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

Masayuki Furukawa,Tetsuhide Ito,Jose Serrano,Akio Sakamoto,Mark Raffeld,Robert T Jensen,David J Venzon,Carmen Mateo,Terry W Moody

doi:10.1158/1078-0432.ccr-04-1915

Abstract

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. 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. 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-IRbeta was found in 31 of 32 tumors (97%) by immunohistochemistry. 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.

Highlights

Growth factors, insulin-like growth factor I (IGF-I) and IGF-I: sense (IGF-Is) 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
Control studies showed that the PCR products were correct by sequencing and that they resulted from tumor mRNA because both the IGF-I primers and the IGF-I receptor (IGF-IR) primers spanned a long intron and gave no amplification with genomic DNA, as well as no product in the absence of reverse transcriptase
Little is known about the molecular pathogenesis or determinants of aggressive growth of neuroendocrine tumors because neither common oncogenes nor tumor suppressor genes (p53, retinoblastoma, etc.), which are important in the pathogenesis of common gastrointestinal adenocarcinomas, are typically altered in neuroendocrine tumors [7]

Summary

Introduction

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 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. Gastrointestinal neuroendocrine tumors, comprising pancreatic endocrine tumors and carcinoids, are generally considered slow-glowing neoplasms; in a significant subset, aggressive growth occurs resulting in decreased survival (1 – 3). Twenty-five percent of gastrinomas, the most common malignant symptomatic pancreatic endocrine tumor [1, 4], show aggressive growth resulting in a decreased survival [5]. The factors responsible for these variable growth patterns with different pancreatic endocrine tumors as well as with gastrinomas, are largely unknown [7] This situation exists because the molecular pathogenesis of neuroendocrine tumors is largely unknown [7]. Gene abnormalities at the DPC4 locus on 18q21 are reported in 18% to 88% of neuroendocrine tumors as well as in the region of the VHL locus on 3p25, which correlate with neuroendocrine tumor growth in some studies, but not others [7]

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