Abstract
Elevated osteopontin (OPN) transcription often correlates with increased metastatic potential of transformed cells, and in several model systems OPN – whether produced by the tumor cells or by stromal cells – has been shown to enhance metastatic ability. Sequence elements in the OPN promoter have been identified on the basis of their ability to interact with protein factors associated with the tumorigenic process in one or more cell lineages. One of these is a Ras-activated enhancer (RAE) that binds a protein, the Ras-response factor (RRF), whose ability to form a complex with the RAE is stimulated by Ras signaling in fibroblasts and epithelial cells. Another is the T cell factor-4 binding site, which in the OPN promoter can retard OPN transcription when bound by the Tcf-4 protein. In Rama 37 rat mammary epithelial cells Tcf-4 suppresses OPN transcription and the metastatic phenotype. A third promoter segment consists of two sequences in the −94 to −24 region of the human OPN promoter able to bind several known transcription factors, including Sp1, Myc and Oct-1, which may act synergistically to stimulate OPN transcription in malignant astrocytic cells. Although expression of other genes may also be regulated by these transcription factors, evidence suggests that often OPN alone can stimulate metastasis. In this communication we address two issues: (1) How does OPN facilitate the metastatic phenotype? (2) What mechanisms are responsible for the increase in OPN transcription in metastatic cells?
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References
Senger DR, Perruzzi CA, Gracey CF et al. Secreted phosphoproteins associated with neoplastic transformation: Close homology with plasma proteins cleaved during blood coagulation. Cancer Res 1988; 48: 5770–4.
Chambers AF, Tuck AB. Ras-responsive genes and tumor metastasis. Crit Rev Oncogen 1993; 4: 95–114.
Denhardt DT, Guo X. Osteopontin a protein with diverse functions. FASEB J 1993; 7: 1475–82.
Oates AJ, Barraclough R, Rudland PS. The role of osteopontin in tumorigenesis and metastasis. Invasion Metastasis 1997; 17: 1–15.
Uede T, Katagiri Y, Iizuka J et al. Osteopontin, a coordinator of host defense system: A cytokine or an extracellular adhesive protein? Microbiol Immunol 1997; 41: 641–8.
Rittling SR, Denhardt DT. Osteopontin function in pathology: Lessons from OPN-deficient mice. Expt Nephrology 1999; 7: 103–13.
Noda M, Denhardt DT. Osteopontin. In Bilezikian JP, Raisz LG, Rodan GA (eds): Principles of Bone Biology, 2nd ed. San Diego: Academic Press 2002.
Chabas D, Baranzini SE, Mitchell D et al. The influence of the proin-flammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001; 294: 1731–5.
Yumoto K, Ishijima M, Rittling SR et al. Osteopontin deficiency protects joints against destruction in anti-type II collagen antibodyinduced arthritis in mice. Proc Natl Acad Sci USA 2002; 99: 4556–61.
Giachelli CM, Steitz S. Osteopontin: A versatile regulator of inflammation and biomineralization. Matrix Biol 2000; 19: 615–22.
Weber GF. The metastasis gene osteopontin: A candidate target for cancer therapy. Biochim Biophys Acta 2001; 1552: 61–85.
Denhardt DT, Noda M, O’Regan AW et al. Osteopontin-a means to cope with environmental insults: Regulation of inflammation tissue remodeling and cell survival. J Clin Invest 2001; 107: 1055–61.
Tuck AB, Chambers AF. The role of osteopontin in breast cancer: Clinical and experimental studies. J Mammary Gland Biol Neoplasia 2001; 6: 419–29.
Furger KA, Menon RK, Tuck AB et al. The functional and clinical roles of osteopontin in cancer and metastasis. Curr Mol Med 2001; 1: 621–32.
Rittling SR, Chen Y, Feng F, Wu Y. Tumor-derived osteopontin is soluble, not matrix associated. J Biol Chem 2002; 277: 9175–82.
Katagiri YU, Sleeman J, Fujii H et al. CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis. Cancer Res 1999; 59: 219–26.
Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med 2000; 11: 279–303.
Suzuki K, Zhu B, Rittling SR et al. Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts. J Bone Miner Res 2002; 17:1486–97.
Denhardt DT, Lopez CA, Rollo EE et al. Osteopontin-induced modi-fications of cellular functions. Ann NY Acad Sci 1995; 760: 127–42.
Noiri E, Dickman K, Miller F et al. Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene. Kidney Int 1999; 56: 74–82.
Scatena M, Almeida M, Chaisson ML et al. NF-κB mediates ανβЗ integrin-induced endothelial cell survival. J Cell Biol 1998; 141: 1083–93.
Lin Y-H, Yang-Yen H-F. The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol-3-kinase/Akt signaling pathway. J Biol Chem 2001; 276: 46024–30.
Khan SA, Lopez-Chua CA, Zhang J, Fisher LW, Sorensen ES, Denhardt DT. Soluble osteopontin inhibits apoptosis of adherent endothelial cells deprived of growth factors. J Cellul Biochem 2002; 85: 728–36.
Senger DR, Asch BB, Smith BD et al. A secreted phosphoprotein marker for neoplastic transformation of both epithelial and fibroblastic cells. Nature 1983; 302: 714–5.
