Abstract
Different Insulin-like growth factor-I (IGF-I) mRNA transcripts are produced by alternative splicing and particularly the IGF-IEc isoform has been implicated in the development and/or progression of various types of cancer. In the present study, we examined the potential role of IGF-IEc expression as a new immunohistochemical marker of aggressiveness in neuroendocrine neoplasms (NENs). We utilized immunohistochemical analysis in tissue specimens of 47 patients with NENs, to evaluate the expression of IGF-IEc (%) and Ki-67 proliferation index (%). Specimens from patients with tumors of different tissue origin, of either primary or metastatic lesions and of different grade were examined. Cytoplasmic IGF-IEc staining was found in 23 specimens of NENs or NECs: 10 pancreatic, 4 small bowel, 3 gastric, 1 lung, 1 uterine and 4 poorly differentiated of unknown primary origin. Ki-67 and IGF-IEc expression was positively correlated in all the samples studied (r=0.31, p=0.03). IGF-1Ec expression was more prevalent in specimens originating from metastatic foci with high Ki-67 compared to primary sites with low Ki-67 expression (p=0.036). These findings suggest a possible role of IGF-IEc in NEN tumorigenesis and progression to metastases that could be used as an additional new marker of a more aggressive behavior and a potential drugable target.
Highlights
Neuroendocrine neoplasms (NENs) constitute a wide range of tumors derived from neuroendocrine cells that are widely distributed throughout the human body [1]
Cases with positive insulin-like growth factor (IGF)-IEc immunohistochemical expression were found in neuroendocrine neoplasms (NENs) or NECs: 10/17 (58.8%) pancreatic, 4/9 (44.4%) small bowel, 4 (100%) poorly differentiated unknown primary origin (UPO), 3/8 (37.5%) gastric, 1/2 (50%) lung and 1 uterine cervical (Figure 2)
This study provides evidence that the alternative splicing of the igf1 gene results in different Insulin-like growth factor-I (IGF-I) mRNA transcripts encoding several IGF-I isoforms that could be implicated in the progression and aggressive behavior of gastrointestinal NENs (GI-NENs)
Summary
Neuroendocrine neoplasms (NENs) constitute a wide range of tumors derived from neuroendocrine cells that are widely distributed throughout the human body [1]. The insulin-like growth factor (IGF) system is considered to play an important role in GI-NENs [4,5,6]. Expression of IGFs and their cognate receptors correlate with increased angiogenesis, development of metastases, reduced survival and tumor de-differentiation in several cancer types including NENs [8,9,10,11]. IGF-I acts in tissue cell model of pancreatic NENs (pNENs: BON cells) through the IGFIR, regulating cell-cycle proteins and stimulating cellular secretion of Chromogranin A (CgA) [12,13,14,15]. IGF-II and IGF-IR are expressed in 30% and 70% of NENs, respectively [8], whereas high IGF-II levels stimulate BON cell growth [15]
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