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Morrione, A. IGF System in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/8269 (accessed on 15 December 2025).
Morrione A. IGF System in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/8269. Accessed December 15, 2025.
Morrione, Andrea. "IGF System in Cancer" Encyclopedia, https://encyclopedia.pub/entry/8269 (accessed December 15, 2025).
Morrione, A. (2021, March 25). IGF System in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/8269
Morrione, Andrea. "IGF System in Cancer." Encyclopedia. Web. 25 March, 2021.
IGF System in Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/biom11020273

The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. 

IGF system cancer

1. The IGF System: Receptors, Ligands and Binding Proteins

Bioactivity of the IGF system initiates with ligands (IGFs and insulin) binding to their cognate receptors. The two major receptors of the IGF system are the IGF1R and IR. They are transmembrane tyrosine kinase receptors (RTKs) composed of two α and two β subunits involved in ligand binding and signal transduction, respectively [1]. The IGF1R is expressed in a variety of human tissues and its activation results in the regulation of cell survival, proliferation, differentiation and protein synthesis [2].

The IR exists in two splicing isoforms: the IR-A, which is mainly expressed in fetal tissues and cancer cells, driving mitogenic signals and partially overlapping with IGF1R signaling [3], and the IR-B, which is preferentially expressed in adult tissues (for a detailed review please see [4]), and mediates metabolic functions [4]. The high sequence homology (60%) and the frequent co-expression of the IGF1R and IR determine the formation of hybrid receptors, consisting of an insulin αβ hemi-receptor and an IGF1 αβ hemi-receptor [5]. Interestingly, IR-A and IR-B are equally capable of forming hybrid receptors with the IGF1R, but those hybrids are functionally distinct [5].

Different downstream responses elicited by the receptors are strictly connected to the different expression pattern and ligand affinity. There are major differences between ligands properties and receptors affinities, which have been recently discussed [6][4]. Briefly, insulin displays the highest affinity for the IR >> IR/IGF1R hybrid > IGF1R; IGF1 displays the highest affinity for IGF1R > IR/IGF1R hybrid > IR; IGF2 displays the highest affinity to IGF1R/IGF2R > IR-A > IR/IGF1R hybrid >> IR-B [6].

While IGF2R lacks intrinsic kinase activity and acts as a scavenger of extracellular IGF2 [7], the IRR has been long viewed as an orphan receptor but recent data have demonstrated that the IRR acts as an extracellular Alkali Sensor [8][9].

A critical modulator of IGF bioactivity is the superfamily of 6 circulating IGFBPs (IGFBP1-6). IGFBPs are characterized by high affinity for IGF1 and IGF2 but not for insulin. Accordingly, 99% of circulating IGFs exist in complex with IGFBPs [10]. Thus, IGFBPs elicit a major modulatory role on IGF-dependent function by prolonging the half-life of IGFs, regulating the clearance of the IGFs, providing tissue specific localization and regulating binding to their receptors [11][10]. IGFBPs also elicit IGF-independent functions interacting with a variety of non-IGF binding partners at the cell surface and within the cell, in both the cytoplasm and the nucleus, thus modulating proliferation and migration [12]. The combined activity of binding proteins, ligands and receptors contributes to the activation of intracellular signaling pathways. Upon ligand binding, the kinase domain of the IGF1R, IR or hybrid receptors undergoes auto-transphosphorylation on tyrosine residues in the tyrosine-kinase domain and receptor activation with subsequent recruitment of downstream effector proteins including the insulin receptor substrate (IRS) proteins IRS-1-6 and Src homology 2 domain-containing transforming protein (Shc) [2]. Phosphorylation of these proteins leads to downstream activation of the phosphoinositide 3-kinase (PI3K)-Akt [13] and mitogen-activated protein kinase (MAPK) [14] pathways and the regulation of the aforementioned effects on metabolism and cell behavior.

