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The Role of Osteopontin in Cancer

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Introduction

Osteopontin (OPN) is a noncollagenous bone extracellular matrix protein. It is secreted as an adhesive glycoprotein with a functional RGD cell-binding domain that interacts with the integrin heterodimer expressed on the cell surface. It is associated with malignant transformation in cells, and it is also a ligand to the CD44 receptor. The role of the extracellular matrix and the intracellular signalling that occurs through the integrin heterodimers in cancer pathogenesis remains to be elucidated. Further, it can be stated safely that the progression of cancer in terms of tumour cell growth, adhesion, migration, and metastasis is critically governed by the extracellular matrix. The amino acid sequence that determines cell attachment is RGD, arginine-glycine-aspartic acid since this binds to the ανβ3 integrin heterodimer. In this respect, it must be noted that the expression of these proteins of the bone matrix is not limited solely to the bone tissue. For example, after translation, OPN is highly modified, is a glycoprotein, and contains the RGD sequence. With the progression of cancer research, it is increasingly recognized that OPN has a role in several cancers, especially those cancers which are known to have bone metastasis. Apart from the elucidation of the molecular mechanism of OPN in progression and metastasis of disease, OPN has become one of the cell surface markers to diagnose cancer in the very early stages. In some cases, its expression has been linked with the prognosis of some diseases (Rittling and Chambers, 2004, 1877-1881).

The Role of Osteopontin in Cancer

Attachment of a tumour cell to the endothelium depends on the interaction of mutually complementary cell surface molecules or cadherins or by receptors that can engage different domains of the same ligand, such as osteopontin. In theory, osteopontin could involve an integrin on one cell, and a variant of CD44 on the other. OPN is a glycosylated phosphoprotein, as described earlier, and is present in bone and all body fluids. The function in mineralised tissues such as bone is that of a cytokine. The service that is relevant to the progression of cancer or cancer pathogenesis is that it acts as a cell adhesion protein through its ability to bind with various integrins and CD44 variants, which maintain the integrity of cells in the tissue architecture. There has been extensive literature which establishes the involvement of OPN in cancer genesis and the progression of tumors in the form of metastatic disease. Some of the latest literature will be reviewed in this article to consolidate information on its role in cancer (Rodrigues et al., 2007, 1087-1097).

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Historically, OPN was identified as a marker of the transformation of epithelial cells. The evidence and knowledge about its role in cancer are now dictating it to be an essential molecule with a significant role in cell signalling. In fact, OPN’s growing popularity in the field of oncology is now attributed to its importance as a predictor of malignancy as well as being a candidate who may suggest prognosis. Such functions emanate from proof of the study, often focused on experiments with animals. It has been reported that OPN protein or mRNA is identified in an array of biological models independent of each other. Apart from it being recognized as the critical noncollagenous bone matrix protein, its functions have been substantiated in the immune system regulation through cytokine production and cell trafficking in the vascular system through inhibition of ectopic mineralization and macrophage accumulation. Physiologically, phosphorylated after secretion, this protein has been found at high concentrations in body fluids (Rittling and Chambers, 2004, 1877-1881). It demonstrates a strong affinity towards the Hydroxyapatite, and thus it accumulates in the areas of bone or other sites of mineralization. In terms of cellular signalling properties, these are derivatives of the molecular architecture of OPN. The molecule lacks a secondary structure. The central region of the unit has integrin-binding sequences of seven different variants. These different integrins are ανβ3 and β5, and a series of β1-containing integrins.

 

Moreover, this protein structure has a cryptic α9β1 site that is available for interaction only following protease cleavage (Rittling and Chambers, 2004, 1877-1881). This indicates OPN fragments may have significant biologic properties. The cellular interaction, as mentioned, is mediated through both integrins and CD44, and recent research suggests that binding with CD44 may also be functionally crucial due to its binding on the interior face of the cellular CD44 molecule. The nontumorigenic functions also bear a resemblance to tumorigenic features. An idea would be available from the fact that in the bone, osteoclast activity is enhanced as a result of the action between OPN and osteoclast cell surface integrins. Calcium is an important cell signalling molecule both in health and disease both in health and disease, and OPN demonstrates multiple interactions with calcium. Along with macrophages, OPN recruits and stimulates lymphocytes. This affects nitric oxide production and is involved in cell migration (Donati et al., 2005, 6459-6465).

