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  • Review Article
  • Published:

Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer

Nature Reviews Cancer volume 8, pages 212–226 (2008)Cite this article

Key Points

  • Small integrin-binding ligand N-linked glycoproteins (SIBLINGs) are a family of glycophosphoproteins comprising osteopontin (OPN), bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE).

  • The genes encoding the SIBLINGs are located within a cluster on chromosome 4 and encode soluble, hydrophilic proteins sharing common functional motifs and domains, including an Arg–Gly–Asp (RGD) motif that binds αvβ3 integrin.

  • SIBLINGs were initially described as mineralized tissue-associated glycophosphoproteins and were thought to be functionally restricted to these tissues. Recent results show that they are more widely distributed and are expressed in non-mineralized normal tissue, such as metabolically active ductal epithelial cells.

  • Some SIBLINGs activate specific metalloproteinases (MMPs; BSP activates MMP2, OPN, MMP3 and DMP1, MMP9). These three SIBLINGs also bind complement factor H and prevent complement attack.

  • SIBLINGs are overexpressed in many cancers. OPN and, less so, BSP are by far the more widely studied to date and their levels of expression are correlated with tumour aggressiveness. SIBLINGs can be detected in the blood and their level of expression is associated with prognosis.

  • Among SIBLINGs, OPN is involved in almost all steps of tumour progression, including invasion, metastasis and angiogenesis.

  • In vitro and in vivo experimental models demonstrated that interference with SIBLINGs, such as small interfering RNA selective knockdown, has potential anticancer therapeutic value.

  • Identifying the specific roles of SIBLINGs in cancer–stroma interactions and signalling cascades involving growth factor–growth factor receptor and cell–matrix interactions could result in the development of additional and refined strategies for the prevention and treatment of metastases.

Abstract

Numerous components and pathways are involved in the complex interplay between cancer cells and their environment. The family of glycophosphoproteins comprising osteopontin, bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein — small integrin-binding ligand N-linked glycoproteins (SIBLINGs) — are emerging as important players in many stages of cancer progression. From their detection in various human cancers to the demonstration of their key functional roles during malignant transformation, invasion and metastasis, the SIBLINGs are proteins with potential as diagnostic and prognostic tools, as well as new therapeutic targets.

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Figure 1: Chromosomal localization and exon–intron similarities of human SIBLING genes.
Figure 2: SIBLINGs mediate cell–matrix interactions and cellular signalling.
Figure 3: The role of SIBLING proteins at different steps of the metastatic cascade.
Figure 4: SIBLINGs and their cell receptors are potential therapeutic targets for cancer therapy.

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Acknowledgements

The work of A.B. and V.C. is supported by grants from the National Fund for Scientific Research (Belgium), the Centre Anti-Cancéreux of the University of Liège and the European Commission through METABRE Contract CEE LSHC-CT-2004-503049. The work of K.O. is supported by National Institute of Dental and Craniofacial Research/National Institutes of Health (NIH) Grant K23 017791-01A1, Medical College of Georgia Research Institute Grant STP 00105W005, and the Wendy Will Case Cancer Fund. The research of L.W.F. is supported by the Intramural Research Program of the NIH, Department of Health and Human Services. The work of N.S.F. is supported by grants from the National Cancer Institute (R21CA87311 and R01 CA113865) and from the Department of Defense Congressionally Directed Medical Research Program (W81XWH-04-1-0844 and BC010478).

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Authors and Affiliations

  1. Metastasis Research Laboratory, University of Liege, Tour de Pathologie, -1, Bât. B23, Sart Tilman via, Liège, 4000, Belgium

    Akeila Bellahcène & Vincent Castronovo

  2. Department of Oral Biology, School of Dentistry, Medical College of Georgia, Augusta, 30912, Georgia, USA

    Kalu U. E. Ogbureke

  3. Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892–4320, Maryland, USA

    Larry W. Fisher

  4. Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, 21224, Maryland, USA

    Neal S. Fedarko

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  1. Akeila Bellahcène
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Correspondence to Larry W. Fisher.