2. The IGF System in Cancer

To date, the role of IGF system in cancer onset and progression has been documented in a variety of human malignancies [15][16][17]. Despite the vast majority of studies originally focused on the specific role of the IGF1R [18], it is now clear that expression or functional alterations of all components of the IGF axis are important factors in contributing to IGF1R action in cancer. Epidemiologic evidences indicated that high serum levels of IGF1 correlate with increased risk of cancer [19][20]. Accordingly, patients affected by Laron syndrome, a disease characterized by congenital deficiency of IGF1, do not develop cancer [21]. In 1993, Sell and colleagues demonstrated that the simian virus 40 large tumor antigen (SV40 TAg) was unable to transform fibroblasts derived from mouse embryos homozygous for a null mutation of the igf1r gene (R− cells) [18]. Subsequent studies demonstrated that a variety of viral and cellular oncogenes require an active IGF1R for transformation [22] including the human papilloma virus E5 [23] and E7 protein [24], an activated c-Ha-ras oncogene [25], c-src [26], the Ewing sarcoma fusion protein EWS-ETS [27], the ETV6-NTRK3 chimeric tyrosine kinase [28], overexpressed growth factor receptors like EGFR [29], PDGFR [30] or IR [31]. In all cases, transformation of R− cells was fully restored upon re-expression of the IGF1R [22].

2.1. Regulation of IGF System in Cancer

Dysregulation of the IGF axis strongly contributes to the malignant phenotype. Mechanisms correlating with an unbalanced IGF network include receptor overexpression, alterations in ligands availability and dysregulation of downstream signaling effectors, while mutations of the receptors are uncommon. A notable exception is represented by osteosarcoma, where recurrent mutations of IGF signaling genes have been recently uncovered [32]. These mutations include focal amplification of IGF1R and IGF1, and frameshift indels in the recessive cancer genes IGF2R and IGFBP5 [32]. Amplification of the IGF1R was also identified in a percentage of breast tumors, co-occurring with the CKS1BP7 pseudogene amplification [33], gastrointestinal stromal tumors [34], melanoma [35], and pancreatic adenocarcinoma [36]. Altered expression of members of the IGF axis is attributed to mutations or aberrant expression of transcriptional regulators. For instance, IGF1R activation occurs as a consequence of mutations of tumor suppressor genes [37][38] including breast cancer gene-1 (BRCA1) [39], the Wilm’s tumor protein-1 (WT1) [40], the von Hippel–Lindau gene (VHL) [41] and p53 (TP53) [42]. Interestingly, p53 regulates gene expression of other IGF system components including INSR [43], IGF2 and IGFBP3 [44]. Increased INSR expression in tumor cells is also modulated by the upregulation of Sp1 and HMGA1 transcription factors [45]. Several studies have identified proteins involved in alternative splicing that favor IR-A prevalence in tumor cells. As previously covered by Vella and colleagues, interesting correlations exist between IR-A abundance and CUG-BP1, hnRNP family, SR proteins and Muscleblind-like (MBNL) proteins [45]. Alterations in IGFs availability result in aberrant activation of the IGF axis. In this landscape, the overexpression of the pregnancy associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves IGFBP4, increases the bioavailability of IGFs on the cell surface, which acts in autocrine/paracrine manner to increase locally available ligands for IGF1R and IR-A activation in tumor cells [46][47]. Similarly, the overexpression of the metalloproteinases ADAM17 and ADAM28, which specifically act on IGFBP3, favors cancer cells proliferation by enhancing IGF1 bioavailability [48][49]. In addition, loss-of-heterozygosity of IGF2R favors the interaction between IGF2 and IGF1R in different tumor types [50][51]. Finally, alterations in intracellular signaling molecules can alter IGF equilibrium. In glioma, a specific mutation in phosphatase and tensin homologue (PTEN) gene, a tumor suppressor and lipid phosphatase, determines the truncation of its C-terminal region with consequent gain of neo-morphic and phosphatase-independent activity, which stimulates IGF1 synthesis [52]. Among other downstream effectors, the docking protein IRS-1 is constitutively activated in a variety of solid tumors, including breast cancers, leiomyomas, Wilms’ tumors, rhabdomyosarcomas, liposarcomas, leiomyosarcomas and adrenal cortical carcinomas [53]. A recent pan-cancer study identified signaling via SHC family adapter proteins and PI3K/Akt/mTOR among the pathways highly mutated in cancer [54].

2.2. Effects of IGF System in Cancer Progression, Response to Therapies and Cellular Metabolism

Many previous reviews have nicely described the important role that the IGF system plays in transformation [16][55][56]. This section will highlight some examples of molecular mechanisms driven by IGF bioactivity, which modulate cell behavior, treatment response and metabolism.

