调控胰腺癌肿瘤生长的。稳定表达Cap43的胰腺癌细胞株Cap43的生长速度与低表达的对照细胞相似。相比之下，Cap43过表达显示体内肿瘤生长速度显著下降。此外，观察到肿瘤诱导的血管生成明显减少。在Cap43高表达的胰腺癌细胞系中，基质金属蛋白酶-9的明胶溶解活性和侵袭能力明显降低。在Cap43过表达的细胞系中，基质金属蛋白酶-9和两种主要的血管生成因子血管内皮生长因子和白细胞介素8的表达也显著低于其亲代细胞系。65例胰腺导管腺癌组织中Cap43的表达与肿瘤微血管密度(P=0.0001)、肿瘤侵袭深度(P=0.0003)、组织学分级(P=0.0244)、总生存率(P=0.0062)显著相关。因此，Cap43可能在胰腺癌肿瘤间质血管生成的开关中起关键作用。
Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (A7DRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma.