Abstract
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. 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. 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. The Id1-IGF-II-IGF-IR-AKT signaling cascade plays an important role in esophageal cancer progression. Blockade of IGF-II/IGF-IR signaling has therapeutic potential in the management of esophageal cancer.
Highlights
Tumor-secreted growth factors can affect tumor microenvironment [1, 2], as well as stimulate the cancer cells themselves to proliferate and develop a more malignant phenotype in an autocrine manner [3,4,5,6]
We investigated the involvement of autocrine mechanisms in the induction of phosphoinositide 3-kinase (PI3K)/AKT by Id1
We found that the HKESC-3-Id1 conditioned medium (CM) induced protein expression of phosphorylated AKT (p-AKT) and cell proliferation in the parental HKESC-3 cells; the AKT activation was attenuated when the proteins in the conditioned medium were denatured (Fig. 1A and B)
Summary
Tumor-secreted growth factors can affect tumor microenvironment [1, 2], as well as stimulate the cancer cells themselves to proliferate and develop a more malignant phenotype in an autocrine manner [3,4,5,6]. A variety of growth factors and cytokines exert their effects on cancer cells by activating the membrane-associated phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, which regu-. We previously reported that the PI3K/AKT signaling pathway can be induced by ectopic expression of Id1 (inhibitor of differentiation or DNA binding), leading to increased proliferation and survival of esophageal cancer cells [7]. The Id1 protein is a helix-loop-helix protein [8] found to be overexpressed in many types of human cancer, including esophageal squamous cell carcinoma Our tissue microarray (TMA) study established that dysregulated Id1 expression is associated with tumor invasion and metastasis in ESCC [10]
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