The IGF axis drives cancer cell proliferation, cell–cell adhesion and migration. As mentioned above, the activation of the PI3K/Akt and MAPK pathways plays a critical role in mediating IGF action in cancer, and it is often associated with aberrant activation/inhibition of transcription factors. The PI3K/Akt pathway is the main regulator of the Forkhead box O (FoxO) family of transcription factors, which acts as a tumor suppressor in different tumors [57][58]. In thyroid cancer, IGF1-mediated activation of Akt promotes FoxO1 export from the nucleus, inhibition of FoxO1-mediated transcriptional activation of target genes like CDKN1B (p27KIP1) cell cycle inhibitor, thus promoting cell proliferation [59]. In addition, IGF1R activation determines phosphorylation and nuclear translocation of STAT3, which modulates transcriptional activation of cancer-associated genes. In ovarian cancer, the activation of the IGF1R/STAT3 axis promotes cell migration, invasion and in vitro spheroid formation and induces in vivo tumor growth [60]. Additional cancer genes modulated by a dysregulated IGF1R-STAT3 axis are ALDH1 [61] and Nanog [62], which enhance the epithelial-to-mesenchymal transition (EMT)-associated cancer stem cells (CSC)-like properties in non-small cell lung cancer and colorectal cancer, respectively.

IGF1R signaling strongly associates with EMT [63]. The expression of EMT-associated proteins like N-cadherin, vimentin, Snail and Twist is positively associated with IGF1/IGF1R activation. However, the mechanisms characterizing this functional interaction are still not fully defined [64]. In hepatocellular carcinoma, EMT is driven by IGF1-induced activation of the transcription factor STAT5 [64], while in prostate cancer cells, IGF1 stimulation up-regulates ZEB1, a zinc finger homeodomain transcriptional repressor. ZEB1 increases the expression of mesenchymal markers such as fibronectin and N-cadherin while repressing E–cadherin, thus favoring cancer cell migration and invasion through the activation of the MAPK pathway [65]. Similarly, IGF1 enhances the expression of CYR61, a member of the extracellular matrix-associated CCN family, which triggers EMT specific features in vitro and in vivo [66][67]. Notably, in osteosarcoma and breast cancer, CYR61 controls the N-cadherin/E-cadherin ratio as well as the expression of other markers such as Snail, Slug, Vimentin, thereby favoring spheroid growth and cell invasion while impairing cell–cell and cell–matrix adhesion [66][67]. As recently reported, the IGF1/IGF1R axis promotes the activation of focal adhesion kinase (FAK) signaling, which in turn regulates nuclear accumulation of YAP (yes-associated protein/yes-related protein), a major component of the Hippo pathway, and increased expression of its target genes including CYR61 [68].

Aberrant activation of IGF system in cancer has been associated with resistance to cytotoxic therapy, including chemotherapy and radiotherapy, and targeted therapy. IGF1R mediates resistance to cisplatin treatment in different tumor types [69][70]. Particularly, in vitro evidences derived from cisplatin-resistant cell lines derived from ovarian and testicular tumors indicated that IGF1R induction and activation of Akt downstream signaling represent major events in the acquisition of resistance. Accordingly, combination of anti-IGF agents with chemotherapeutics could promote re-sensitization to treatment in chemo-resistant disease [70]. In addition to the IGF1R, other effectors of the IGF system play a role in treatment response. In esophageal adenocarcinoma, treatment-resistant patients display high expression levels of IGFBP2 as compared to chemo-naive patients. Significantly, simultaneous IGFBP2 depletion and pharmacological inhibition of Akt and MAPK pathways sensitized esophageal adenocarcinoma cells to cisplatin therapy [71]. The relevance of IGFBPs in treatment response has been additionally reported in glioblastoma, where IGF2/IGF1R expression is associated with poor response to temozolomide. In addition, in vitro studies indicate a heterogeneous model where proliferation of temozolomide-resistant cells, characterized by an active IGF2/IGF1R axis, is controlled at paracrine level by temozolomide-sensitive cells, expressing high levels of circulating IGFBP6. Temozolomide treatment destroys treatment-responsive cells therefore enriching the tumor mass with resistant cells [72]. Recent evidence has highlighted the role that the IGF system plays in promoting resistance to novel epigenetic anti-cancer agents. In Ewing sarcoma cells, constitutive activation of the IGF1R confers resistance to inhibitors of the family of bromodomain and extra-terminal domain (BET) proteins, which recognize acetylated histone marks, thus recruiting supramolecular complexes to promote active transcription. Accordingly, over expression of a constitutively active form of Akt significantly increased resistance to the BET inhibitor in Ewing sarcoma cells [73].

