Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance—Implications for IGF-II and IGF-IR–Targeted Therapy

Abstract

Purpose: To investigate the autocrine/endocrine role of Id1-induced insulin-like growth factor-II (IGF-II) in esophageal cancer, and evaluate the potential of IGF-II-and IGF-type I receptor (IGF-IR)-targeted therapies.Experimental Design: Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing esophageal cancer cells. In vitro and in vivo assays were performed to confirm the induction of IGF-II by Id1, and to study the autocrine and endocrine effects of IGF-II in promoting esophageal cancer progression. Human esophageal cancer tissue microarray was analyzed for overexpression of IGF-II and its correlation with that of Id1 and phosphorylated AKT (p-AKT). The efficacy of intratumorally injected IGF-II antibody and intraperitoneally injected cixutumumab (fully human monoclonal IGF-IR antibody) was evaluated using in vivo tumor xenograft and experimental metastasis models.Results: Id1 overexpression induced IGF-II secretion, which promoted cancer cell proliferation, survival, and invasion by activating AKT in an autocrine manner. Overexpression of IGF-II was found in 21 of 35 (60%) esophageal cancer tissues and was associated with upregulation of Id1 and p-AKT. IGF-II secreted by Id1-overexpressing esophageal cancer xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells. Targeting IGF-II and IGF-IR had significant suppressive effects on tumor growth and metastasis in mice. Cixutumumab treatment enhanced the chemosensitivity of tumor xenografts to fluorouracil and cisplatin.

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

“…Besides upregulation of thymidylate synthase (TS; ref. 1), which is an essential enzyme for de novo synthesis of thymidylates and a critical target of 5-FU (2, 3) and activation of AKT (4), we have obtained novel evidence in the present study that there was significant increase in the expression of E2F1, inhibitor of DNA binding 1 (Id1), and insulin-like growth factor 2 (IGF2) proteins in these 5-FU-resistant (FR) cell lines. The increase of E2F1 in the FR cell lines was not surprising because E2F1 has been reported to increase the resistance of cancer cells to 5-FU and to directly induce the transcription and expression of thymidylate synthase (5,6).…”

“…The E2F1 immunostaining in the TMA was assessed using a grading system on the basis of the percentage of positive nuclei (13): 0, no nuclear staining; 1, <10% positive staining; 2, 10%-50%; 3, >50%. Immunostaining of IGF2 was performed with an anti-human IGF2 antibody (#AF-292-NA) from R&D Systems and evaluated as described previously (1). Specimens assigned scores of 0 to 1 were considered weak, whereas scores 2 to 3 were considered strong.…”

“…However, the functions of Id1 and IGF2 in 5-FU resistance have not been reported. Our previous study showed that Id1 overexpression upregulates IGF2 in a variety of cancer cells and that blockade of insulin-like growth factor type 1 receptor (IGF1R), which is the main receptor that mediates the biologic functions of IGF2, can inhibit the PI3K/AKT pathway and sensitize esophageal cancer cells to 5-FU treatment (1). Whether there is a causal link between increased Id1/IGF2 and E2F1 upregulation in 5-FU chemoresistance warrants investigation.…”

IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress

“…Previous reports suggest that activation of the IGF/insulin signaling is limited by feedback inhibition, which is mediated by the PI3K-AKT-mTOR pathway. Activated S6K phosphorylates IRS proteins, which induces degradation of IRS proteins, A very recent report suggests the direct implication of IGF2 in the emergence of therapeutic resistance in cancer (33). Overexpression of IGFs and IGFRs is commonly observed in human osteosarcoma and is implicated in disease pathogenesis (34)(35)(36)(37).…”

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner

“…ID1 expression correlates directly with tumor invasion, metastasis, and poor prognosis in ESCC (6,11,12). Notably, ID1 was involved in chemotherapy and radiotherapy resistance in human cancers including pancreatic adenocarcinoma, breast cancer, lung cancer, colorectal cancer, and esophageal cancer and becomes a new potential therapeutic target (13)(14)(15)(16)(17). ID1 is transactivated in the context of 5-fluorouracil therapy, which provides a resource for future study addressing the molecular mechanisms of chemotherapy in breast cancer (18).…”