The insulin-like growth factor (IGF) system plays a pivotal role in regulating cell growth, proliferation, and survival. Dysregulation of this system has been implicated in various types of cancer, making it a promising target for therapeutic interventions.
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Introduction of IGF
The discovery and history of the IGF system have roots in the identification of insulin and its subsequent exploration in the realms of glucose metabolism and diabetes mellitus. The IGF system's nomenclature evolved from sulfation factor to somatomedin and eventually insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2). While GH was initially believed to act primarily on the liver to stimulate IGF-1 production, it is now evident that GH has independent actions, and IGF-1 synthesis occurs in various tissues under diverse controls. The liver serves as the primary site for producing circulating IGFs, influenced by hormonal factors like GH and nutritional factors. Insulin-like growth factor binding proteins (IGFBPs), synthesized in the liver, contribute to the endocrine delivery of IGFs to responsive tissues.
The IGFs act in autocrine/paracrine manners through the IGF-1 receptor (IGF-1R), playing a crucial role in regulating cell proliferation and inhibiting apoptosis. Local factors, including receptor levels, IGFBPs, and IGFBP proteases, influence IGF bioavailability. High IGF levels throughout the body, maintained by IGFBPs, confer specificity to their actions on cell survival, growth, metabolism, and differentiated function.
Fig. 1 Insulin-like growth factor-1.
Targeting IGF-1R
The IGF-1R pathway, activated by tyrosine phosphorylation, propels cell survival and proliferation through PI3K/AKT and RAS/MAPK pathways. Genetic alterations in IGF-1R are linked to cancer, prompting the development of therapeutic approaches such as small molecule tyrosine kinase inhibitors (TKIs), anti-IGF-1R antibodies, antisense technology, and small interfering RNAs (siRNAs). The complexity increases with the formation of IGF-1R/IR hybrids, necessitating innovative targeting strategies.
Targeting IGFs
IGF-1 and IGF-2, the ligands binding to IGF-1R, have been identified as crucial players in cancer cell proliferation, survival, and metastasis. Therapeutic avenues include high-affinity antibodies neutralizing both IGF-1 and IGF-2, showcasing promising inhibitory effects on IGF signaling. Higher circulating levels of IGF-1 and IGF-2 are associated with increased cancer risk, highlighting the potential of these ligands as therapeutic targets.
Targeting IGFBPs
IGFBPs emerge as key players in the IGF system, with the ability to induce apoptosis in an IGF-independent manner. However, their dual role-preventing IGF binding and inducing tumor growth-poses challenges. Specific IGFBPs, such as IGFBP-3, exhibit cancer-suppressive functions, but the context-dependent nature of their effects necessitates a nuanced understanding for effective therapeutic targeting.
Cotargeting Strategies
Overcoming resistance to conventional therapies involves exploring cotargeting strategies. Combining IGF-R targeting with other pathways, such as EGFR and HIF-1, presents a novel approach. Noteworthy is the interaction of IGF-2R, implicated as a tumor suppressor in liver carcinogenesis, opening avenues for further exploration.
Natural Products Targeting IGF Signaling Pathways
Natural products have long been recognized for their medicinal benefits. Compounds like curcumin, genistein, and resveratrol exhibit anticarcinogenic activities by interfering with various stages of cancer, including IGF signaling. These natural products, with their rich historical significance, hold promise as potential sources for novel anticancer drugs.
In conclusion, therapeutic strategies targeting the IGF system in cancer have witnessed significant advancements, from understanding the intricacies of IGF-1R pathways to exploring the potential of natural products. The evolving landscape of cotargeting strategies and the exploration of modified IGFBPs offer hope for more effective and tailored approaches in the fight against cancer.
References
- Weroha S. J.; Haluska P. The insulin-like growth factor system in cancer. Endocrinology and Metabolism Clinics. 2012, 41(2): 335-350.
- Brahmkhatri V. P.; et al. Insulin-like growth factor system in cancer: novel targeted therapies. BioMed Research International. 2015.
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