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Insulin-like growth factor-1 signaling in renal cell carcinoma
© The Author(s). 2016
- Received: 11 October 2015
- Accepted: 28 June 2016
- Published: 12 July 2016
Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells.
- Renal cell carcinoma (RCC
- Insulin-like growth factor-1 (IGF-1)
- IGF-1 receptor (IGF1R)
Renal cell carcinoma (RCC) comprise 2–3 % of malignant tumors in adults. Clear cell RCC (ccRCC) develops from epithelium of the proximal tubules and is the most common a histological type of RCC – diagnosed in 60-70 % of cases. Initial treatment of RCC is most often partial or radical nephrectomy. Nevertheless one third of patients are diagnosed with synchronous metastases . IGF-1 plays an important role in protection from apoptosis and regulation of cell growth. Deregulation in downstream IGF-1 receptor results in angiogenesis, cell viability, proliferation and invasion. IGF1R expression is poor prognostic factor especially among those presenting with high-grade disease at the initial evaluation. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression of that receptor . IGF-1 and insulin share overlapping downstream pathways of cancer cell metabolism. Cell line based studies have shown that down-regulation, knock-out, pharmacological inhibition of IGF-IR may in turn increase in IR signaling and therefore insulin analogs may promote cancerogenesis . On the other hand first preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells [4, 5]. All these findings suggest that IGF1R expression is significant in ccRCC and understanding of the molecular mechanism of IGF-1 and insulin signaling pathway in RCC may give opportunity to design molecular markers of disease or even finding a new molecular targets for drugs.
Renal cell carcinoma
Drugs used in RCC therapy
Group of drug
1) Interleukin 2 - overall response rate - 15 %, complete response rate - 5 %, achieved by high dose. Problems with selection of patients who may benefit from treatment.
2) Interferon alfa - inferior to most new agents considering PFS (progression free survival), except in combination with bevacizumab.
1) Sorafenib – second and subsequent lines of treatment.
2) Sunitinib – first line treatment for metastatic RCC.
3) Pazopanib – non-inferior to sunitinib
4) Axitinib – treatment refractory RCC.
5) Bevacizumab – used with interferon alfa. Superior PFS when compared with monotherapy of interferon alfa.
1) Temsirolimus – for patient with poor risk as a first line druga
2) Everolimus – used as a second line or third line drug.
General IGF-1 function
Insulin-like growth factor 1 (IGF-1, somatomedin C) is a natural anabolic peptide hormone produced mainly by hepatocytes. IGF-1 with molecular weight of 7649 Da is built by 70 amino acids and single polypeptide chain with three intramolecular disulfide bridges. Production of IGF-1 is stimulated by growth hormone (GH) secreted by anterior pituitary. IGF-1 production is also stimulated by insulin and has influenced on reduction of lipolysis, glycolysis, inhibition of lipolytic function of adrenaline, embryonic growth and differentiation of cells. IGF-1 may also be released independently of GH. Circulating IGF-1 produced in liver acts in endocrine manner, but locally produced IGF-1 acts also in an autocrine manner. IGF functions therefore both as circulating hormone and tissue growth factor. Circulating IGF-1 forms a complex with two other proteins – the IGF binding protein (IGFBP) and the acid labile subunit (ALS). Six different IGFBPs were characterized, but about 75 % of serum IGFs are bound to IGFBP3 and only 1 % of serum IGF-1 is free-bioactive form . IGFBPs are also mostly synthesized in the liver. Nevertheless IGFs and IGFBPs are also produced in other organs, acting locally in autocrine and paracrine manner and mediating stromal - epithelial cell interactions . IGFBPs acts in a competing manner against IGFR (IGF receptors) and IGFBP proteases. IGF-1 and IGFBP-3 complex play crucial role in mitogenesis, cell differentiation and survival . IGF-1 null mice die shortly after birth .
