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Review
. 2013 May;280(10):2138-49.
doi: 10.1111/febs.12149. Epub 2013 Feb 15.

Dichotomy of decorin activity on the insulin-like growth factor-I system

Andrea Morrione  1 , Thomas Neill, Renato V Iozzo
Affiliations
Review

Dichotomy of decorin activity on the insulin-like growth factor-I system

Andrea Morrione et al. FEBS J. 2013 May.

Abstract

The stromal-specific proteoglycan decorin has emerged in recent years as a critical regulator of tumor initiation and progression. Decorin regulates the biology of various types of cancer by modulating the activity of several receptor tyrosine kinases coordinating growth, survival, migration, and angiogenesis. Decorin binds to surface receptors for epidermal growth factor and hepatocyte growth factor with high affinity, and negatively regulates their activity and signaling via robust internalization and eventual degradation. The insulin-like growth factor (IGF)-I system plays a critical role in the regulation of cell growth both in vivo and in vitro. The IGF-I receptor (IGF-IR) is also essential for cellular transformation, owing to its ability to enhance cell proliferation and protect cancer cells from apoptosis. Recent data have pointed to a role of decorin in regulating the IGF-I system in both nontransformed and transformed cells. Significantly, there is a surprising dichotomy in the mechanism of decorin action on IGF-IR signaling, which differs considerably between physiological and pathological cellular models. In this review, we summarize the current knowledge on decorin regulation of the IGF-I system in normal and transformed cells, and discuss possible decorin-based therapeutic approaches to target IGF-IR-driven tumors.

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Figures

Fig. 1
Fig. 1
Schematic representation of the IGF-I system. The IGF-I system includes 6 binding proteins, three ligands and three major receptors. The IGF-IIR has no kinase activity and functions as a cellular “sink” to titrate IGF-II levels in the plasma. The alternatively-spliced IR genes, which gives rise to IR-B and IR-A, is critical for tissue glucose homeostasis while the IGF-IR is essential for cell proliferation. In neoplastic conditions, decorin binds IGF-I and IGF-IR to indirectly or directly, respectively, inhibit downstream signaling to IRS-1 and therefore stifle MAPK and PI3K coordinated pathways.
Fig. 2
Fig. 2
The dichotomy of decorin action on the IGF-I system. In normal cells decorin promotes IGF-IR phosphorylation and activation of downstream signaling, which is followed by receptor degradation. In cancer cells instead decorin inhibits ligand-induced IGF-IR activation and negatively regulates IGFIR-downstream signaling but do not affect receptor stability.
Fig. 3
Fig. 3
IGF-IR and decorin show a differential expression in bladder cancer. (A-D) Gallery of immunohistochemical images of low- and high-grade bladder cancer samples stained with antibodies specific for IGF-IR (A,B) or decorin (C,D). Notice that the IGF-IR is specifically expressed by the basal urothelium (arrows, A), but is markedly increased and extended to the full-thickness of the tumor in high-grade bladder cancer (B), with no stromal (St) expression. In contrast decorin is expressed primarily in the submucosal stroma of the urinary bladder (C) and its expression is markedly reduced in the stroma of high-grade bladder cancers. Bar = 200 μm.
See this image and copyright information in PMC

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References

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