Annals of Oncology Advance Access originally published online on March 27, 2008
Annals of Oncology 2008 19(7):1293-1298; doi:10.1093/annonc/mdn040
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gastrointestinal tumors |
Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients
1 Centro Regionale di Genetica Oncologica-Oncologia Medica, Università Politecnica delle Marche
2 Clinica di Oncologia Medica, Ospedali Riuniti Ancona
3 Anatomia ed Istologia Patologica
4 Scuola di Specializzazione in Oncologia, Università Politecnica delle Marche, Ancona, Italy
* Correspondence to: Dr C. Braconi, Centro Regionale di Genetica Oncologica-Oncologia Medica, Istituto di Medicina Clinica e Biotecnologie Applicate, Università Politecnica delle Marche, Via Tronto 1, 60100 Ancona, Italy. Tel: +39 0712206151; Fax: +39 0712206191; E-mail: chiarabraconi{at}tiscali.it
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Abstract |
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Background: The expression of the insulin-like growth factor (IGF) system has never been studied in gastrointestinal stromal tumors (GISTs).
Patients and methods: We studied the immunohistochemical expression of IGF1 receptor (IGFR-I), IGF1 and IGF2 in 94 samples of GISTs. IGF1 and IGF2 expression was scored in three classes: negative (N), moderate (M) and strong (S), according to staining intensity and extent.
Results: IGFR-I was overexpressed in all cases. IGF1 and IGF2 expression was absent in 25 and 48 cases, moderate in 29 and 16 cases and strong in 40 and 30 cases, respectively. Strong IGF1 expression significantly correlated with higher mitotic index (P = 0.0001), larger (P = 0.01), higher risk (P = 0.0002), metastatic (P = 0.0001) and relapsed (P = 0.04) GISTs. Strong IGF2 expression correlated with higher mitotic index (P = 0.05) and higher risk GISTs (P = 0.001). The Kaplan–Meier analysis (N versus M versus S) showed a significant worsening of the disease-free survival (DFS) with the increase of IGF1 (P = 0.02) and IGF2 (P = 0.02) expression. In the subgroup of patients with operated high-risk GISTs, there was a better trend in DFS for patients affected by GISTs with negative IGF1 and IGF2.
Conclusions: The expression of IGF1 and IGF2 seems to predict relapse in GIST patients.
Key words: GIST, IGF1, IGF2
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Introduction |
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The majority of gastrointestinal stromal tumors (GISTs) are due to the hyperactivation of KIT and platelet-derived growth factor receptor alpha (PDGFRa) [1, 2] downstream signaling, involving the phosphatidylinositol-3-phosphate-kinase (PI3K), the mitogen-activated protein kinase (MAPK) and the Janus Kinase (JAK) pathways. Recent evidence, however, indicates that other signaling routes might be involved in GIST pathogenesis [3]. We speculate that the insulin-like growth factor (IGF) system might have a role in the evolution of this disease.
The IGF family includes two ligands (IGF1 and 2), two receptors (IGFR-I and II) and six binding proteins [insulin-like growth factor binding protein (IGFBP) 1–6]. The interaction between IGFs and IGFRs triggers a signaling cascade (PI3K, MAPK) leading to cellular proliferation and inhibition of apoptosis [4].
The binding of IGF2 to IGFR-II results in IGF2 degradation and reduction of its biological potential. Therefore, it has been hypothesized that IGFR-II is lost during carcinogenesis, leading to an increase in IGF2-induced proliferation stimulus [5]. The interaction between IGFR-I and IGF1 causes a structural modification and activation of the receptor. Several adaptor proteins, such as insulin receptor substrates (IRS1–4), are involved in this activation process. IGFR-I is involved in cell proliferation, apoptosis, differentiation, cellular motility and anchorage-independent growth and is overexpressed in tumor tissues [6]. Several epidemiological studies looked at the correlation between serum level of IGF1 and IGFBPs in healthy people and the risk of cancer development. Altered levels of IGF1 and IGFBPs seemed to be associated with the risk of prostate [7, 8] and breast cancer [9], even though some more recent trials did not confirm this datum [10, 11]. A recent analysis [12] in Japanese patients did not confirm a previous significant association found between IGF1 plasmatic levels and risk of colon cancer [7, 13–15]; however, there is emerging in vitro evidence regarding the involvement of IGF system in colon carcinogenesis [16–18].
The involvement of the IGF system in GISTs is indicated by the several cases of non-hyperinsulinemic hypoglycemia observed in GISTs patients [19–25]. In these patients, elevated plasmatic levels of pro-IGF2 have been detected and it has been hypothesized that it is produced by GIST cells. Pro-IGF2 is generated by abnormal processing of IGF2 precursor in tumors. The mechanism by which the hypoglycemia is induced has not been fully clarified yet, but it was speculated that tumor-derived IGF2 may suppress growth hormone secretion at pituitary level, leading to a defected metabolic response to hypoglycemia [26]. To date no data exist regarding the involvement of the IGF system in GISTs. In this study, we looked at the immunohistochemical expression of IGFs and IGFR-I in GIST specimens and we investigated the prognostic role of these factors.
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patients and methods |
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Tumor specimens included in this study were retrieved from patients who received diagnosis of primary GISTs at the Pathology Department of Ancona from November 1987 to June 2006. The hematoxylin–eosin-stained slides were reviewed and immunohistochemical reaction for KIT (anti-CD117) was carried out in every case with a polyclonal rabbit antibody (DAKO, Denmark). IGF1, IGF2 and IGFR-I expression was detected by immunohistochemistry using the following antibodies: polyclonal rabbit anti-IGF1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA), monoclonal human anti-IGF2 (Chemicon International, Temecula, CA) and polyclonal rabbit anti-IGFR-Iβ H60 (against amino acids 741–800) (Santa Cruz Biotechnology, Santa Cruz, CA). A section of normal human breast, previously proven to be IGF1–IGF2 and IGFR-Iβ positive, was used as positive control, whereas an invasive ductal carcinoma case that was negative for protein expression was included as negative control. Two pathologists (I. B. and A. M.), who were blinded to clinical information, evaluated and scored immunohistochemical stains for IGF1 and IGF2 protein in tumor tissue. Immunohistochemical staining was scored taking into account both staining intensity and extent. Intensity of staining was graded as follows: negative (score 0), weak (‘+’; score 1), moderate (‘++’; score 2) and strong (‘+++’; score 3). Extent of staining was evaluated as the percentage of cells with cytoplasmic immunoreactivity and was graded in six classes as follows: negative (0),
10% (1), 11%–25% (2), 26%–50% (3), 51%–75% (4) and >75% (5). A final score was calculated by adding intensity and extent scores for each sample and we distinguished three classes: negative expression (final score 0: N), moderate expression (final score 1–4: M) and strong expression (final score 5–8: S). A further classification was obtained calculating the addition of both IGF1 and IGF2 scores, resulting in two classes (negative N1-2 and positive P1–2).
The following clinicopathological characteristics have been assessed: location (stomach, small bowel, other sites), tumor size (10 and >10 cm), mitotic index (10 and >10 mitoses/50 high power fields), morphological subtype (spindle, epithelioid, mixed) and stage at presentation (localized disease or metastatic disease including both intra-abdominal and distant spread). GISTs have been assigned a class of risk for malignant behavior (high, intermediate, low, very low) according to the literature [27]. In our analysis, we grouped very low and low-risk GISTs together in the low class.
A molecular analysis was carried out in all cases. DNA was extracted from formalin-fixed and paraffin-embedded tumor tissue samples. Polymerase chain reaction (PCR) was carried out in order to amplify KIT exons (9, 11, 13 and 17) and PDGFRa exons (exons 18, 12 and 14). PCR products were analyzed by direct sequencing with an ABI 310 genetic Analyzer (Applied Biosystem, Foster City, CA). All the mutations found in the sequencing analysis were confirmed by a new PCR and a new sequencing analysis of both DNA strands. Our results were compared with normal sequences available on Gene ID 3815 (KIT) and Gene ID 5156 (PDGFRa).
Disease-free survival (DFS) was used as the end point of the study. Disease recurrence was defined as presence of peritoneal or liver disease. Follow-up lasted through May 2007 (range 0.1–13.2 years). The association of clinicopathological variables and type of mutations (mutations in KIT exon 11, KIT exon 9, PDGFRa) with IGF1 and IGF2 scores (class N versus class M versus class S and class N1–2 versus class P1–2) was tested using 
2 test. Univariate analysis was done to assess the relationship between immunohistochemical scores and DFS. P value <0.05 was considered to be statistically significant. Patients did not receive any adjuvant or neoadjuvant therapy. Informed consent was obtained by each subject.
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results |
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We examined 94 patients with CD117-positive GISTs (female: 44, male: 50) (Table 1).