 

Before going specifically into its role in cancer, the cellular functions of OPN needs to be comprehended. Its services about adhesive activity have been established through the observation that all its receptors mediate cell adhesion. Additionally, it also regulates migration in that it is an essential chemotactic agent for many cell types, and the cells which lack OPN also lack motility and movement. This function is exceptionally relevant to cancer pathogenesis since these can be correlated well with its intrinsic role in cellular migration. Since it regulates cytokine production by macrophages, it can act as a survival factor in many diverse systems. Although its position and action in different disease states remains to be elucidated further, it has been reported that exogenous OPN has been demonstrated to induce a dose-dependent transformation of preneoplastic mouse epidermal JB6 cells in artificial media. In some situations, OPN has been shown to stimulate angiogenesis and tumour cell growth (Rudland et al., 2006, 1192-1200).

 

A large number of studies have established that OPN expression renders cells more tumorigenic. In some cases, along with this, the metastatic potential of the specific tumour is enhanced following its appearance. OPN is overexpressed in human cancers, and overexpression of OPN confers malignant transformation. This phenomenon has been observed in multiple human cell lines that are tumorigenic. This observation is consistent with substantially elevated levels of OPN in patients with metastatic cancers.

The suggested mechanisms by which it might enhance the metastatic proficiency of cancer cells may include its ability to promote cell adhesion or to inhibit expression of inducible nitric oxide synthase since OPN production by metastasizing cancer cells might protect them from being killed by NO produced by cytotoxic macrophages. There is also growing evidence that OPN may facilitate metastases of many cancers to bone (Zhang, He, and Weber, 2003, 6507-6519).

 

OPN has been shown in many studies to inhibit apoptosis, perhaps thereby allowing higher levels of expression of the ras oncogene. Ha-ras-transfected NIH 3T3 fibroblasts are tumorigenic and metastatic in contrast to untransformed and unmodified fibroblasts, and these express increased levels of OPN. These cells, when transfected with anti-sense OPN RNA, the tumorigenic and metastatic potentials are drastically reduced. An example may be human esophageal cancer, where ras-regulated gene products OPN and cathepsin-L were demonstrated to be associated with invasive tumours with high metastatic potential. Another mechanism by which OPN might foster metastasis is by promoting the migratory and invasive properties of the cells. OPN enhances the migratory and invasive properties of mammary epithelial cells, apparently by upregulating expression of urokinase-type plasminogen activator (uPA) and improving the activity of various growth factor receptor kinases including hepatocyte growth factor receptor (Met) and epidermal growth factor (EGF). Others have reported that OPN could synergize with VEGF to stimulate endothelial cell migration or could enhance FGF-2-mediated angiogenesis (Kim et al., 2002, 1671-1679).

 

On the face of an enormous amount of data accumulated and extensive continuing research, OPN mRNA and protein be present in histological sections of a variety of human cancers, and they are elevated relative to healthy tissues. Discussion of specific diseases and its relation to OPN is outside the scope of this article; however, it can be clearly stated that the role of OPN in tumour development is complex and is determined by various factors such as the type of the tumour and the experimental system utilized to study this. The microenvironment in the tumour largely determines the effect of OPN on it. OPN, in turn, can be expressed by multiple cell types in the internal micro milieu of cancer including the tumour cells themselves, activated immune cells, remodelling vascular cells, and even bone cells, when the tumour grows in the bone itself (Zhang, He, and Weber, 2003, 6507-6519). It would be legitimate to expect from the available findings that OPN from different sources mediate different effects, such as various post-translational modifications, differential cleaving and fragmentations, leading to differential functions. Cancer of breasts, ovary, and prostate, non-small cell lung cancers have all been associated with the expression of OPN, especially when the patient presents with metastatic disease and progressive cancer. OPN positivity, as a prognostic marker, has been associated with patient survival. The present state of affairs is such that immunohistochemistry of tumour tissue sections, expression array studies in tumour tissues, or quantification of OPN RNA in the tumour cells have been able to detect OPN in human lung, breast, prostate, gastric, oesophageal, ovarian cancers and glioma. For example, outcome data suggest that studies on OPN expression may be a method of marker studies for tumour progression. It can also be a prognostic indicator in the sense that OPN immunopositivity in lung cancer can be used to predict patient survival in a statistically significant manner (Hu et al., 2005, 4646-4652).

