Nguyen Quang-Dé, Rodrigues Sylvie, Rodrigue Christelle M, Rivat Christine, Grijelmo Clara, Bruyneel Erik, Emami Shahin, Attoub Samir, Gespach Christian
Institut National de la Sante et de la Recherche Medicale U673, Université Pierre et Marie Curie-Paris 6, Molecular and Clinical Oncology of Solid Tumors, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
Mol Cancer Ther. 2006 Aug;5(8):2070-7. doi: 10.1158/1535-7163.MCT-06-0044.
We recently showed by DNA microarray analysis that vascular endothelial growth factor (VEGF) receptor (VEGFR) is expressed in HCT8/S11 human colon cancer cells, suggesting that several angiogenic factors may target colon cancer cells themselves. In this study, transcripts encoding the VEGF-165 and semaphorin 3A (Sema3A) receptors and coreceptors Flt-1, KDR/Flk-1, plexin A1, and neuropilins NP-1 and NP-2 were identified by reverse transcription-PCR in the human colon cancer cell lines HCT8/S11, HT29, HCT116, and PCmsrc. Collagen invasion induced by VEGF-165 and Sema3A in HCT8/S11 cells (EC(50), 0.4-1 nmol/L) required p42/44 mitogen-activated protein kinase and signaling through RhoA/Rho-kinase-dependent and -independent pathways, respectively. As expected, the VEGFR signaling inhibitor ZD4190 selectively abrogated the proinvasive activity of VEGF in collagen gels (IC(50), 10 nmol/L) and chick heart fragments. We identify a novel function for VEGF-165 and Sema3A as proinvasive factors for human colorectal cancer cells. Interestingly, oral administration of the single drug ZD4190 to athymic mice (50 mg/kg/d, once daily) inhibited by 70% the growth of HCT8/S11 tumor cell xenografts. Combinations between the src tyrosine kinase inhibitor M475271 and ZD4190 or cisplatin resulted in additive therapeutic activity against LNM35 human lung tumor xenografts. Our data have significant implications for new therapeutic approaches and individualized treatment targeting VEGFR and src signaling pathways in combination with established clinical drugs at primary tumors and distant metastases in colon and lung cancer patients.
我们最近通过DNA微阵列分析表明，血管内皮生长因子（VEGF）受体（VEGFR）在HCT8/S11人结肠癌细胞中表达，这表明几种血管生成因子可能靶向结肠癌细胞本身。在本研究中，通过逆转录PCR在人结肠癌细胞系HCT8/S11、HT29、HCT116和PCmsrc中鉴定出编码VEGF-165和信号素3A（Sema3A）受体及共受体Flt-1、KDR/Flk-1、丛状蛋白A1以及神经纤毛蛋白NP-1和NP-2的转录本。VEGF-165和Sema3A在HCT8/S11细胞中诱导胶原侵袭（半数有效浓度[EC(50)]，0.4 - 1 nmol/L）分别需要p42/44丝裂原活化蛋白激酶，并通过RhoA/ Rho激酶依赖性和非依赖性途径进行信号传导。正如预期的那样，VEGFR信号抑制剂ZD4190选择性地消除了VEGF在胶原凝胶（IC(50)，10 nmol/L）和鸡心脏碎片中的促侵袭活性。我们确定了VEGF-165和Sema3A作为人结肠癌细胞促侵袭因子的新功能。有趣的是，给无胸腺小鼠口服单一药物ZD4190（50 mg/kg/天，每日一次）可使HCT8/S11肿瘤细胞异种移植瘤的生长受到70%的抑制。src酪氨酸激酶抑制剂M475271与ZD4190或顺铂联合使用，对LNM35人肺肿瘤异种移植瘤具有相加的治疗活性。我们的数据对于针对VEGFR和src信号通路，结合已确立的临床药物，在结肠癌和肺癌患者的原发性肿瘤和远处转移中进行新的治疗方法和个体化治疗具有重要意义。