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KIT mutations were found in 75% of the sample and PDGFRa mutations in 12%. IGFR-I expression in cytoplasm was strongly detected in all tumors, without the possibility of subdividing the whole series into different classes. Cytoplasmic IGF1 expression was negative (N) in 27% of tumors, moderate (M) in 31% and strong (S) in 42%. Cytoplasmic IGF2 expression was negative (N) in 51% and positive (M + S) in 49% of samples. Sixteen (17%) GISTs were moderately positive for IGF2 and 30 (32%) tumors strongly overexpressed IGF2. Nineteen tumors (20%) were negative for both IGF1 and IGF2 (class N1–2), while 75 (80%) were positive for at least one of them.
In our series, IGF1 and IGF2 expression did not correlate with site of tumor and histotype. IGFs expressions were strongly correlated with the class of risk. In fact, the proportion of tumors with a strong IGF1 expression was higher among high-risk GISTs (P = 0.0002); the same was true for tumors with strong IGF2 expression (P = 0.001). A stronger expression of IGFs was also evident in tumors with higher mitotic index (P = 0.0001 for IGF1 and P = 0.05 for IGF2) and larger size (P = 0.01 for IGF1). Most of the non-relapsed patients had GISTs belonging to N or M class for both IGF1 (P = 0.04) and IGF2 (P = 0.01), while >50% of 18 relapsed patients belonged to IGF1 S class (P = 0.04) and IGF2 S class (P = 0.01). Considering the stage of the disease at presentation, there was a significant correlation between the strong expression of IGF1 and the metastatic onset of the disease (P = 0.0001).
IGF1 expression did not seem to correlate with mutational status. Conversely, there was a higher proportion of IGF2-negative GISTs (64%) among 11 PDGFRa-mutated GISTs and a higher percentage of strongly IGF2-expressing tumors (70%) among exon 9 KIT-mutated GISTs (P = 0.04).
When the two protein scores were considered together, the correlation between positive IGF1–IGF2 expression (P1–2) and higher class of risk (P = 0.004) and mitotic index (P = 0.005) was maintained. Moreover, the association between the lack of IGF1–IGF2 expression (N1–2) and the localized stage at presentation was confirmed (P = 0.03).
At the time of analysis, 36 patients had died. Twenty-three of them died because of GISTs, while the others died for other causes still free of relapse. DFS was calculated in 77 patients who underwent radical resection of the tumor. Eighteen patients relapsed after a median DFS of 1.2 years (median DFS not reached in the whole group).
GISTs with negative IGF1 and IGF2 expression have a significantly better DFS compared with tumors with IGFs overexpression (Figure 1). In addition, if we distinguish GISTs with moderate and strong IGFs expression, a significant difference in DFS is maintained (Figure 2). There is a significant difference in DFS also between class N1–2 and class P1–2 (Figure 3).
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The mitotic index and the IGF2 expression significant influenced DFS (P = 0.0001) at the multivariate analysis performed taking into account mitotic index, size of tumor, IGF2 expression (negative vs positive), IGF1 expression (negative vs positive) and mutational assessment.
We also evaluated DFS in the subgroup of patients with high-risk GISTs [35]. Interestingly, we found a trend towards a better outcome for patients with GISTs lacking the expression of IGF1- versus IGF1-positive GISTs (median DFS not reached versus 5.4 years) and for patients with IGF2-negative versus IGF2-positive GISTs (median DFS 10.6 versus 3.8 years). A statistical significance, however, was not reached, likely due to the small size of the sample.
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conclusion |
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Prognostic factors for GISTs, recognized worldwide, are class of risk, mitosis index and size of tumor [27]. Although the classification in different classes according to the Bethesda score is useful to predict patients' outcome, it is not satisfactory, since many high-risk GISTs do not relapse and occasionally low- or intermediate-risk GISTs recur. Studies looking at the efficacy of adjuvant treatment in high-risk patients are ongoing and preliminary data seem to indicate that imatinib might help to prolong DFS [28]. Thus, additional prognostic factors could be useful to achieve the best selection of patients eligible for adjuvant therapy. New prognostic factors have been evaluating and the immunohistochemical expression of vascular endothelial growth factor [29, 30] and hypoxia inducible factor 1alpha [31] seems to correlate with prognosis.