 

Research has established that if OPN expression is upregulated explicitly in a good rat mammary cell line, RAMA37, either by transfection with specific “metastasis-inducing sequences” or a plasmid engineered to express OPN, the cells acquire a malignant phenotype. It has provided compelling evidence that OPN can enhance the metastatic potential of cancer cells. Taking the example of prostate cancer, these cancer cells are known to very frequently metastasize to bone, and these cells commonly adhere to and increase in bone. Clinically, these events are characterized by an induction of osteoblastic activity in the metastatic spots. OPN has been shown to recruit quiescent human prostatic epithelial cells into the proliferative phase (Rudland et al., 2006, 1192-1200). OPN could also alter the tumour microenvironment in that it alters local macrophage synthesis of nitric oxide to favour tumour growth and androgen-dependent progression. Studies have also indicated that OPN may be the significant soluble factor secreted by the osteoblasts as well as prostate cancer cells, and this may account for such stimulated anchorage-dependent growth of prostate cancer cells. Moreover, clinical prostate tumour specimens from high Gleason score cases of metastatic samples express higher levels of OPN (Khodavirdi et al., 2006, 883-888). 

 

Conclusion

Substantial data have accumulated that document the expression of OPN in human cancers, produced by stromal cells or by the tumour cells themselves. OPN production has been demonstrated in human breast cancers, and it has been confirmed by in situ hybridizations that tumour cells are often, but not always, responsible for elevated OPN synthesis. Not only in highly invasive breast cancers but human primary breast cancer cells also predominantly express OPN. From the evidence presented here, OPN can have utility as potential blood or tissue marker of metastatic cancer, since it is present in body fluids and blood. OPN blood levels have been elevated in several diseases, and an ELISA test has already been developed to measure this. Research is underway, and one day will come, OPN will have more varied clinical applications in cancer detection, prediction, prognostication, and management (Bramwell et al., 2006, 3337-3343). 

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Reference

  • Bramwell, VHC., Doig, GS., Tuck, AB., Wilson, SM., Tonkin, KS., Tomiak, A., Perera, F., Vandenberg, TA., and Chambers, AF., (2006). Serial Plasma Osteopontin Levels Have Prognostic Value in Metastatic Breast Cancer. Clin. Cancer Res.; 12: 3337 – 3343.
  • Donati, V., Boldrini, L., Dell’Omodarme, M., Prati, MC., Faviana, P., Camacci, T., Lucchi, M., Mussi, A., Santoro, M., Basolo, F. and Fontanini, G., (2005). Osteopontin Expression and Prognostic Significance in Non–Small Cell Lung Cancer. Clin. Cancer Res.; 11: 6459 – 6465.
  • Hu, Z., Lin, D., Yuan, J., Xiao, T., Zhang, H., Sun, W., Han, N., Ma, Y., Di, X., Gao, M., Ma, J., Zhang, J., Cheng, S., and Gao, Y. (2005). Overexpression of Osteopontin Is Associated with More Aggressive Phenotypes in Human Non–Small Cell Lung Cancer. Clin. Cancer Res.; 11: 4646 – 4652.
  • Khodavirdi, AC., Song, Z., Yang, S., Zhong, C., Wang, S., Wu, H., Pritchard, C., Nelson, PS., and Roy-Burman, P., (2006). Increased Expression of Osteopontin Contributes to the Progression of Prostate Cancer. Cancer Res.; 66: 883 – 888.
  • Kim, J., Skates, SJ., Uede, T., Wong, K., Schorge, JO., Feltmate, CM., Berkowitz, TS., Cramer, DW., and Mok, SC., (2002). Osteopontin as a Potential Diagnostic Biomarker for Ovarian Cancer. JAMA; 287: 1671 – 1679.
  • Rittling, SR. and Chambers, AF., (2004). Role of osteopontin in tumour progression; British Journal of Cancer, 90, 1877–1881.
  • Rodrigues, LR., Teixeira, JA., Schmitt, FL., Paulsson, M., and Lindmark-Mänsson, H., (2007). The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer. Cancer Epidemiol. Biomarkers Prev.; 16: 1087 – 1097.
  • Rudland, S., Martin, L., Roshanlall, C., Winstanley, J., Leinster, S., Platt-Higgins, A., Carroll, J., West, C., Barraclough, R., and Rudland, P., (2006). Association of S100A4 and Osteopontin with Specific Prognostic Factors and Survival of Patients with Minimally Invasive Breast Cancer. Clin. Cancer Res.; 12: 1192 – 1200.
  • Zhang, G., He, B., and Weber, GF., (2003). Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer. Mol. Cell. Biol.; 23: 6507 – 6519.

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