胆管癌组织中α_1-肾上腺素受体表达的临床意义及其对胆管癌细胞增殖的影响
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摘要
目的
近来国内外大量研究发现,许多肿瘤上存在着自主神经受体特别是交感神经受体的异常分布,结果提示去甲肾上腺素等一些经典的神经递质与肿瘤的生长和侵袭有密切关系。
我们在对胆管癌细胞的研究中发现,人胆管癌细胞对神经纤维具有亲嗜性,神经浸润转移是胆管癌的重要特点之一,也是导致胆管癌病人术后复发率高和预后差的重要原因。肿瘤组织发生神经及神经周围浸润的机制至今尚不明朗,过去认为主要是神经周围间隙中张力较低,易于肿瘤生长;最近的研究表明肿瘤微环境中的神经递质以及受体的影响在肿瘤的嗜神经性上可能起重要作用。近年来的众多实验中已经证实β2-肾上腺素受体对卵巢癌、结肠癌及肺癌细胞的增殖及定向趋化中具有重要的影响。同时,在肝胆管系统肿瘤的研究中发现,NE可以通过激动α1-肾上腺素受体促进肝癌细胞增殖,鉴于α1-肾上腺素受体在动脉平滑肌细胞、前列腺癌细胞中被发现具有促细胞增殖或凋亡的能力,提示该受体在细胞生长过程中具有重要作用,因此我们研究了α1-肾上腺素受体、β2-肾上腺素受体与胆管癌临床病理因素的关联性,并观察了肾上腺素对胆管癌细胞增殖能力的影响,旨在证明交感神经递质及其受体参与胆管癌生长和转移的可能性。
方法
为了验证我们的假想,本实验设计如下:首先,在胆管癌组织标本上,应用SABC免疫组织化学法检测α1-肾上腺素受体、β2-肾上腺素受体在胆管癌组织的表达,并评价其临床意义;然后用去甲肾上腺素(NE)以及非选择性、选择性肾上腺素受体阻滞剂酚妥拉明、哌唑嗪处理胆管癌QBC939细胞,用Alamar-blue法观察细胞的增殖变化,采用检验分析观察结果,评价去甲肾上腺素是否具有促进胆管癌QBC939细胞增殖的能力,并初步观察去甲肾上腺素在胆管癌细胞上的作用位点。
结果
1.α1-肾上腺素受体的高表达与淋巴结转移以及胆管癌部位呈明显相关,肿瘤淋巴结转移组中α1-肾上腺素受体表达强阳性率(68%)明显高于未转移组(9.1% , P <0.05) ,且α1-肾上腺素受体的表达与胆管癌的部位存在显著相关性(P < 0.05)。
2.β2-肾上腺素受体在所检测的组织标本及人胆管癌细胞株QBC939中未见明显阳性表达。
3.去甲肾上腺素促进胆管癌细胞株QBC939的增殖,且随着时间的延长,促增殖作用逐渐减弱,该作用由α1-肾上腺素受体介导,在非选择性α-肾上腺素受体及选择性α1-肾上腺素受体阻滞剂(酚妥拉明及哌唑嗪)存在的情况下可消除NE对胆管癌细胞的促增殖作用。
结论
1.与正常胆管组织相比较,以神经周围组织间隙转移为独立重要转移途径的胆管癌中存在着α1-肾上腺素受体的高表达,并且在发生淋巴转移及远处转移的病例中,其强阳性表达率显著高于未发生淋巴转移组,提示α1-肾上腺素受体与胆管癌转移有密切关系,此外β2-肾上腺素受体在胆管癌组织及胆管癌QBC939细胞无明显表达。
2.通过胆管癌细胞增殖实验发现,去甲肾上腺素可以通过α1-肾上腺素受体促进胆管癌细胞增殖,而α1-肾上腺素受体阻滞剂酚妥拉明及哌唑嗪单独作用于胆管癌细胞,对细胞增殖无抑制作用,提示胆管癌细胞上的α1-肾上腺素受体参与了NE对胆管癌细胞的促增殖过程。
Purpose: Recently, increasing evidences suggested that norepinephrine(NE) and its receptors were involved in cancer invasion and metastasis,meanwhile,many studys found the abnormal distribution of adrenergic receptors in a veriaty of tumors such as oophoroma and liver cancer. In our previous study, the neural pro-tropic of cholangiocarcinoma (CC) was revealed. And some other researches suggest thatα1-adrenergic receptor might play an important role in proliferation and apoptosis of various tumors such as prostate cancer and colon cancer. So we investigated the correlation between the expression ofα1-adrenergic receptor and its biologic behavior in cholangiocarcinomas. As previous studies have proved that NE could promote the proliferation of hepatoma carcinoma cell by stimulating theα1-adrenergic receptor, so we observed the effect of NE in the proliferation process of bile duct carcinoma cell line (QBC939), which could probobaly imply the participation ofα1-adrenergic receptor in the proliferation and metastasis of cholangiocarcinoma.