Our results indicate that the IGFs might help to distinguish the aggressiveness of the disease. Scoring the immunohistochemical expression of IGF1 and IGF2 into three different classes (negative, moderate and strong expression), we were able to find a significant correlation between these and DFS. In our study, IGFs-negative GISTs had a significantly better outcome compared with GISTs overexpressing IGFs. Moreover, the different degrees of IGFs expression are correlated to different prognoses. It is well known that the IGF system is involved in carcinogenesis and cancer proliferation, and in some solid tumors IGFR-I was found to be associated with different degrees of malignancy [32–34]. In the present study, we detected a strong immunohistochemical expression of IGFR-I in all cases. It is not surprising that this receptor is expressed and activated in cancer cells. However, having detected a cytoplasmic immunoreactivity, we may speculate that GIST cells produce this receptor, but we cannot speculate on any activation of this receptor or on any of its functions within proliferation and survival mechanisms of the cell. For the detection of IGFR-I, we used an antibody against the subunit beta of the receptor and we wondered whether this could have influenced the results. Some studies, however, showed a comparable pattern of expression using antibodies to the subunit alpha and to the subunit beta of IGFR-I [35, 36], making this hypothesis weaker.
Up to now the IGF system in GISTs has never been studied; therefore, we do not know the exact mechanism of action in the evolution of this disease. We do know from the literature, however, that IGFR-I, under the IGF1 and IGF2 stimulation, activates both the PI3K and the MAPK pathways. Interestingly, recent evidence indicates that the MAPK route might be activated in GISTs by different receptor than KIT. Tarn et al. [37] demonstrated that, after imatinib treatment, AKT was inhibited in GIST cells, but the MAPK pathway continued to be active, leading to cell proliferation. Tarn et al. indicated that other ways could be involved in the activation of the MAPK pathway accounting for both the imatinib resistance and the tumor progression. Recently, PI3K, STAT1 and STAT3 activation in GISTs was shown to be only partially KIT dependent, confirming the possibility of an alternative route involved in the proliferation of GIST cells [3].
We might hypothesize that the IGF system, and in particular IGFR-I in presence of high concentration of IGF1 and IGF2, has an active role in cell proliferation through the activation of MAPK and PI3K bypassing KIT. It is likely that GISTs tend to produce IGFs, which in turn, through a paracrine, autocrine and sometimes an endocrine loop, might create an auto-enhancing stimulation of cell proliferation, causing a more aggressive and malignant behavior of the tumor. This is why we found a stronger expression of IGFs in metastatic GISTs versus localized GISTs, in relapsed versus non-relapsed GISTs and in higher risk GISTs. Our findings regarding the association between weaker IGF2 expression and PDGFRa-mutated GISTs follow this logic, since others [38] and we [39] previously demonstrated that PDGFRa-mutated GISTs have a favorable outcome.
The Kaplan–Meier analysis showed a significant improvement of the DFS according to the lack of expression of IGFs. In order to exclude the confounding influence of another important prognostic factor, such as class of risk, we also investigated DFS in the subgroup of patients with high-risk GISTs. We found a better trend in DFS for those patients with lack of IGF1 and IGF2. Unfortunately, we did not reach the statistical significance, but we think this is due to the small size of the sample and might deserve further evaluation.
In conclusion, we showed that IGF1, IGF2 and IGFR-I are variably expressed in GIST tissues. Our data are certainly too preliminary to state that IGF system is involved in the pathogenesis of GIST. They are, however, promising and prompt additional investigation addressing this question. The expression of these factors at messenger RNA and protein levels and the evaluation of the contribution of IGFs in cell proliferation, apoptosis and migration are warranted, before concluding for a definitive involvement of the IGF system in GIST carcinogenesis and progression. The aim of the present work, however, was to study the expression of the IGF system in GIST and to correlate this expression to clinical outcome, in order to evaluate whether a simple and widely accessible technique might contribute in providing new factors useful in the clinical management of GIST patients. According to our findings, IGF1 and IGF2 should be further evaluated as new factors useful to predict relapse and distinguish GISTs with an aggressive behavior. This information might also be useful in evaluating adjuvant treatment results because adjuvant imatinib could be more useful in high-risk GISTs expressing IGFs. Finally, the emergence of new anti-IGFR-I drugs [40] might be explored in GISTs.
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"Università Politecnica delle Marche - Ancona" and "Regional Grant - Associazione Italiana per la Ricerca sul Cancro (AIRC)".
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These authors have contributed equally to the work. 
Received for publication October 19, 2007. Revision received January 24, 2008. Accepted for publication January 25, 2008.
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