Mechanism of development and progression of gastrointestinal cancer by analysis of insulirrlike growth factor system and extracelluar matrix degrading enzymes

胰岛素样生长因子（IGF）-I受体（IGF-IR）信号传导是胃肠道癌的致癌性和增殖所必需的。本研究旨在探讨手术切除的食管鳞状细胞癌（ESCC）中胰岛素样生长因子-IR和胰岛素样生长因子-II配体（IGF-II ligand）的表达与预后的关系。然后，我们评估了在体外使用显性负性IGF-IR（IGF-IR/dn）阻断IGF-IR信号传导在ESCC中的治疗效果。IGF-IR和IGF-II的表达分别在60%和50%的肿瘤中检测到，并且与进展和复发相关。在单因素和多因素分析中，肿瘤同时表达IGF-IR和IGF-II的患者预后最差。IGF-IR/dn通过阻断配体诱导的Akt激活抑制细胞增殖和运动，并上调化疗诱导的细胞凋亡。IGF-IR/IGF-II在食管鳞癌中的检测可能有助于预测复发和不良预后，并有助于选择患者接受IGF-IR靶向治疗。 ...更多信息 我们评估了一种新的IGF-IR酪氨酸激酶抑制剂NVP-AEW 541对胃肠道癌细胞的信号转导、增殖、存活和迁移的影响。在体外和裸鼠异种移植物中研究了NVP-AEW 541单独和与化疗的作用。我们还分析了NVP-AEW 541对胰岛素信号和IGF-IR与胰岛素受体之间的杂合受体形成的影响。NVP-AEW 541阻断IGF-IR的自磷酸化以及IGFs对Akt和ERK的激活，但不阻断胰岛素对Akt和ERK的激活。NVP-AEW 541在所有细胞系中以剂量依赖性方式抑制体外增殖和致瘤性。该药物作为单一药剂抑制肿瘤，并且当与应激物组合时，以剂量依赖性方式上调细胞凋亡，并抑制移动性。NVP-AEW 541增强了化疗对体外生长和诱导凋亡的影响。此外，NVP-AEW 541和化疗的组合对小鼠的肿瘤非常有效。因此，NVP-AEW 541可能在人胃肠道癌中具有显著的治疗效用，无论是单独使用还是与化疗联合使用。少

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. The association between the expression of IGF-IR and IGF-II ligand and prognosis was investigate in surgically resected esophageal squamous cell carcinoma (ESCC). We then assessed the therapeutic effect of blocking IGF-IR signaling using dominant negative IGF-IR (IGF-IR/dn) in ESCC in vitro. Expression of IGF-IR and IGF-II were detected in 60 and 50% of tumors, respectively, and were associated with the progression and recurrence. Patients with tumors expressing both IGF-IR and IGF-II had the worst prognosis in both single and multivariate analysis. IGF-IR/dn suppressed proliferation and motility as well as upregulating chemotherapy-induced apoptosis through blocking ligand-induced Akt activation. Detection of IGF-IR/IGF-II in ESCC may be useful for the prediction of recurrence and poor prognosis and for selecting patients for IGF-IR-targeted the … More rapy.We assessed the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541 on signal transduction, proliferation, survival, and migration in gastrointestinal cancer cells. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by IGFs, but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose dependent manner in all cell lines. The drug inhibited tumor as a single agent and when combined with stressors, up-regulated apoptosis in a dose dependent fashion, and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. Thus, NVP-AEW541 may have significant therapeutic utility in human gastrointestinal carcinomas, both alone and incombination with chemotherapy. Less