The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma

Insulin-like growth factor-I receptor (IGF-IR) signaling is essential for tumor development and carcinogenesis but remains understudied in human esophageal cancer. This malignancy has one of the poorest prognoses and comprises two main histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previously, we reported that IGF axis detection could predict recurrence and poor prognosis in ESCC. Additionally, we demonstrated the therapeutic efficacy of recombinant adenoviruses expressing dominant-negative IGF-IR (Ad-IGF-IR/dn) in several gastrointestinal cancers.
This study aims to develop targeted IGF-IR therapeutics and evaluate the impact of IGF-IR inhibition in both esophageal cancer subtypes. Using a tissue microarray, we assessed IGF-IR expression via immunohistochemistry. We then examined the effects of IGF-IR blockade on signaling pathways, proliferation, apoptosis, and motility using Ad-IGF-IR/dn, the tyrosine kinase inhibitor BMS-536924, and an adenovirus expressing IGF-IR shRNA. IGF-IR was commonly expressed in tumors but absent in normal tissues, with similar expression levels in primary and metastatic sites. IGF-IR inhibition reduced proliferation and colony formation, enhanced stress- and chemotherapy-induced apoptosis, and suppressed migration. While Ad-IGF-IR/dn primarily blocked ligand-induced Akt-1 activation, BMS-536924 effectively inhibited both Akt and MAPK signaling.
These findings suggest that the IGF axis plays a crucial role in esophageal cancer progression, and IGF-IR-targeted therapies may represent a promising strategy for treating these malignancies.