Circulation of IGF-1
High level concentrations of circulating IGF-1 are related with higher risk of prostate, colorectal and breast cancers [28–30]. Circulating concentrations of IGFBP-3 is associated with increased risks of breast cancers in postmenopausal women and prostate cancer in men [28, 29, 31]. Transgenic mouse with deletion in liver-specific IGF-1 that result 75 % reduction in circulating IGF-1 exhibit reduction in development of colon cancer and reduced growth tumor xenografts [31, 32]. Laron syndrome is genetic condition characterized by GH insensitivity and in consequence IGF-1 deficiency . People with Laron syndrome are resistant to cancer what was shown by Steuerman et al. . They found that none of the 230 patients with Laron syndrome developed cancer and that only 1 out of 116 patients with inborn IGF-1 loss was diagnosed with malignancy .
IGF-1 receptor and insulin receptor homology
Molecular deregulation of IGF1R pathway and cancerogenesis
IGF-1/insulin pathways were show as significant in cancer research. First of all IGF-1 and insulin share overlapping downstream pathways of cancer cell metabolism. Chronic hyperinsulinemia and diabetes mellitus type 2 were associated with tumor development through the obesity-cancer association [31, 44]. According to the Werner et all. IGF1R activation is pre-requisite for malignant transformation. As oncogenic transformation is initiated, cell survival of transformed cells is strongly dependent on IGF-1 signaling . Further multiple studies confirmed the role of IGF −1 and its receptors on RCC cancerogenesis [41, 45]. Deregulated IGF1R kinase activity and its overexpression was reported in multiple cancers including RCC [46–48]. In particular constitutively active IGF1R leads to salivary and mammary adenocarcinomas in transgenic mice . Transgenic overexpression of IGF1R increases epithelial mammary gland hyperplasia and tumor formation . In the RCC cell lines including Caki-2 (from a primary tumor) and SK-RC-52 (from a metastatic tumor) IGF-1 was shown to enhance transforming growth factor-β (TGF-β) signaling and via TGF-β raise IGF-binding protein 3 (IGFBP-3) levels with growth-promoting effect .
SNP’s and mutations of IGF1R gene associated with cancers
Type of cancer
BRCA1 carriers with homozigosity TT at this SNP site experience a 40 % higher risk of breast cancer.
T > C
Significantly related with shorter OS in patients with metastatic colorectal cancer (mCRC). CT and TT associated with increased risk for glioma.
G > T
Colorectal cancer, glioma
Related to reduced responsiveness to cetuximab treatment. Shorter OS in patients with mCRC. G allele associated with increased risk for Glioma (3’UTR in 3129 site)
Non–small cell lung cancer (NSCLC)
Homozygous TT in this SNP had a significantly better OS compared with heterozygous individuals and a trend toward improved survival compared with patients that were homozygous for CC .
CNV in IGF1R gene
Non–small-cell lung cancers (NSCLC)
High IGF1R gene copy number harbors positive prognostic value in NSCLC
Amplification in 15q26
High grade glioma
Amplification in 15q25-26
Related with the rearrangement of PAX7 gene
Lung squamous cell carcinoma
Unknown; mutation occur in the C-terminal lobe of the kinase catalytic domain
Renal clear cell carcinoma
Unknown; deletion occur in the C-terminal tail region of the receptor
Unknown; mutation occur in in the C-terminal lobe of the kinase catalytic domain
Unfavorable substitution Arg1216Cys; showed an increase in energy (less favorable change) in comparison with the native structure.
