The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer
The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer
复制标题
DOI：
10.3892/ijo_00000733
复制
发表时间：
2010-10-01
影响因子：
5.2
通讯作者：
Masaki, Tsutomu
中科院分区：
文献类型：
--
作者：
Morishita, Asahiro;Gong, Jian;Masaki, Tsutomu
一些研究已经报道，活化的受体酪氨酸激酶（RTK）在结肠癌中高度表达，并且可以促进肿瘤生长和存活。然而，关于RTK在结肠癌中的功能和信号传导的信息很少。在本研究中，我们进行了蛋白质阵列技术，以确定在结肠癌中激活的各种RTK的表达状态相比，正常的结肠细胞和组织。在42种不同的磷酸化-RTK中，5种（ErbB 2、FGFR 1、FGFR 2a、FGFR 3和MSPR）在Caco-2、SW 480、WiDr、Lovo结肠癌细胞系和癌组织中被激活。为了确定RTKs，特别是ErbB 2的抑制作用，用ErbB 2靶向药物曲妥珠单抗单独或与5-氟尿嘧啶（5-FU）联合治疗携带异种移植肿瘤的无胸腺裸鼠。与5-FU单独治疗相似，曲妥珠单抗抑制结肠癌的生长。与单独使用5-FU或单独使用曲妥珠单抗治疗相比，曲妥珠单抗和5-FU联合治疗可显著抑制肿瘤生长。此外，还通过磷酸化MAPK蛋白阵列分析异种移植肿瘤。单独使用5-FU和曲妥珠单抗可抑制Akt 3/PKB γ的活性，表明曲妥珠单抗可通过ErbB 2-Akt 3/PKB γ信号传导抑制结肠癌生长。这些数据表明，ErbB 2可能是结肠癌治疗的重要候选药物，在5-FU治疗中加入曲妥珠单抗可能会增加结肠癌患者的临床应答。因此，通过蛋白质阵列分析磷酸化RTK表达作为一种有用的工具，可能会为结肠癌患者个体识别新的治疗方法。
Several studies have reported that activated receptor tyrosine kinases (RTKs) are highly expressed in colon cancer and may promote tumor growth and survival. However, there is little information available as to the function and signaling of RTKs in colon cancers. In the present study, we performed protein array technology to determine the expression status of various RTKs that are activated in colon cancer compared to normal colonic cells and tissues. Of the 42 different phospho-RTKs, 5 (ErbB2, FGFR1, FGFR2a, FGFR3 and MSPR) were activated in Caco-2, SW480, WiDr, Lovo colon cancer cell lines and cancerous tissues. In order to determine the effect of inhibition of RTKs, especially ErbB2, athymic nude mice bearing xenograft tumors were treated with the ErbB2-targeting drug trastuzumab alone, or in combination with 5-Fluorouracil (5-FU). Similar to the treatment of 5-FU alone, trastuzumab suppressed the growth of colon cancer. Combination therapy of trastuzumab and 5-FU inhibited tumor growth significantly compared to the treatment of 5-FU alone or trastuzumab alone. In addition, xenograft tumors were also analyzed by phospho-MAPK protein array. The activity of Akt3/PKB gamma was inhibited with 5-FU alone and trastuzumab, indicating that trastuzumab may inhibit colon cancer growth through ErbB2-Akt3/PKB gamma signaling. These data demonstrate that ErbB2 could be an important candidate for colon cancer therapy and the addition of trastuzumab to 5-FU therapy might augment the clinical response in colon cancer patients. Therefore, the analysis of phospho-RTK expression by protein array as a useful tool might identify novel therapies for individual patients with colon cancer.