Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice
Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice
复制标题
DOI：
10.1677/erc.1.01100
复制
发表时间：
2006-03-01
影响因子：
3.9
通讯作者：
Bologna, M
中科院分区：
文献类型：
--
作者：
Angelucci, A;Gravina, GL;Bologna, M
表皮生长因子受体(EGF-R)的激活在促进前列腺癌(Pca)的增殖和侵袭中起着关键作用。吉非替尼(Iressa；ZD1839)是一种口服活性的EGF-R酪氨酸激酶抑制剂，在体外和体内都显示出对表达EGF-R的肿瘤具有重要的抗增殖活性。我们的目的是阐明吉非替尼在调节前列腺癌细胞转移扩散中的作用。通过体外实验和裸鼠心内注射评价吉非替尼对PC3细胞及其高转移亚系PCb2增殖和侵袭能力的影响。在裸鼠皮下或左心室内注射前列腺癌细胞，每日给药150 mg/kg，观察吉非替尼的体内抑制作用。虽然所有PCa细胞系的异种移植生长均受到抑制(约50%)，但与PC3细胞(47%)相比，高转移性PCb2亚系(81%)的骨转移形成受到抑制。体外比较分析表明，PCb2细胞对吉非替尼的侵袭能力较亲本PC3细胞更为敏感，但对其增殖率无明显影响。此外，PCb2细胞在体外对骨髓基质细胞条件培养液(BCM)的侵袭能力增强。同时加入0.1 ng/mlGefitinib，足以减少EGF和BCM共同作用下的侵袭细胞数。高侵袭性PCa亚系的分子特征表明，这种现象与uPA/uPAR轴的增加有关，而与EGF-R的表达无关。综上所述，我们的数据提示吉非替尼作为一种治疗药物可能被用于控制前列腺癌向骨扩散。
The activation of epidermal growth factor receptor (EGF-R) plays a key role in the promotion of proliferation and invasion in prostatic carcinoma (PCa). Gefitinib (Iressa; ZD1839), an orally active EGF-R tyrosine kinase inhibitor, has shown an important anti-proliferative activity in tumors expressing EGF-R both in vitro and in vivo. Our aim was to elucidate the role of gefitinib in the modulation of the metastatic spread of PCa cells. The therapeutic role of gefitinib was investigated by evaluating the proliferative and invasive ability of the PCa cell line PC3 and of its high metastatic sub-line, PCb2, by in vitro assays and intracardiac injection in nude mice. The inhibitory effect of gefitinib was tested in vivo by injecting PCa cells subcutaneously or in the left ventricle of nude mice and by administrating daily 150 mg/kg of gefitinib. While xenograft growth was equally reduced in all PCa lines (about 50%), the bone metastasis formation was inhibited especially for the high metastatic PCb2 sub-line (81%) in comparison to PC3 cells (47%). The comparative in vitro analysis among PCa cell lines showed that PCb2 cells were more sensitive to the inhibitory effect of gefitinib in their invasive ability compared to parental PC3 cells but not in their proliferation rate. Moreover, PCb2 cells demonstrated an increased invasive ability in vitro in response to bone stromal cell conditioned medium (BCM). The simultaneous presence of 0.1 ng/ml gefitinib was sufficient to reduce the number of invaded cells in the presence of both EGF and BCM. The molecular characterization of the highly aggressive PCa sub-lines demonstrated that this phenomenon was associated with an increment in uPA/uPAR axis but not in EGF-R expression. In conclusion, our data suggest that the use of gefitinib as a therapeutic agent may be indicated in the control of PCa spreading to bone.