Experimental Design: In the first part of the experiment,α1-adrenergic receptor was detectived with the immunohistochemical staining in the samples of cholangiocarcinoma, their correlation and clinicopathological significance was accessed by statistical methods . In the second part of the experiment, The cells of QBC939 cell line were cultured and exposed to NE with or without the presence ofα1-adrenergic receptor’s antagonists. Alamar-blue assay was employed to determine the proliferation of the cell line and then the results were analyzed.
Results:
1. The percentage of the positive and high positive expression rate ofα1-adrenergic receptor in 36 cases of cholangiocarcinoma were 86.1 % and 50 % , respectively. There were significant differences ofα1-adrenergic receptor ( P < 0.05) between the different lacations of cholangiocarcinoma. The metastatic rate of tumor stained positively forα1-adrenergic receptor was higher than in that with negative staining ( P < 0.05).
2. NE could increase the proliferative response in QBC939, and the effect could be reduced by the antagonists ofα1-adrenergic receptor such as phentolamine and prazosin. Besides, the antagonists alone wouldn’t restrain the proliferation of QBC939.
Conclusion:
1. Compared with the normal bile duct, the CC cell had a high expression ofα1-adrenergic receptor, and its strong positive expression was observed mostly in the cases which had lymph node metastasis or distant metastasis, suggestingα1-adrenergic receptor participates the process of cholangiocarcinoma’s metastasis.
2. Take advantage of the present experimental conditions,β2-adrenergic receptor had a low expression on both normal bile duct and CC.
3. From the study of NE and QBC939, NE was found the ability of promoting the proliferation of QBC939. Furthermore,α1-adrenergic receptor, which was abnormal distributed in cholangiocarcinoma, may play a critical role in the process.
近来国内外大量研究发现,许多肿瘤上存在着自主神经受体特别是交感神经受体的异常分布,结果提示去甲肾上腺素等一些经典的神经递质与肿瘤的生长和侵袭有密切关系。
我们在对胆管癌细胞的研究中发现,人胆管癌细胞对神经纤维具有亲嗜性,神经浸润转移是胆管癌的重要特点之一,也是导致胆管癌病人术后复发率高和预后差的重要原因。肿瘤组织发生神经及神经周围浸润的机制至今尚不明朗,过去认为主要是神经周围间隙中张力较低,易于肿瘤生长;最近的研究表明肿瘤微环境中的神经递质以及受体的影响在肿瘤的嗜神经性上可能起重要作用。近年来的众多实验中已经证实β2-肾上腺素受体对卵巢癌、结肠癌及肺癌细胞的增殖及定向趋化中具有重要的影响。同时,在肝胆管系统肿瘤的研究中发现,NE可以通过激动α1-肾上腺素受体促进肝癌细胞增殖,鉴于α1-肾上腺素受体在动脉平滑肌细胞、前列腺癌细胞中被发现具有促细胞增殖或凋亡的能力,提示该受体在细胞生长过程中具有重要作用,因此我们研究了α1-肾上腺素受体、β2-肾上腺素受体与胆管癌临床病理因素的关联性,并观察了肾上腺素对胆管癌细胞增殖能力的影响,旨在证明交感神经递质及其受体参与胆管癌生长和转移的可能性。