Affect splicing regulation; to be associated with higher plasma concentrations of circulating IGF1R
rs55895813; rs36108138; rs45495500
A/G; A/C; C/T
Expression of IGF-1 and IGF1R in kidney
Locally synthesize IGF-1 in kidney acts as a paracrine or autocrine factors. Level of IGF-1 in venous renal blood is higher than in renal arterial blood. There are no strong proves on IGF-1 epithelial expression. Studies indicates connective tissue adjacent to epithelial renal cells to be responsible for local synthesis of IGF-1 [64, 65]. Research on human fetal kidney shows no expression of mRNA of IGF-1 in nephrogenic zone but only probably sequestration of IGF-1 peptide in proximal and distal tubules. Studies on rats and mouse shows the IGF-1 (mRNA and peptide) expression (immunolabeling) in collecting ducts. In situ hybridization studies indicate the mRNA expression in medullary thick ascending limb of henle’s loop [64, 66, 67]. IGF- 1 mediated decline in renal vascular resistance, leads to elevated glomerular perfusion, sodium and water resorption leading in turn to soft tissue swelling and glomerular hypertrophy [65, 68]. IGF1R gene expression were detected in whole nephogenic zone including the strong expression in glomeruli and the tubular epithelium of medulla with the least expression in proximal tubules . In contrary Kamenicky et al. shows the strong expression of mRNA of IGF1R in proximal tubule obtained from murine cells by microdissection [65, 70].
Expression of IGF-1 and IGF1R in ccRCC
The type 1 insulin-like growth factor receptor (IGF1R) has an influence on renal cells malignant transformation by induction of cell proliferation, dedifferentiation and anti-apoptotic effect [71, 72]. IGF-1 and IGF1R expression is modulated in kidney development. In mouse model of kidney development IGF-I mRNA is expressed in all cell types with peak in the proximal tubules, peritubular capillaries of the outer medulla and inner cortex one week after birth. The expression of IGF1R in normal proximal tubules was similar to IGF-1 during kidney development until birth , but it is poor prognosis factor in RCC . Overexpression of IGF family members was reported observed in oxidative stress (ferric nitrilotriacetate) induced RCC in rats . What is interesting RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression of that receptor . IGF-I pretreatment levels in RCC patients was predictive to impaired response to interleukin-2 (IL-2) therapy . In SN12K1 cells (cell line derived from metastatic RCC) it was shown that RCC express IGF-I and IGFBP-3, and autocrine IGF-I and IGFBP-3 stimulate and inhibit growth respectively. These cells are also are responsive to exogenous IGF-I stimulation - DNA synthesis is increased. These RCC cells are also responsive to exogenous IGF-I stimulation . Further experiments on RCC cell lines - Caki-2 (primary tumor) and SK-RC-52 (metastatic tumor) – have shown that IGF-I enhances transforming growth factor (TGF)-beta signaling including phosphorylation and nuclear translocation of mothers against decapentaplegic homolog 2 (Smad2). In turn TGF-beta promotes IGFBP-3 production . In mice model injection of MZ-4–71 - growth hormone-releasing hormone antagonist - reduced the IGF-1 induced growth of Caki 1 RCC cell line derived tumors .
In first clinical reports high serum IGF-I levels have been associated with an increased risk of developing RCC . At the same time in the analysis of 256 patients serum IGF-1 was not correlated with tumor stage or grade, but was independent favorable prognostic factors in a multivariable analysis . More recently the prospective study of 29 133 Finnish male smokers reported that men with IGF-I levels >113 ng ml(−1) were 59 % less likely to develop RCC than men with levels below or =113 ng ml(−1). Among those 100 men with RCC the IGF binding protein-3 (IGFBP-3) levels did not alter the association . In the study of 90 patients with ccRCC and 20 normal renal tissue samples, hyper-methylation of IGFBP-3 was not found, but in 786–0, ACHN, HRC51 and HRC59 cell lines methylation of IGFBP-3 was observed . Moreover IGF-I and its binding proteins IGFBP-3 and −6 are up-regulated in ccRCC tumor tissues . IGF1R expression was also associated with ccRCC and indicated molecular prognostic marker and potential targets for therapeutic intervention. Data of 280 patients who had ccRCC treated with radical nephrectomy showed that IGF1R expression had a 70 % increased risk of death than patients who had tumors without IGF1R expression . Finally nuclear IGF-1R was detected in primary renal cancer tissues of high proliferation rate and was associated with adverse prognosis .
