IGF-IEc expression is increased in secondary compared to primary foci in neuroendocrine neoplasms

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.

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

“…When it comes to the overexpression of transcription factor SP1, it was proven that it positively correlates with IGF1 upregulation only in precancerous lesions, with no correlations with P1/P2 activity detected in CC tissue [ 49 ]. Furthermore, positive cytoplasmic expression of the MGF was also detected in one study concerning neuroendocrine uterine cervical cancer [ 32 ].…”

“…Among the known IGF1 mRNA variants and IGF1 precursor proteins, a clearly mitogenic role in tumor biology is attributed to the IGF1Ec isoform [ 30 , 32 , 108 , 109 , 166 ]. A confirmation of this statement can be found in studies of human cancer cell lines [ 14 , 16 , 106 , 167 ].…”

“…Anti-MGF-conjugated AuNPs were localized in epithelial cells [ 34 ]. However, no expression of the MGF was determined in colonic and retrosigmoidal neuroendocrine neoplasms (NENs) [ 32 ].…”

“…Bioinformatic analysis performed on almost a thousand LC patients shows that overexpression of IGF1 correlates with high risk of cancer progression [ 182 ]. Positive cytoplasmic expression of the IGF1Ec peptide (MGF) was described in half of the neuroendocrine cancers of the lung [ 32 ]. Other studies on IGF1 mRNA/protein isoforms were only undertaken in in vitro models.…”

“…In turn, alternative IGF1 mRNA splices generate different precursor peptides (IGF1 protein isoforms), but do not alter the structure of mature IGF1 protein [ 9 , 23 , 26 , 29 ]. Mitogenic and anti-apoptotic activity of mature IGF1, as well as different precursor IGF1 peptides, qualify IGF1 to the group of growth factors implicated in the initiation and progression of various cancers [ 16 , 30 , 31 , 32 , 33 , 34 , 35 ].…”