方法
为了验证我们的假想,本实验设计如下:首先,在胆管癌组织标本上,应用SABC免疫组织化学法检测α1-肾上腺素受体、β2-肾上腺素受体在胆管癌组织的表达,并评价其临床意义;然后用去甲肾上腺素(NE)以及非选择性、选择性肾上腺素受体阻滞剂酚妥拉明、哌唑嗪处理胆管癌QBC939细胞,用Alamar-blue法观察细胞的增殖变化,采用检验分析观察结果,评价去甲肾上腺素是否具有促进胆管癌QBC939细胞增殖的能力,并初步观察去甲肾上腺素在胆管癌细胞上的作用位点。
结果
1.α1-肾上腺素受体的高表达与淋巴结转移以及胆管癌部位呈明显相关,肿瘤淋巴结转移组中α1-肾上腺素受体表达强阳性率(68%)明显高于未转移组(9.1% , P <0.05) ,且α1-肾上腺素受体的表达与胆管癌的部位存在显著相关性(P < 0.05)。
2.β2-肾上腺素受体在所检测的组织标本及人胆管癌细胞株QBC939中未见明显阳性表达。
3.去甲肾上腺素促进胆管癌细胞株QBC939的增殖,且随着时间的延长,促增殖作用逐渐减弱,该作用由α1-肾上腺素受体介导,在非选择性α-肾上腺素受体及选择性α1-肾上腺素受体阻滞剂(酚妥拉明及哌唑嗪)存在的情况下可消除NE对胆管癌细胞的促增殖作用。
结论
1.与正常胆管组织相比较,以神经周围组织间隙转移为独立重要转移途径的胆管癌中存在着α1-肾上腺素受体的高表达,并且在发生淋巴转移及远处转移的病例中,其强阳性表达率显著高于未发生淋巴转移组,提示α1-肾上腺素受体与胆管癌转移有密切关系,此外β2-肾上腺素受体在胆管癌组织及胆管癌QBC939细胞无明显表达。
2.通过胆管癌细胞增殖实验发现,去甲肾上腺素可以通过α1-肾上腺素受体促进胆管癌细胞增殖,而α1-肾上腺素受体阻滞剂酚妥拉明及哌唑嗪单独作用于胆管癌细胞,对细胞增殖无抑制作用,提示胆管癌细胞上的α1-肾上腺素受体参与了NE对胆管癌细胞的促增殖过程。
Purpose: Recently, increasing evidences suggested that norepinephrine(NE) and its receptors were involved in cancer invasion and metastasis,meanwhile,many studys found the abnormal distribution of adrenergic receptors in a veriaty of tumors such as oophoroma and liver cancer. In our previous study, the neural pro-tropic of cholangiocarcinoma (CC) was revealed. And some other researches suggest thatα1-adrenergic receptor might play an important role in proliferation and apoptosis of various tumors such as prostate cancer and colon cancer. So we investigated the correlation between the expression ofα1-adrenergic receptor and its biologic behavior in cholangiocarcinomas. As previous studies have proved that NE could promote the proliferation of hepatoma carcinoma cell by stimulating theα1-adrenergic receptor, so we observed the effect of NE in the proliferation process of bile duct carcinoma cell line (QBC939), which could probobaly imply the participation ofα1-adrenergic receptor in the proliferation and metastasis of cholangiocarcinoma.
Experimental Design: In the first part of the experiment,α1-adrenergic receptor was detectived with the immunohistochemical staining in the samples of cholangiocarcinoma, their correlation and clinicopathological significance was accessed by statistical methods . In the second part of the experiment, The cells of QBC939 cell line were cultured and exposed to NE with or without the presence ofα1-adrenergic receptor’s antagonists. Alamar-blue assay was employed to determine the proliferation of the cell line and then the results were analyzed.