Pathological and clinical grading system and IGF1R status
Fuhrman nuclear grading system correlates with staging of ccRCC. Studies on expression of IGF1R and Furman score in 68 ccRCC showed the statistically significance increasing correlation between Fuhrman grading and IGF1R staining . Also the high serum concentration of IGF1R is associated with the risk of many cancers such as breast, prostate, colorectal, and lung cancers . Overexpression of IGF1R is related with poor prognosis in many human cancers besides the renal cancer also in breast and ovarian cancers [84, 85]. Antisense strategies against the IGF1R suppresses the expression of IGF1R can abolish cell transformation [71, 83]. No correlation was observed between serum IGFBP-3 levels and RCC , but high expression of IGFBP-3 was found in ccRCC tumors. Fuhrman grades 3 and 4 ccRCC tumors showed higher IGFBP-3 expression than low grade tumors [80, 86].
Although the IGF1R and Insulin receptor (IR) show great homology and interaction they have different relation to the prognosis in ccRCC. Lkhagvadrj et al. investigated the role of IR expression in 126 ccRCC cases. Researchers showed that there was no differences of total IR protein between tumor and non-tumor but immunoreactivity of IR in tumor was mostly observed in nuclear but in non-tumor tissue in nuclear and cytoplasm. The expression of IR was elevated in low-grade tumor but not in higher-grade. Also the IR expression was inversely correlate with Furman nuclear grade and TNM, pathologic T stage in ccRCC. Higher expression of IR correlated with cystic changes in RCC which is favorable prognostic factor. What is interesting IR expression was not related to the diabetes presence. The authors suggest that although IR and IGF1R share the major down-stream signaling pathway, in RCC there are specific substrates for each receptor .
Interaction of VHL and IGF1R
Hereditary RCC is commonly associated loss or mutation of the Von Hippel-Lindau (VHL) tumor suppressor gene. VHL mutation was first discovered in patients with VHL disease by Latif F et al.  and VHL mutation or loss is identified in 60-90 % of sporadic RCC cases [7, 89]. Next 20 % of ccRCC show silencing of VHL expression by methylation in promoter region . VHL gene encodes protein with ubiquitin ligase E3 activity directing hypoxia-inducible factor-1α (HIF-1α) for degradation . HIF-1α regulate hypoxia response and promote angiogenesis, cell migration, and metabolism [7, 91] via VEGF, PDGF and TGF . Independently of oxygen status IGF1R activates HIF-1α protein by suppressing VHL and promote RCC development . At the same time IGF-1-mediated signaling is inhibited in the presence of wild-type VHL and VHL decrease stability of IGF-1R . In RCC cells beta-domain of VHL interact with protein kinase C delta (PKCD) and inhibits its association with IGF-IR and subsequent downstream signaling . It was also shown that receptor for activated C kinase 1 (RACK1) serves as a direct mediator between loss of pVHL function and IGF-IR signaling in RCC cells. Upon IGF-1 stimulation, pVHL-deficient RCC cells exhibit high rate of RACK1/IGF-IR binding and up-regulated IGF-1R tyrosine kinase activity, phosphoinositide 3-kinase/serine-threonine kinase Akt (PI3K/Akt) signaling and matrix metalloproteinase-2 (MMP-2) activity and high cellular invasiveness . VHL protein has no influence on ubiquitination of IGF1R. On the contrary the activity of IGF1R expression is regulated by VHL at the transcriptional level and is mediated by Sp1 transcription factor. Sp1 protein is sequestered by VHL and act on promoter of IGF1R. Loss of VHL gene increases therefore IGF1R mRNA stability. The levels of IGF1R is higher in ccRCC samples than in benign renal tumors which could be associated with VHL mutation rate in RCC [63, 96]. At the same time depletion of IGF1R enhance the chemosensitivity of ccRCC, but this effect is significant in cells with no functional VHL. Depletion of IGF1R changed sensitivity to mTOR inhibitors, 5-FU, etoposide but not cisplatin .