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DATABASES

National Cancer Institute

bladder cancer

breast cancer

cervical carcinoma

colorectal cancer

gastric cancer

glioma

head and neck cancer

leukaemia

lung cancer

melanoma

multiple myeloma

non-small cell lung carcinoma

oral cancer

pancreatic cancer

prostate cancer

renal cell cancer

skin cancer

thyroid carcinomas

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Glossary

Integrin

Integrins are a large family of heterodimeric cell surface adhesion receptors that bind extracellular matrix and cell surface ligands. They promote stable interactions between cells and their environment and mediate intracellular signalling.

Dentin

The main, calcareous part of a tooth, beneath the enamel and surrounding the pulp chamber and root canals.

RGD motif

A tripeptide, Arg–Gly–Asp (RGD), found in numerous proteins that support cell adhesion. A subset of the integrins recognize the RGD motif within their ligands, the binding of which mediates both cell–substratum and cell–cell interactions.

Hydroxyapatite crystals

The principal inorganic constituent of bone matrix and teeth, imparting rigidity to these structures, and consisting of hydrated calcium phosphate, Ca5(PO4)3 OH.

Metabolically active normal duct

Epithelia, such as that of the kidney nephrons, that alter the tonicity of the fluid they process in the course of normal physiology. The kidney nephrons process isotonic urine into the voided hypotonic urine.

Type 0 introns

Introns that disrupt an open reading frame between codon junctions and therefore permit any splicing combination to other type 0 exons without causing frameshifts.

Metabolically passive normal duct

Epithelia, such as that of the lacrimal gland ducts, that do not alter the tonicity of the fluid they process in the course of normal physiology. Tears from the lacrimal acini are isotonic and are secreted unchanged through the duct system.

CD44

A family of cell surface signal-transducing glycoproteins involved in cell–cell interactions, cell adhesion and migration. CD44s bind hyaluronan, a high-molecular-mass polysaccharide found in the extracellular matrix, and a variety of extracellular as well as cell surface ligands. CD44 exists in multiple spliced forms and shows a high variability in glycosylation.

Transglutaminases

A family of enzymes that catalyse the crosslinking of proteins at a glutamine in one chain with lysine in another chain. Although the family members have different structures, they share an active site (Tyr–Gly–Gln–Cys–Trp) and strict Ca2+ dependence.

Osteoclast

A cell that breaks down mineralized bone and is responsible for bone resorption.

Dental pulp cells

Cells that comprise the soft tissue forming the inner structure of a tooth and containing nerves and blood vessels as well as possibly dentin stem cells.

Osteotropic

Describes tumours that metastasize preferentially to the skeleton.

Bone lesions

Lytic lesions are areas of the bone marked by destruction, whereas sclerotic lesions are areas of the bone marked by thickening or hardening. A mixed lytic and sclerotic lesion exhibits facets of both resorption (destruction) and thickening (formation).

Opsonization

The process whereby opsonins (antibodies or complement proteins) make an invading cell or microorganism more susceptible to phagocytosis by binding to its surface.

Chicken chorioallantoic membrane assay

A biological assay using the well-vascularized chorioallantoic membrane of the chicken egg to evaluate the biological activity of pro- and anti-angiogenic factors.

Renal osteodystrophy

A bone disease characterized by softening and fibrous degeneration of bone and the formation of cysts in bone tissue, caused by chronic renal failure.

Eccrine sweat ducts

These ducts transport sweat to the surface of the skin and are involved in evaporative cooling.

Oncogenic hypophosphataemic osteomalacia

Osteomalacia (softening of the bones) resulting from renal phosphate wasting and low serum 1, 25-dihydroxy vitamin D secondary to the presence of a tumour of which complete resection results in rapid resolution of the symptoms and signs.

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Bellahcène, A., Castronovo, V., Ogbureke, K. et al. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer 8, 212–226 (2008). https://doi.org/10.1038/nrc2345

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