Results:
1. The percentage of the positive and high positive expression rate ofα1-adrenergic receptor in 36 cases of cholangiocarcinoma were 86.1 % and 50 % , respectively. There were significant differences ofα1-adrenergic receptor ( P < 0.05) between the different lacations of cholangiocarcinoma. The metastatic rate of tumor stained positively forα1-adrenergic receptor was higher than in that with negative staining ( P < 0.05).
2. NE could increase the proliferative response in QBC939, and the effect could be reduced by the antagonists ofα1-adrenergic receptor such as phentolamine and prazosin. Besides, the antagonists alone wouldn’t restrain the proliferation of QBC939.
Conclusion:
1. Compared with the normal bile duct, the CC cell had a high expression ofα1-adrenergic receptor, and its strong positive expression was observed mostly in the cases which had lymph node metastasis or distant metastasis, suggestingα1-adrenergic receptor participates the process of cholangiocarcinoma’s metastasis.
2. Take advantage of the present experimental conditions,β2-adrenergic receptor had a low expression on both normal bile duct and CC.
3. From the study of NE and QBC939, NE was found the ability of promoting the proliferation of QBC939. Furthermore,α1-adrenergic receptor, which was abnormal distributed in cholangiocarcinoma, may play a critical role in the process.
引文
1 Schuller H,Porter B,Riechert A. Beta-adrenergic modulation of NNK-induced lung cancinogenesis in hamsters.J Cancer Res Clin Oncol,2000,126(11):624-630.
2 Drell T,Joseph J,Lang K,et al. Effects of neurotransmitters on the Chemokinesis and chemotaxis of MDA-MB-468 human breast cancinoma cells.Breast Cancer Res Treat,2003,80(l):63-70.
3 Masur K,Niggemann B,Zanker KS,et al, Norepinephrine-induced migration of SW480 colon carcinoma cells is inhibited by beta-blockers.Cancer Res,200l,61(7):2866-2869.
4 Hasegawa H, Saiki L.Psychosocial stress augments tumor development through beta-adrenergic activation in mice.Jpn J Cancer Res,2002,93(7):729-735.
5 Bevilacqua M, Norbiato G, Chebat E, Baldi G, Bertora P, Regalia E, Colella G, Gennari L, Vago T.Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma. Cancer. 1991 May 15;67(10):2543-51.
6李立,陈刚,郭永章,神经递质对肝细胞增殖的影响,中国普外基础与临床杂志2002年04(9) 0238-04。
7郑秀海,马宽生,王曙光,人胆管癌细胞神经周围浸润模型的构建和初步观察,消化外科2005年04(5)354-356。
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17王曙光,韩本立,段恒春。肝外胆管癌细胞的建立。中华实验外科杂志。1997;14(2):67-68。
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25. Drell T,Joseph J,Lang K,et al. Effects of neurotransmitters on the Chemokinesis and chemotaxis of MDA-MB-468 human breast cancinoma cells.Breast Cancer Res Treat,2003,80(l):63-70.
26. Lang K, Drell TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS,et al. Induction of a metastatogenic tumor cell type by neurotransmittersn and its pharmacological inhibition by established drugs. Int J Cancer 2004; 112:231–238.
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31.李立,陈刚,郭永章,神经递质对肝细胞增殖的影响,中国普外基础与临床杂志2002年04(9) 0238-04.
2 Drell T,Joseph J,Lang K,et al. Effects of neurotransmitters on the Chemokinesis and chemotaxis of MDA-MB-468 human breast cancinoma cells.Breast Cancer Res Treat,2003,80(l):63-70.
3 Masur K,Niggemann B,Zanker KS,et al, Norepinephrine-induced migration of SW480 colon carcinoma cells is inhibited by beta-blockers.Cancer Res,200l,61(7):2866-2869.
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5 Bevilacqua M, Norbiato G, Chebat E, Baldi G, Bertora P, Regalia E, Colella G, Gennari L, Vago T.Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma. Cancer. 1991 May 15;67(10):2543-51.
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31.李立,陈刚,郭永章,神经递质对肝细胞增殖的影响,中国普外基础与临床杂志2002年04(9) 0238-04.