The role of IGF-1/Insulin pathway in cancerogenesis remain unclear. IGF-1 and insulin share major downstream regulation pathway and both are engaged in cancerogenesis and diabetes . There are evidences that diabetic patients have risk of development of renal cancer. Increase in mortality and incidence of renal cell carcinoma among diabetic patients is linked to hyperinsulinemia and obesity. The interaction of hyperglycemia, hyperinsulinemia causes the insulin resistant state and contribute to central adiposity which result in chronic inflammation. The adipose tissue-derived cytokines like resistin, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) promotes persistent inflammation and result in genetic instability, putting cells at risk to malignant transformation. Nuclear factor-kB is strongly activated by TNF-α what is associated with cell proliferation and surviving malignant cells . Associations between hyperinsulinemia and increased circulating levels of IGF-1 is proposed to be involved in carcinogenesis. IR and IGF-1 has a nuclear translocation potential and were postulated to be nonclassical transcription factors. IGF1R physically interact with gDNA and also stimulates itself expression. Study of nuclear IGF1R in primary renal cancer cells revealed that IGF1R expression was associated with poor prognosis in renal cancer . Cell culture experiments have proven that active IGF-IR is necessary for cell transformation by multiple cellular and viral oncogenes. IGF-IR signaling regulate the cell cycle, cell survival/proliferation, cell-cell interactions, ECM attachment, cell motility and metastatic spread. In mice model IGF-IR overexpression promotes tumor growth and metastases development, whereas down-regulation of IGF leads to slower tumor development . In general anti-diabetic treatment may increase the risk of RCC cancer development, but large prospective data is not available at this point of time. Exception is metformin an oral anti-diabetic drug has a RCC-protective effect as it interacts with the IGF signaling pathway which results in inhibition of proliferation and apoptosis regardless the p53 status .
ccRCC, Clear cell renal cell carcinoma; CTLA-4, cytotoxic T lymphocyte antigen 4; IGF-1, Insulin-like growth factor-1; IGF1R, IGF-1 receptor; IGFBPs, IGF-binding proteins; PD-1, programmed cell death 1; PDGFR, Platelet-derived growth factor receptors; RCC, renal cell carcinoma; VEGF, Vascular endothelial growth factor; VHL, Von Hippel–Lindau protein
This work has been supported by National Science Centre (NCN) grant No. UMO-2012/05/D/NZ5/01844 and Military Institute Medicine Statutory Founding (355).
Availability of data and material
Conceptualizing and refining research ideas - AMC; Literature search - AMC, AT; Creating review design - AMC; Collection of literature data - AMC, AT; Data selection - AT, AMC; Interpreting analyses - AMC, AT, CP, CS; Drafting manuscript AT, AMC; Editing manuscript AMC. All authors read and approved the final manuscript.
AMC is MD PhD - expert in molecular biology and medical doctor - specializes in clinical oncology and has been trained at the Universite degli Studi di Palermo, Paracelsus Medizinische Privatuniversität and Emory University School of Medicine. CS – MD PhD - is professor of clinical oncology specialist since 1986, and has worked at Temple University School of Medicine, Jefferson Cancer Institute at Thomas Jefferson University, and in the last 10 years has participated in major renal cancer treatment clinical trials including AXIS, EU-ARCCS or TARGET and is an expert in renal cancer treatment. AT is specialist in Medical Biotechnology and is MD in training, researcher in the Laboratory of Molecular Oncology, Military institute of Medicine, Warsaw, Poland. CP - Professor of Medical Oncology at the University of Pavia, School of Biotechnology, Responsible of the Laboratory of Pre-Clinical Oncology and Developmental Therapeutics at the IRCCS San Matteo University Hospital in Pavia, Member of ESMO Scientific Committee, involved in Development of new anticancer drugs, e.g., WR2721 (Amifostine), Nolatrexed (Thymitaq), BBR3438, Rampirnase (Onconase), BAY 43–9006 (Sorafenib), SU011248 (Sunitinib), RAD001 (Everolimus), Perifosine, ARQ197, Pazopanib and Satraplatin.
The authors declare that they have no competing interests.
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