Abstract 4361: Role of Id1-induced IGF2 in autocrine/endocrine promotion of esophageal cancer tumorigenesis and metastasis

Abstract

Abstract Esophageal cancer is the 7th leading cause of cancer death in Hong Kong. The disease is highly lethal (with a 5-year survival rate of ∼14%) because many cases go undetected until the disease is at an advanced stage. Understanding of the underlying mechanisms and the signaling pathways involved in esophageal tumorigenesis is the key to identify new molecular targets for intervention. Id1 (inhibitor of differentiation or DNA binding), a member of the helix-loop-helix (HLH) proteins, is overexpressed in many types of human cancer. Our previous reports provided the first evidence that Id1 activates the phosphatidylinositol-3-kinase (PI3K)/AKT pathway in esophageal squamous cell carcinoma (ESCC) cells, and that there is a positive correlation between Id1 and phosphorylated (p)-AKT expressions in clinical esophageal cancer specimens. We also demonstrated in experimental animal models that Id1 promotes tumor growth and metastasis through activation of PI3K/AKT. Increasing evidence suggests that growth factors secreted from cancer cells can play an important role in cancer progression by modulating the tumor microenvironment and the host systemic environment via autocrine, paracrine, and endocrine mechanisms. In this study, we found that Id1 induced the expression and secretion of IGF2 (insulin-like growth factor 2) in ESCC cells, and that this induction mediated the activation of PI3K/AKT in an autocrine manner. Knockdown of IGF2 in cancer cells or addition of IGF2 neutralizing antibody abrogated the effects of Id1 on proliferation, survival, and invasion of esophageal cancer cells. The mechanisms by which Id1 upregulates IGF2 were studied, and the results indicated that Id1 could protect IGF2 from ubiquitin-proteasomal degradation in ESCC cells. Immunohistochemical analysis of human esophageal cancer tissue microarray showed elevated IGF2 expression in ESCC, which correlated with increased Id1 and p-AKT expressions. Furthermore, our in vivo experiments showed that IGF2 secreted by Id1-overexpressing ESCC xenograft could instigate the growth of distant ESCC tumors, as well as promote metastasis of circulating ESCC cells. Targeting IGF2 with the use of neutralizing antibody had significant antitumor effects on esophageal cancer xenografts in mice. Our findings therefore support that the Id1-IGF2-PI3K/AKT signaling cascade plays an important role in esophageal cancer, and that Id1-overexpressing primary tumors may affect the host systemic environment and contribute to cancer progression. In conclusion, we have uncovered a novel mechanism in the role of Id1 in tumorigenesis which may have significant implications for the development of targeted therapy for esophageal cancer. [This study is supported by the Research Grants Council of the Hong Kong SAR, China (General Research Fund Project no. HKU 762610M)] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4361. doi:1538-7445.AM2012-4361