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Insulin-like growth factor system in cancer: novel targeted therapies.

Brahmkhatri VP, Prasanna C, Atreya HS - Biomed Res Int (2015)

Bottom Line: These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs).We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions.This can lead to the development of novel cancer therapies.

View Article: PubMed Central - PubMed

Affiliation: NMR Research Centre, Indian Institute of Science, Bangalore 560012, India.

ABSTRACT
Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies.

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Related in: MedlinePlus

The IGF axis: circulating IGFs are protected from degradation by forming complex with IGFBPs. IGFs, apart from their local functioning in an autocrine or a paracrine manner, enter the bloodstream, where they exist as binary complexes with each IGFBP. In addition, ternary complex also exists when the binary complexes with IGFBP-3 or IGFBP-5 interact with the acid labile subunit (ALS). After dissociation of ternary complex, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors.
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fig1: The IGF axis: circulating IGFs are protected from degradation by forming complex with IGFBPs. IGFs, apart from their local functioning in an autocrine or a paracrine manner, enter the bloodstream, where they exist as binary complexes with each IGFBP. In addition, ternary complex also exists when the binary complexes with IGFBP-3 or IGFBP-5 interact with the acid labile subunit (ALS). After dissociation of ternary complex, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors.

Mentions: IGF-1 circulates in relatively high concentrations in plasma, approximately 150–400 ng per mL, where it mostly exists as the protein-bound form. The free ligand concentration is very little that is less than 1% [1]. IGFs in circulation are protected from degradation by forming a complex with a family of high affinity IGF binding proteins (IGFBPs) [2]. IGFBP-3 is the most abundant IGF binding protein in the blood stream followed by IGFBP-2, which is produced in the liver. Most of the circulating IGF-1 and IGF-2 are associated with a high molecular weight complex ~150 kDa consisting of IGFBP-3 and the acid labile subunit (ALS) [2]. Once the ternary complex dissociates, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors (Figure 1). In the tissues, IGFBPs may inhibit the interaction of the IGFs with their receptors, as the IGFBPs have a higher affinity for the IGFs than the receptors. In some cases, IGFBPs can enhance IGF action in the local microenvironment by acting as a reservoir that can slowly release the ligands. In addition, some IGFBPs can have IGF-independent effects on cells [2].


Insulin-like growth factor system in cancer: novel targeted therapies.

Brahmkhatri VP, Prasanna C, Atreya HS - Biomed Res Int (2015)

The IGF axis: circulating IGFs are protected from degradation by forming complex with IGFBPs. IGFs, apart from their local functioning in an autocrine or a paracrine manner, enter the bloodstream, where they exist as binary complexes with each IGFBP. In addition, ternary complex also exists when the binary complexes with IGFBP-3 or IGFBP-5 interact with the acid labile subunit (ALS). After dissociation of ternary complex, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383470&req=5

fig1: The IGF axis: circulating IGFs are protected from degradation by forming complex with IGFBPs. IGFs, apart from their local functioning in an autocrine or a paracrine manner, enter the bloodstream, where they exist as binary complexes with each IGFBP. In addition, ternary complex also exists when the binary complexes with IGFBP-3 or IGFBP-5 interact with the acid labile subunit (ALS). After dissociation of ternary complex, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors.
Mentions: IGF-1 circulates in relatively high concentrations in plasma, approximately 150–400 ng per mL, where it mostly exists as the protein-bound form. The free ligand concentration is very little that is less than 1% [1]. IGFs in circulation are protected from degradation by forming a complex with a family of high affinity IGF binding proteins (IGFBPs) [2]. IGFBP-3 is the most abundant IGF binding protein in the blood stream followed by IGFBP-2, which is produced in the liver. Most of the circulating IGF-1 and IGF-2 are associated with a high molecular weight complex ~150 kDa consisting of IGFBP-3 and the acid labile subunit (ALS) [2]. Once the ternary complex dissociates, the binary complexes of IGFBP-IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors (Figure 1). In the tissues, IGFBPs may inhibit the interaction of the IGFs with their receptors, as the IGFBPs have a higher affinity for the IGFs than the receptors. In some cases, IGFBPs can enhance IGF action in the local microenvironment by acting as a reservoir that can slowly release the ligands. In addition, some IGFBPs can have IGF-independent effects on cells [2].

Bottom Line: These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs).We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions.This can lead to the development of novel cancer therapies.

View Article: PubMed Central - PubMed

Affiliation: NMR Research Centre, Indian Institute of Science, Bangalore 560012, India.

ABSTRACT
Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies.

Show MeSH
Related in: MedlinePlus