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Increased Expression of Insulin-Like Growth Factor I and/or Its Receptor in Gastrinomas Is Associated with Low Curability, Increased Growth, and Development of Metastases

Authors' Affiliations: ¹ Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, ² Hematopathology Section, Laboratory of Pathology, National Cancer Institute, ³ Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, ⁴ Center for Cancer Research, National Cancer Institute, and ⁵ Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, Maryland

Request for reprints: Robert T. Jensen, NIH/National Institutes of Diabetes, Digestive and Kidney Diseases/DDB, Room 9C-103, Building 10, 10 Center Drive MSC 1804, Bethesda, MD 20892-1804. Phone: 301-496-4201; Fax: 301-402-0600; E-mail: robertj{at}bdg10.niddk.nih.gov.

Purpose: Growth factors, particularly insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR) in some nonendocrine and a few endocrine tumors, are thought important in recurrence, growth, and aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. The aim of this study was to address this question in gastrinomas.

Experimental Design: IGF-I and IGF-IR expression in gastrinomas from 54 patients with Zollinger-Ellison syndrome were analyzed and correlated with clinical/tumor characteristics. IGF-I and IGF-IR mRNA levels were determined by competitive reverse transcription-PCR. IGF-IR expression, assessed by immunohistochemistry, was done on a subset.

Results: IGF-IR mRNA was found in 100% and IGF-I in 89%. IGF-I mRNA expression varied by >254-fold, IGF-IR by 2,670-fold, and the levels correlated in a given tumor. The IGF-IR level was lower in gastrinomas of patients who were rendered disease free and increased levels correlated with tumor growth, aggressiveness, extent, and with liver metastases. Increased IGF-I levels correlated with increased growth, tumor extent, and aggressiveness. Neither IGF-IR nor IGF-I levels correlated with tumor location, size, or its clinical/functional features. The IGF-IR correlated with disease-free survival. IGF-IRß was found in 31 of 32 tumors (97%) by immunohistochemistry.

Conclusions: These results indicate that IGF-I and IGF-IR are expressed in almost all gastrinomas. Furthermore, assessment of IGF-I/IGF-IR expression in gastrinomas may be clinically useful in identifying those patients with more aggressive tumors who might benefit from more aggressive treatment.

Key Words: insulin-like growth factor I • gastrinoma • pancreatic endocrine tumor • carcinoid • Zollinger-Ellison syndrome

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