Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice.
Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice.
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DOI：
10.1186/1471-2407-10-67
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发表时间：
2010-02-24
期刊：
影响因子：
3.8
通讯作者：
Tamura M
中科院分区：
文献类型：
--
作者：
Doi C;Egashira N;Kawabata A;Maurya DK;Ohta N;Uppalapati D;Ayuzawa R;Pickel L;Isayama Y;Troyer D;Takekoshi S;Tamura M
胰腺癌是最具侵袭性的人类恶性肿瘤之一，预后非常差。为了研究血管紧张素II (Ang II) 2型受体（AT2）在宿主体内表达对胰腺癌生长的影响，我们研究了同基因野生型和AT2受体缺陷（AT2- ko）小鼠胰腺导管癌移植物的生长情况。采用体外和体内实验研究了基质细胞中AT2受体信号在小鼠胰腺癌细胞（PAN02）生长中的作用。采用Ki-67免疫染色法、TUNEL免疫染色法和血管性血癌因子免疫染色法分别监测肿瘤细胞增殖、凋亡和血管系统的变化。在共培养研究中，采用MTT细胞活力法测定细胞增殖。所有资料采用t检验，p < 0.05为显著。我们的研究结果表明，与对照野生型小鼠相比，AT2-KO小鼠皮下移植的小鼠胰腺导管癌细胞PAN02细胞（来源于C57/BL6株）的同种异种移植物的生长速度明显更快。肿瘤组织免疫组化分析显示，AT2-KO小鼠生长的异种移植物中Ki-67阳性细胞明显多于野生型小鼠。TUNEL法测定野生型小鼠细胞凋亡指数略高于AT2-KO小鼠。AT2-KO小鼠肿瘤血管数量明显高于野生型小鼠。体外共培养研究发现，转染AT2受体基因的野生型和AT2- ko小鼠源性成纤维细胞培养后，PAN02细胞的生长明显下降。AT2-KO小鼠肿瘤生长速度的加快可能与基质细胞中较高的VEGF生成有关。这些结果表明，Ang II通过调节宿主基质细胞的功能来调节胰腺癌细胞的生长；此外，Ang II AT2受体信号是胰腺癌细胞生长的负调控因子。这些发现表明，间质成纤维细胞中的AT2受体是胰腺癌化疗的潜在重要靶点。
Pancreatic cancer is one of the most aggressive human malignancies, with a very poor prognosis. To evaluate the effect of angiotensin II (Ang II) type 2 receptor (AT2) expression in the host's body on the growth of pancreatic carcinoma, we have investigated the growth of mouse pancreatic ductal carcinoma grafts in syngeneic wild type and AT2 receptor-deficient (AT2-KO) mice. The role of AT2 receptor-signaling in stromal cells on the growth of murine pancreatic carcinoma cells (PAN02) was studied using various in vitro and in vivo assays. In vivo cell proliferation, apoptosis, and vasculature in tumors were monitored by Ki-67 immunostaining, TUNEL assay, and von Willebrand factor immunostaining, respectively. In the co-culture study, cell proliferation was measured by MTT cell viability assay. All the data were analyzed using t-test and data were treated as significant when p < 0.05. Our results show that the growth of subcutaneously transplanted syngeneic xenografts of PAN02 cells, mouse pancreatic ductal carcinoma cells derived from the C57/BL6 strain, was significantly faster in AT2-KO mice compared to control wild type mice. Immunohistochemical analysis of tumor tissue revealed significantly more Ki-67 positive cells in xenografts grown in AT2-KO mice than in wild type mice. The index of apoptosis is slightly higher in wild type mice than in AT2-KO mice as evaluated by TUNEL assay. Tumor vasculature number was significantly higher in AT2-KO mice than in wild type mice. In vitro co-culture studies revealed that the growth of PAN02 cells was significantly decreased when grown with AT2 receptor gene transfected wild type and AT2-KO mouse-derived fibroblasts. Faster tumor growth in AT2-KO mice may be associated with higher VEGF production in stromal cells. These results suggest that Ang II regulates the growth of pancreatic carcinoma cells through modulating functions of host stromal cells; Moreover, Ang II AT2 receptor signaling is a negative regulator in the growth of pancreatic carcinoma cells. These findings indicate that the AT2 receptor in stromal fibroblasts is a potentially important target for chemotherapy for pancreatic cancer.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
卡托普利在人肾细胞癌的异种移植模型中抑制肿瘤生长。
影响因子：
8.8
作者：
Hii, SI;Nicol, DL;Gotley, DC;Thompson, LC;Green, MK;Jonsson, JR
通讯作者：
Jonsson, JR
影响因子：
37.3
作者：
Keleg, Shereen;Buchler, Peter;Ludwig, Roman;Buchler, Markus W;Friess, Helmut
通讯作者：
Friess, Helmut
影响因子：
5.1
作者：
Mazzolini, G;Narvaiza, I;Melero, I
通讯作者：
Melero, I
影响因子：
4.7
作者：
Fujita, M;Hayashi, I;Majima, M
通讯作者：
Majima, M