Limits...
Targeting insulin-like growth factor axis in hepatocellular carcinoma.

Wu J, Zhu AX - J Hematol Oncol (2011)

Bottom Line: The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins.Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC.Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Hematology and Medical Oncology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. jennifer.wu@nyumc.org

ABSTRACT
The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC.

Show MeSH

Related in: MedlinePlus

IGF-IR downstream signal transduction. The activated IGF-IR initiates signalling through two separate connections, the insulin receptor substrate (IRS) and the Shc proteins. Both IRS and Shc proteins can in turn activate both MAP Kinase (MAPK) and PI3 kinase (PI3K) pathways. MAPK pathway leads to activation of Ras and then ERK, and PI3K pathway activates AKT/mTOR, both then stimulate signals for mitogens.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3141798&req=5

Figure 2: IGF-IR downstream signal transduction. The activated IGF-IR initiates signalling through two separate connections, the insulin receptor substrate (IRS) and the Shc proteins. Both IRS and Shc proteins can in turn activate both MAP Kinase (MAPK) and PI3 kinase (PI3K) pathways. MAPK pathway leads to activation of Ras and then ERK, and PI3K pathway activates AKT/mTOR, both then stimulate signals for mitogens.

Mentions: Among the substrates of IGF-1R, IRS plays a prominent role in exerting the activity of IGF-1R by activating downstream signals [16]. After IGF-1R activation, additional tyrosine residues are then phosphorylated, which act as docking stations for substrates such as the insulin receptor substrate (IRS) and Shc adaptor proteins (Figure 2). IRS and Shc adaptor proteins then recruit additional factors to yield activations of two major cascades, the phosphatidyl inositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK), both result in cell differentiation, proliferation and anti-apoptosis [16,22]. There are currently 4 types of IRS proteins [48], the effects of IRS-1 and 2 are opposite to that of IRS-3 and 4 [16]. IRS-1 is the most well understood IRS, and it is essential to the activation of IGF-1R. When IRS-1 was abundant, it promoted cell size growth, activated p70 S6K, a kinase that promotes cell proliferation and leads to transformation [49]. Meanwhile, IRS-1 turned off IGF-1R's stimulation for differentiation through its phosphotyrosine binding (PTB) domain, therefore inhibited differentiation and stimulated transformation [50]. When IRS-1 was inhibited or malfunctions, such as the case when there was a mutation of its PTB domain, transformation no longer continued and these cells tend to undergo differentiation. The inhibitor of p70S6K such as rapamycin, which is an inhibitor in the mammalian target of rapamycin (mTOR) pathway, also produced similar effects as the mutated PTB domain, thus cells exposed to rapamycin tend to grow slowly with good differentiation [51].


Targeting insulin-like growth factor axis in hepatocellular carcinoma.

Wu J, Zhu AX - J Hematol Oncol (2011)

IGF-IR downstream signal transduction. The activated IGF-IR initiates signalling through two separate connections, the insulin receptor substrate (IRS) and the Shc proteins. Both IRS and Shc proteins can in turn activate both MAP Kinase (MAPK) and PI3 kinase (PI3K) pathways. MAPK pathway leads to activation of Ras and then ERK, and PI3K pathway activates AKT/mTOR, both then stimulate signals for mitogens.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3141798&req=5

Figure 2: IGF-IR downstream signal transduction. The activated IGF-IR initiates signalling through two separate connections, the insulin receptor substrate (IRS) and the Shc proteins. Both IRS and Shc proteins can in turn activate both MAP Kinase (MAPK) and PI3 kinase (PI3K) pathways. MAPK pathway leads to activation of Ras and then ERK, and PI3K pathway activates AKT/mTOR, both then stimulate signals for mitogens.
Mentions: Among the substrates of IGF-1R, IRS plays a prominent role in exerting the activity of IGF-1R by activating downstream signals [16]. After IGF-1R activation, additional tyrosine residues are then phosphorylated, which act as docking stations for substrates such as the insulin receptor substrate (IRS) and Shc adaptor proteins (Figure 2). IRS and Shc adaptor proteins then recruit additional factors to yield activations of two major cascades, the phosphatidyl inositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK), both result in cell differentiation, proliferation and anti-apoptosis [16,22]. There are currently 4 types of IRS proteins [48], the effects of IRS-1 and 2 are opposite to that of IRS-3 and 4 [16]. IRS-1 is the most well understood IRS, and it is essential to the activation of IGF-1R. When IRS-1 was abundant, it promoted cell size growth, activated p70 S6K, a kinase that promotes cell proliferation and leads to transformation [49]. Meanwhile, IRS-1 turned off IGF-1R's stimulation for differentiation through its phosphotyrosine binding (PTB) domain, therefore inhibited differentiation and stimulated transformation [50]. When IRS-1 was inhibited or malfunctions, such as the case when there was a mutation of its PTB domain, transformation no longer continued and these cells tend to undergo differentiation. The inhibitor of p70S6K such as rapamycin, which is an inhibitor in the mammalian target of rapamycin (mTOR) pathway, also produced similar effects as the mutated PTB domain, thus cells exposed to rapamycin tend to grow slowly with good differentiation [51].

Bottom Line: The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins.Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC.Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Hematology and Medical Oncology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. jennifer.wu@nyumc.org

ABSTRACT
The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC.

Show MeSH
Related in: MedlinePlus