Several studies implicate the IGF system in radioresistance. It is well established that ionizing radiation activates tyrosine kinase receptors involved in DNA damage response, including the IGF1R, as in fact targeting the IGF1R enhances radiosensitivity of different cancer cell lines [74][75]. A study conducted in murine glioma stem cells indicated that exposure to radiation increases IGF1 secretion, induces gradual increase in IGF1R expression, a decrease in phosphorylated Akt, activation of FoxO3a with consequent reduced proliferation, enhanced self-renewal through FoxO3 target genes and, ultimately, radioresistance [76]. Exposure of nasopharyngeal carcinoma cells to ionizing radiation boosted the expression of both phosphorylated IGF1R and γH2AX, a double-strand DNA breaks marker. Interestingly, combinatorial treatment with ionizing radiation and the anti-IGF1R agent linsitinib increased radiosensitivity by evoking G2-M cell cycle delay and enhanced apoptosis as compared to single treatments [77]. However, the molecular mechanisms underlying IGF1R-mediated radioresistance are cell context-dependent. In colorectal adenocarcinoma cells, IGF1R expression was associated with γ-irradiation resistance via transcriptional up-regulation of genes involved in DNA repair, including MSH4, RAD51 and BRCA2, rather than double strand breaks repair mechanisms [17].

Compensatory activation of various components of the IGF system often occurs in response to target therapies. In Ewing sarcoma, transcriptional up-regulation and autocrine activation of the IGF2/IR-A axis represents a major mechanism of resistance to anti-IGF1R agents [78]. Accordingly, dual IGF1R/IR inhibitors have been developed and their efficacy has been proved in different tumor types [55][79][80]. Over-activation of the IGF1R accounts for resistance to EGFR tyrosine kinase inhibitors. Interestingly, in non-small cell lung cancer cells, resistance to EGFR inhibitors was attenuated upon incubation with EGFR tyrosine kinase and IGF1R pathway inhibitors, which synergistically induce apoptosis by blocking Akt phosphorylation and inducing the expression of FoXO-regulated pro-apoptotic genes [81]. More recently, experiments conducted in Ewing sarcoma cells have demonstrated that IGF1R upregulation promotes resistance to CDK4/6 inhibitors suggesting that dual targeting of CDK4/6 and IGF1R may represent a synergistic combination with potential clinical implications for therapy in this disease [82]. Alterations in IGFBP2 expression are associated with resistance to both anti-IGF1R agents and dasatinib in rhabdomyosarcoma [83] and non-small cell lung cancer cells [84], respectively. Particularly, loss of IGFBP2 is associated with resistance to anti-IGF1R treatment due to hyperactivation of IGF signaling in rhabdomyosarcoma [83], while overexpression of IGFBP2 drives dasatinib resistance through activation of FAK in non-small cell lung cancer cells [84].

Metabolic reprogramming is a hallmark of cancer. Tumor cells metabolize glucose through aerobic glycolysis, rather than oxidative phosphorylation. This metabolic change determines an enhanced need of glucose uptake for ATP synthesis and generation of those metabolic intermediates necessary for biosynthesis of nucleotides, lipids and protein supporting cell proliferation [85][86]. Cancer cells also display metabolic flexibility, which allows the switch from glycolysis to oxidative phosphorylation and vice versa, supporting a role of mitochondria in cancer progression [87]. Experimental evidences have demonstrated a strong connection between the IGF system and metabolic reprogramming in cancer. IGF1R activation enhances glucose consumption, lactate and ATP production through the Akt pathway and consequent upregulation of GLUT1, a glucose transporter [88][89]. A study conducted by Vella and colleagues demonstrated that the IGF2/insulin/IR-A/PI3K/MAPK axis contributes substantially to energetic metabolic phenotype of breast cancer MCF-7 cells by increasing glycolytic activity, mitochondrial functions and cell bioenergetics [86]. In particular, IGF2 overexpression determined enhanced transforming capability of MCF7 cells compared to control cells as well as increased glucose consumption, increased lactate production, increased mRNA expression of glucose and lactate transporters and glycolytic enzymes. Significantly, the more aggressive phenotype was associated with increased mRNA expression of genes involved in mitochondrial biogenesis, fusion and activity, increased ATP production and enhanced glycolysis. Similarly, in breast cancer cells, IGF1 stimulates mitochondrial homeostasis by increasing oxidative phosphorylation to produce ATP required for proliferation. Particularly, IGF1 stimulates mitochondrial biogenesis and autophagy (mitophagy) through the PI3K pathway and induction of PGC-1β expression and PRC transcriptional activators, which support the transcription of mitochondrial genes and maintain mitochondrial morphology and mass, and induction of BNIP3, a major mediator of mitochondrial turnover [90].

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