Mini reviewIGF2 signaling and regulation in cancer
Introduction
The mitogenic peptide IGF2 is a component of the phylogenetically ancient insulin/IGF-signaling axis that regulates cell survival, growth and proliferation, and metabolism. Other IGF-axis components include the related peptide IGF1, IGF2 mRNA binding proteins (IGF2BPs, IMPs) and IGF binding proteins (IGFBPs) that regulate IGFs post-transcriptionally and post-translationally, as well as the IGF receptors IGF1R and IGF2R. As the name indicates, insulin and IGF peptides, as well as their receptors IR and IGF1R, share significant sequence homology. The IR and IGF1R form homodimers as well as heterodimeric hybrid receptors that bind insulin, IGF1 and IGF2 with differing affinity (reviewed in [1]). IGF2 binds to IGF1R with a lower affinity compared to IGF1 but interestingly has the ability to signal through IR due to high affinity binding to the A isoform [2]. IGF2R lacks a tyrosine kinase domain and reduces IGF2 bioavailability for binding to IR or IGF1R.
IGF2 is one of a relatively small number of imprinted genes (including IGF2R) in mammals, by which epigenetic silencing results in monoallelic expression specific to parental origin. Most imprinted genes have key functions during embryonic development, as is the case for IGF2, which due to maternal imprinting is typically expressed from the paternal allele only. Mice with homozygous null-mutated or paternal heterozygous null-mutated Igf2 give rise to a dwarfed but viable embryo, indicating the essential role of IGF2 in fetal growth [3], [4]. In human adults, hepatocytes continue to secrete IGF2, but its physiological role seems to be of less physiological importance [5]. IGF2, unlike IGF1, is not regulated by Growth Hormone.
Upregulation of IGF2 occurs in both childhood and adult malignancies [6]. The Beckwith–Wiedemann childhood overgrowth disorder is associated with IGF2 loss of imprinting in 25–50% of cases [7] and confers a significantly increased risk of developing early childhood tumors such as Wilms’ tumor and hepatoblastoma [8]. Another pediatric tumor type, Ewing's sarcoma, is also characterized by increased IGF2 expression [9]. In recent years, IGF2 abnormalities have been demonstrated in a variety of adult malignancies, where its overexpression is usually associated with worse prognosis [10], [11] (Table 1). In this review, we describe the mechanisms of IGF2 signaling and regulation in normal and malignant tissues and their clinical implications [6], [12].
Section snippets
Gene structure of IGF2
The IGF2 gene is located on chromosome 11p15.5. IGF2 is one of only a few hundred imprinted genes in mammals. Normally, the IGF2 maternal allele is methylated, and expression occurs only from the paternally inherited allele. This imprinting is done reciprocally between IGF2 and its downstream neighbor H19, which is usually expressed only from the maternal allele [13]. Imprinting is maintained by epigenetic mechanisms, primarily DNA methylation.
Currently, there are four different transcript
IGF2 peptides
The main isoform of IGF2 (isoform 1), translated from exons 7, 8 and part of 9, gives rise to a 180-residue pre-pro-protein. A 24-residue signal peptide is cleaved off to give the 156 residue pro-protein. This pro-protein exists of the 67 residues of mature IGF2 plus the 89 residues of the e-domain and has up to four O-glycosylation sites. The weights of proteins ranges from 10 to 19 kDa, depending on cleavage. At least three non-mature IGF2 forms have been described to have biological activity:
Loss of imprinting and methylation changes
As IGF2's functions are essential for the correct development of an organism, its usage is exquisitely regulated [25]. Loss of imprinting, meaning both alleles are expressed, occurs but does not necessarily indicate disease [26]. LOI occurs normally by a decrease in binding of the enhancer-blocking element CCCTC-binding factor (CTCF) to the IGF2-H19 imprint control region. This allows for increased DNA methylation, silencing the maternal imprinting, which results in biallelic expression. A
Involvement of IGF2 in drug resistance
Our group has shown that IGF2 is upregulated after Taxol treatment of ovarian cancer cell lines. Cell lines made resistant to Taxol and other microtubule-stabilizing drugs showed constitutive IGF2 increase. Inhibition of IGF2 signaling in the Taxol-resistant cell line HEY-T30 by the small molecule tyrosine kinase inhibitor of IR/IGF1R NVP-AEW541 or by IGF2-targeting RNA interference reverted sensitivity and decreased proliferation [53]. In ovarian cancer xenografts, Taxol resistance could be
Targeting IGF2 in cancer
Most early efforts to target the insulin/IGF signaling axis focused on the IGF1 receptor as a therapeutic target. Several companies, including Imclone with cixutumumab, Amgen with ganitumab and Pfizer with figitumumab, developed humanized antibodies against IGF1R, but clinical trials have been disappointing so far [58]. Few IGF1R antibodies are still being developed, such as dalotuzumab from Merck [59]. Trials of combination therapies (IGF1R antibody together with standard chemotherapy or
Conclusions
IGF2 overexpression is a hallmark of many pediatric and adult malignancies, where reactivation of fetal promoters is a key feature of its upregulation. Several important IGF2 regulatory mechanisms have been identified, many of which overlap with functions during fetal development, including altered transcription factor expression, epigenetic changes such as altered DNA methylation, as well as changes in post-transcriptional and post-translational modulators of IGF2 expression. Despite its
Acknowledgements
Grant support was provided by the National Cancer Institute-National Institute of Child Health and Human Development (K12 HD000849) and the American Congress of Obstetricians and Gynecologists through the Reproductive Scientist Development Program award to G.S.H.
Jurriaan Brouwer-Visser Ph.D. is a graduate of Pontificia Universidad Católica de Chile. His thesis research on IGF2 in ovarian cancer was done in Dr. Huang's laboratory, where he currently focuses on preclinical tumor models and combination therapies to target IGF signaling in gynecological cancers.
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Jurriaan Brouwer-Visser Ph.D. is a graduate of Pontificia Universidad Católica de Chile. His thesis research on IGF2 in ovarian cancer was done in Dr. Huang's laboratory, where he currently focuses on preclinical tumor models and combination therapies to target IGF signaling in gynecological cancers.
Gloria S. Huang M.D. is an Associate Professor of the Departments of Obstetrics and Gynecology & Women's Health (Division of Gynecologic Oncology) and Molecular Pharmacology, Albert Einstein College of Medicine and Montefiore Medical Center. She is a graduate of Yale University and Stanford University School of Medicine, where she also completed an Obstetrics and Gynecology residency and an NIH-supported post-doctoral fellowship. Her clinical sub-specialty fellowship in gynecologic oncology was at Einstein/Montefiore. She has received awards from the Reproductive Scientist Development Program (RSDP), Gynecologic Cancer Foundation, and the American Association of Obstetricians and Gynecologists Foundation for her studies on the role of the insulin/IGF signaling axis in gynecologic cancers.