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

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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