The role of osteopontin in the progression of solid organ tumour

Abstract

Osteopontin (OPN) is a bone sialoprotein involved in osteoclast attachment to mineralised bone matrix, as well as being a bone matrix protein, OPN is also a versatile protein that acts on various receptors which are associated with different signalling pathways implicated in cancer. OPN mediates various biological events involving the immune system and the vascular system; the protein plays a role in processes such as immune response, cell adhesion and migration, and tumorigenesis. This review discusses the potential role of OPN in tumour cell proliferation, angiogenesis and metastasis, as well as the molecular mechanisms involved in these processes in different cancers, including brain, lung, kidney, liver, bladder, breast, oesophageal, gastric, colon, pancreatic, prostate and ovarian cancers. The understanding of OPN's role in tumour development and progression could potentially influence cancer therapy and contribute to the development of novel anti-tumour treatments.

Fig. 1. The OPN gene, protein, signalling pathway and function in normal tissues.

a The schematic representation of the location of OPN on human chromosome 4.OPN is at location 4q22.1. Genes encompassed within a 600 kb region on chromosome 4 encodes several noncollagenous bone and dentin proteins including OPN, bone sialoprotein(BSP), dentin matrix protein I (DMPI) and dentin sialophosphoportin (DSPP). All of them are classified as small intergrin-binding ligand N-linked glycoprotein (SIBLING) family proteins. b The signalling pathway of osteopontin. Osteopontin binds integrin α4β1 which causes degradation of phospharylated inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). Inhibitor of nuclear transcription factor kappa-B (IκBα) and nuclear transcription factor kappa-B (NF-κB; p50 and p65) are both freed following this process. IκBα is degraded by the ubiquitination pathway, while NF-κB enters the cell nucleus where it is phosphorylated and it enhances the expression of pro-survival genes. Moreover, upon binding of osteopontin to integrin α4β1, phosphorylated IKKβ causes inactivation of Forkhead box O3 (FOXO3A). Active FOXO3A is important in decreasing the expression of anti-survival genes such as BIM, BAK and BAX which cause caspase activation and cell apoptosis via mitochondrion and release of cytochrome c. Activation of OPN mediate a diverse range of cellular function, including cell survival/ proliferation, cell-cycle progression, cell migration, endothelial mesenchymal transition, T cell activation, cytokine production, fibrosis, angiogenesis and bone calcification and mineralisation

Fig. 2. The signalling pathway of osteopontin in tumour progression.

Osteopontin (OPN) can interact with several integrins in Arg-Gly-Asp (RGD) dependent and RGD independent manners. OPN can also interact with the CD44 family of receptors. Upon binding of receptors, OPN can induce cellular reactions include: survival, motility and tumour progression, MMP localisation and complement inhibition. By interacting with CD44 family of receptors, OPN can activate the cell anti-apoptotic signals in tumour cells through hospholipase C-γ(PLCγ–protein kinase C (PKC)–phosphatidylinositol 3-kinase (PI3K)–Akt pathway. Phosphatase and tensin homologue (PTEN) could inhibit Akt phosphorylation. Upon binding to αv β3, OPN activates AP1 through nuclear factor-inducing kinase (NIK)–ERK (extracellular signal-related kinase) and MEKK1 (mitogen-activated protein kinase kinase kinase1)–JNK1 (c-Jun N-terminal kinase 1) signalling pathways. AP1 promotes cancer cells motility and tumour progression. In addition, transactivation of epidermal growth factor receptor (EGFR) by OPN promotes phosphorylation of ERK which ultimately leads to activation of AP1. Activation of both MMP and HIF-1 pathways leads to enhanced tumour cell survival, proliferation, invasion and angiogenesis

Fig. 3. The role of osteopontin in multi-steps of cancer cell metastasis.

The OPN overexpression induces multi-steps of cancer cell metastasis through activating different protein mediators. A primary tumour undergoes vascularisation by angiogenesis as various growth factors such vascular endothelial growth factor are secreted. Detachment of the cancerous cell then occurs followed by intravasation; the tumour cell enters and circulates the vascular system. The cell eventually attaches to the wall of the blood vessel before undergoing extravasation and leaving the blood vessel. The tumour cell then grows as a secondary tumour causing metastasis

Fig. 4. The role of osteopontin in various solid organ tumours.

Osteopontin (OPN) has demonstrated a role in the development of various solid organ tumours via various differing mechanisms. In breast, brain, ovarian and prostate cancers, OPN has been shown to preferentially bind to a variety of integrins including αvβ1, and αvβ5, αvβe, αvβ3, resulting in an increase in cell adhesion, migration, and invasion, whilst OPN has been shown to bind to both integrin and CD44 receptors in lung cancers. In addition to receptor binding, OPN is involved in enhancing MMP release and thus increasing cell invasiveness and tumour growth in brain, liver, pancreas, colorectal, ovarian and prostate, and oesophageal and gastric cancers. OPN-mediated upregulation of the PI3K/Akt signalling pathway is a common feature of liver, lung, ovarian and prostate tumour progression, thus preferentially regulating cell survival, cell cycle progression and cellular growth in favour of tumour development. Activation of VEGF and its downstream effector, HIF-1α, by OPN may occur dependently or independently of PI3K/Akt activation and promotes tumour angiogenesis, recruitment of endothelial cells and tumour growth, particularly in colorectal, pancreatic, lung, and oesophageal and gastric malignancies. Activation of the JNK pathway by OPN has been shown to be most specific to colorectal cancer, whilst the precise role of OPN in bladder and kidney cancers, particularly, remains to be elucidated. OPN osteopontin, MMP metalloproteinase, PI3K Phosphatidylinositol-3 kinase, VEGF vascular endothelial growth factor, HIF-1α hypoxia-inducible factor 1