The Role of Osteopontin in Cancer - Essay Example

Critically discuss the role of osteopontin in cancer 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 has been shown to be 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 signaling that occurs through the integrin heterodimers in cancer pathogenesis remain to be elucidated further, it can be stated safely that progression of a cancer in terms of tumor cell growth, adhesion, migration, and metastasis is critically governed by extracellular matrix. The amino acid sequence that determines cell attachment is RGD, arginine-glycine-aspartic acid, since this binds to the '''3 integrin heterodimer. In this regard, it must be remembered that the expression of these bone matrix proteins is not confined to the bone tissue exclusively. OPN, for example is highly modified after translation, is a glycoprotein, and contains the RGD sequence. With progression of cancer research, it is being increasingly recognised that OPN has role in several cancers, especially those cancers which are known to have bone metastasis. Apart from elucidation of the molecular mechanism of OPN in progression and metastasis of cancer, OPN has become one of the cell surface markers to diagnose cancer in the very early stages, and in some cases, its expression has been linked with the prognosis of some cancers (Rittling and Chambers, 2004, 1877-1881). Attachment of a tumor cell to the endothelium depends on the interaction of mutually complementary cell surface molecules or cadherins or by receptors that are able to engage different domains of the same ligand, such as osteopontin. In theory, osteopontin could engage an integrin on one cell and a CD44 variant on the other cell. As mentioned earlier, OPN is a glycosylated phosphoprotein, and it is found in bone and all body fluids. In mineralized tissues such as bone, its function is that of a cytokine. The function that is relevant to 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 integrity of cells in the tissue architecture. The literature that establishes the involvement of OPN in genesis of cancer and in the progression of tumor in the form of metastatic disease has been extensive. In this article, some of those latest literatures will be reviewed to consolidate the knowledge about its role in cancer (Rodrigues et al., 2007, 1087-1097). Historically, OPN was identified as a marker of transformation of epithelial cells. The evidence and knowledge about its role in cancer are now dictating it to be an important molecule with significant role in cell signaling. Moreover, the considerable interest about OPN in the field of Oncology is now for its significance as a marker of malignancy as well as a candidate that can indicate prognosis. These roles emanate from research evidence, mostly based on animal experiments. OPN protein or mRNA has been reported to be identified in an array of biological models that are independent of each other. Apart from it being identified as the key 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, this protein is variably phosphorylated following secretion, and high concentrations have been detected in the 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 in other sites of mineralization. In terms of cellular signaling properties, these are derivatives of the molecular architecture of OPN. Apparently, the molecule lacks a secondary structure. The central region of the molecule has integrin binding sequences of seven different variants. These different integrins are '''3 and '5, and a series of '1-containing integrins. Moreover, this protein structure has a cryptic '9'1 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 indicates that binding with CD44 may also be functionally important due to its binding on the interior face of the cellular CD44 molecule. The nontumorigenic functions also bear resemblance to tumorigenic functions. An idea would be available from the fact that in the bone, osteoclast activity is enhanced as a result of action between OPN and osteoclast cell surface integrins. Calcium is a significant cell signaling 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 functions in relation to 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 important chemotactic agent for many cell types, and the cells which lack OPN also lack motility and movement. This function is extremely 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 role 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 tumor cell growth (Rudland et al., 2006, 1192-1200). A large number of studies have established that OPN expression renders cells more tumorigenic, and in some cases, along with this, the metastatic potential of the specific tumor is enhanced following its expression. OPN has been shown to be 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 tumor 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 enhancing 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 enormous amount of data accumulated and extensive continuing research, OPN mRNA and protein have been found to be present in histological sections of a variety of human cancers, and they are elevated relative to normal tissues. Discussion of specific cancers and its relation to OPN is outside the scope of this article; however, it can be clearly stated that the role of OPN in tumor development is complex and is determined by various factors such as the type of the tumor and the experimental system utilised to study this. The microenvironment in the tumor largely determines the effect of OPN on it. OPN in turn can be expressed by multiple cell types in the internal micromilieu of a cancer including the tumor cells themselves, activated immune cells, remodeling vascular cells, and even bone cells, when the tumor grows in 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, different 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 expression of OPN, specially when the patient presents with a 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 tumor tissue sections, expression array studies in tumor tissues, or quantification of OPN RNA in the tumor 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 tumor 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 specifically upregulated in a benign rat mammary cell line, RAMA37, either by transfection with certain "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 proliferate 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 proliferative phase (Rudland et al., 2006, 1192-1200). OPN could also alter the tumor microenvironment in that it alters local macrophage synthesis of nitric oxide to favour tumor growth and androgen-dependent progression. Studies have also indicated that OPN may be the major 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 tumor specimens from high Gleason score cases or metastatic specimens 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 tumor cells themselves. OPN production has been demonstrated in human breast cancers, and it has been confirmed by in situ hybridization that tumor cells are often, but not always, responsible for elevated OPN synthesis. Not only in highly invasive breast cancers, human primary breast cancer cells also predominantly express OPN . From the evidence presented here, OPN can have utility as a potential blood or tissue marker of metastatic cancer, since it is present in body fluids and blood. OPN blood levels have been elevated in a number of cancers, 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 application in cancer detection, prediction, prognostication, and management (Bramwell et al., 2006, 3337-3343). Reference List 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-M'nsson, 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. Read More