Although IGF2BP3 is expressed in a variety of malignant neoplasms including pulmonary small cell , endometrial , and cervical carcinomas , the prognostic value has been demonstrated only in renal clear cell carcinomas [16, 17], low-stage urothelial carcinomas of the bladder , and more recently in ovarian clear cell carcinoma . The present study showed for the first time that IGF2BP3 overexpression correlates with poor survival in pancreatic ductal adenocarcinoma. We also demonstrated that the expression of IGF-2 significantly correlates with that of IGF2BP3, which has been previously reported to promote IGF-2 mRNA translation . An attractive feature of IGF2BP3 as a biomarker in pancreatic ductal adenocarcinoma is that its expression is only found in tumor tissue and is absent in normal adult pancreatic ductal tissue. This on-off pattern of expression makes staining interpretation very simple in practice. The expression of IGF2BP3 during embryogenesis  but not in adulthood suggests that IGF2BP3 is epigenetically silenced in adult tissues. In pancreatic ductal adenocarcinoma, re-expression of IGF2BP3 might be the result of promoter hypomethylation. The IGF2BP3 gene is located on chromosome 7p (at location 23,316,354-23,476,520), a region not subject to frequent perturbation in pancreatic ductal adenocarcinoma . It is therefore unlikely that gene amplification is responsible for the observed IGF2BP3 expression in pancreatic ductal adenocarcinoma. We are currently testing the hypothesis that the IGF2BP3 promoter is hypomethylated in pancreatic ductal adenocarcinoma, and that this correlates with expression levels. If this hypothesis holds true, IGF2BP3 could be regarded as a target for re-methylating enzymes.
The mechanisms by which IGF2BP3 and IGF-2 facilitate tumor progression in pancreatic ductal adenocarcinoma remain to be elucidated. However, IGF2BP3-mediated activation of IGF-2 translation has been shown to increase human leukemia cell proliferation . Vikesaa et al.  reported that IGF2BP3 modulates the expression of specific extracellular matrix and cell adhesion proteins (e.g., collagen V α1, ALCAM) and stabilizes CD44 mRNA, thereby promoting invadopodia formation in cervical cancer cells. Moreover, IGF2BP3 has been demonstrated to enhance the motility of human colorectal cancer cells . While less studied than its family member IGF-1, IGF-2 is also known to play a role in cancer progression. Corcoran et al.  recently noted that induction of IGF-2 expression in pre-malignant lesions coincides with progression to advanced medulloblastoma. In addition to its direct effect on tumor cells, IGF-2 was shown to promote tumor angiogenesis and lymphangiogenesis [30, 31]. Decreases in IGF-2 mRNA levels and IGF-2 secretion using growth hormone-releasing hormone antagonists were associated with decreased cancer cell proliferation in vitro  and tumor growth in vivo [33, 34]. Furthermore, IGF-2 deficient tumor cells were shown to be more sensitive to chemotherapy-induced apoptosis . It seems reasonable to speculate that the IGF2BP3/IGF-2 pathway may drive progression in pancreatic ductal adenocarcinoma by similar means, and that therapeutically targeting either or both of these proteins may result in tumor control. These possibilities are being investigated in our laboratory. Interestingly, Wang et al. reported that IGF2BP3 is immunogenic in lung cancer patients, suggesting that it may be a potential target for immunotherapy . In a recent Phase I trial, IGF2BP3 vaccine was shown to be safe and well tolerated .
In summary, this is a retrospective study of a post-surgical, heterogeneously treated cohort of patients with resected pancreatic adenocarcinoma. Thus, prognostic associations, defined as tumor behavior after primary surgery and uninfluenced by different regimens of adjuvant therapy, cannot be assessed. A strength of this study is the relatively large sample size (n = 127) of pancreatic ductal adenocarcinoma. Our data suggest that IGF2BP3 overexpression denotes a subset of pancreatic adenocarcinomas with an extremely poor outcome, and supports the rationale for developing therapies to target the IGF2BP3/IGF-2 pathway in pancreatic ductal adenocarcinoma.