TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis
TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis
复制标题
DOI：
10.1006/jsre.2001.6318
复制
发表时间：
2002-01-01
影响因子：
2.2
通讯作者：
Rosemurgy, AS
中科院分区：
文献类型：
--
作者：
Bloomston, M;Shafii, S;Rosemurgy, AS
背景。基质金属蛋白酶（MMP）参与胰腺癌的进展。本研究旨在确定 MMP 天然组织抑制剂 (TIMP-1) 过度表达对胰腺癌细胞生长、转移和血管生成的影响。方法。对低分化的人胰腺癌细胞系 (PANC-1) 进行基因转染以过表达 TIMP-1（CD-1 细胞）。将一百万个 PANC-1 或 CD-1 细胞皮下注射 (N = 20) 或原位注射 (N = 20) 到 40 只裸鼠中。 120天时处死小鼠。 CD-1细胞过度表达TIMP-1在注射前和尸检后得到证实。尸检后进行免疫组织化学染色，以评估肿瘤的 TIMP-1、MMP-2、细胞凋亡 (TUNEL) 和血管生成 (CD-31)。 结果。与 PANC-1 细胞的肿瘤相比，CD-1 细胞的肿瘤植入的可能性较小（35% vs 70%，P = 0.05），并且生长到较小的尺寸（0.5 g +/- 0.03 vs 1.5 g +/- 0.20，P < 0.001）。同样，皮下CD-1肿瘤出现晚于PANC-1肿瘤（45天+/-2.0 vs 27天+/-2.2，P<0.001）。原位 CD-1 肿瘤的转移率低于 PANC-1 肿瘤（20% vs 60%，P < 0.05）。 MMP-2 表达在 PANC-1 和 CD-1 肿瘤中相似，而 CD-1 肿瘤相对于 PANC-1 肿瘤，TIMP-1 表达增加，细胞凋亡增加，血管生成减少。结论。 TIMP-1 过表达会减少胰腺癌细胞的植入、生长、转移和血管生成，同时增加肿瘤细胞凋亡，所有这些都不会改变 MMP-2 的产生。这项研究证明了 TIMP-1 作为胰腺癌基因治疗靶点的潜在作用。 (C) 2002 年爱思唯尔科学。
Background. Matrix metalloproteinases (MMPs) are involved in pancreatic cancer progression. This study was undertaken to determine the effects of overexpression of a natural tissue inhibitor of MMP (TIMP-1) on pancreatic cancer cell growth, metastasis, and angiogenesis.Methods. A poorly differentiated human pancreatic cancer cell line (PANC-1) underwent gene transfection to overexpress TIMP-1 (CD-1 cells). One million PANC-1 or CD-1 cells were injected into 40 nude mice subcutaneously (N = 20) or orthotopically (N = 20). Mice were sacrificed at 120 days. TIMP-1 overexpression by CD-1 cells was confirmed prior to injection and after necropsy. Immunohistochemical staining was undertaken after necropsy to evaluate tumors for TIMP-1, MMP-2, apoptosis (TUNEL), and angiogenesis (CD-31).Results. Tumors of CD-1 cells were less likely to implant (35% vs 70%, P = 0.05) and grew to smaller size (0.5 g +/- 0.03 vs 1.5 g +/- 0.20, P < 0.001) than tumors of PANC-1 cells. As well, subcutaneous CD-I tumors appeared later than PANC-1 tumors (45 days +/- 2.0 vs 27 days +/- 2.2, P < 0.001). Orthotopic CD-1 tumors metastasized less often than PANC-1 tumors (20% vs 60%, P < 0.05). MMP-2 expression was similar in PANC-1 and CD-1 tumors, while CD-1 tumors showed increased TIMP-1 expression, increased apoptosis, and decreased angiogenesis relative to PANC-1 tumors.Conclusions. TIMP-1 overexpression reduces pancreatic cancer cell implantation, growth, metastasis, and angiogenesis, while increasing tumor apoptosis, all without altering MMP-2 production. This study demonstrates the potential role of TIMP-1 as a target in gene therapy for pancreatic cancer. (C) 2002 Elsevier Science.