Brown LF, Papadopoulos-Sergiou A, Berse B et al. Osteopontin expression and distribution in human carcinomas. Am J Pathol 1994; 145: 610–23.
Bellahcene A, Castronovo V. Increased expression of osteonectin and osteopontin two bone matrix proteins in human breast cancer. Am J Pathol 1996; 146: 95–100.
Casson AG, Wilson SM, McCart JA et al. Ras mutation and expression of the ras-regulated genes osteopontin and cathepsin L in human esophageal cancer. Int J Cancer 1997; 72: 739–45.
Gillespie MT, Thomas RJ, Zhou PU et al. Calcitonin receptors bone sialoprotein and osteopontin are expressed in primary breast cancers. Int J Cancer 1997; 10: 812–815.
Tuck AB, O’Malley FP, Singhal H et al. Osteopontin expression in a group of lymph node negative breast cancer patients. Int J Cancer 1998; 79: 502–8.
Sung V, Gilles C, Murray A et al. The LCC15-MB human breast cancer cell line expresses osteopontin and exhibits invasive and metastatic phenotype. Exp Cell Res 1998; 241: 273–84.
Sharp JA, Sung V, Slavin J et al. Tumor cells are the source of osteopontin and bone sialoprotein expression in human breast cancer. Lab Invest 1999; 79: 869–77.
Price JE, Polyzos A, Zhang RD et al. Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 1990; 50: 717–21.
Zhang RD, Fidler IJ, Price JE. Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis. Invasion Metastasis 1991; 11: 204–15.
Price JE. Metastasis from human breast cancer cell lines. Breast Cancer Res Treat 1996; 39: 93–102.
Bautista DS, Xuan JW, Hota C et al. Inhibition of Arg-Gly-Asp (RGD)-mediated cell adhesion to osteopontin by a monoclonal antibody against osteopontin. J Biol Chem 1994; 269: 23280–5.
Tuck AB, Arsenault DM, O’Malley FP et al. Osteopontin induces increased invasiveness and plasminogen activator expression of human mammary epithelial cells. Oncogene 1999; 18: 4237–46.
Yoneda T, Williams PJ, Niewolna M. Promotion of angiogenesis and enhancement of breast cancer metastasis to bone. Bone 1998; 23/5S: S201.
Mukhopadhyay R, Price JE. Stable expression of antisense osteopontin inhibits the growth of human breast cancer cells. Proc Am Assoc Cancer Res 1999; 40: 448.
Senger DR, Perruzzi CA, Papadopoulos A. Elevated expression of secreted phosphoprotein I (osteopontin, 2ar) as a consequence of neoplastic transformation. Anticancer Res 1989; 9: 1291–300.
Chambers AF, Tuck AB. Osteopontin: A Ras-regulated gene that contributes to tumor metastasis. InWelch DR (ed): Cancer Metastasis-Related Genes. Dordrecht, The Netherlands: Kluwer Academic Publishers 2002; 231–46.
Hwang S-M, Lopez CA, Heck DE et al. Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. J Biol Chem 1994; 269: 711–5.
Rollo EE, Laskin DL, Denhardt DT. Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW2647 macrophages. J Leuk Biol 1996; 60: 397–404.
Scott JA, Weir ML, Wilson SM et al. Osteopontin inhibits inducible nitric oxide synthase activity in rat vascular tissue. AmJ Physiol 1998; 275: H2258–65.
Denhardt DT, Chambers AF. Overcoming obstacles to metastasis — defenses against host defenses: Osteopontin (OPN) as a shield against attack by cytotoxic host cells. J Cell Biochem 1994; 56: 48–51.
Yue TL, McKenna PJ, Ohlstein EH et al. Osteopontin-stimulated vascular smooth muscle cell migration is mediated by β3 integrin. Exp Cell Res 1994; 214: 459–64.
Liaw L, Skinner MP, Raines EW et al. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins: Role of ανβ3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest 1995; 95: 713–24.
Senger DR, Perruzzi CA. Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. Biochim Biophys Acta 1996; 1314: 13–24.
Weintraub AS, Giachelli CM, Krauss RS et al. Autocrine secretion of osteopontin by vascular smooth muscle cells regulates their adhesion to collagen gels. Am J Path 1996; 149: 259–72.
Tuck AB, Elliott BE, Hota C et al. Osteopontin-induced integrindependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor. J Cell Biochem 2000; 78: 465–75.
Tuck AB, Hota C, Chambers AF. Osteopontin-induced increase in human mammary epithelial cell invasiveness is urokinase (uPa)-dependent. Breast Cancer Res Treat 2001; 70: 197–204.
Takahashi F, Akutagawa S, Fukumoto H et al. Osteopontin induces angiogenesis of murine neuroblastoma cells in mice. Int J Cancer 2002; 98: 707–12.
Chambers AF, Wilson SM, Kerkvleit N et al. Osteopontin expression in lung cancer. Lung Cancer 1996; 15: 311–23.
Rudland PS, Platt-Higgins A, El-Tanani M et al. Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Res 2002; 62: 3417–27.
Kim JH, Skates SJ, Uede T et al. Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 2002; 287: 1671–9.
Gotoh M, Sakamoto M, Kanetaka K et al. Overexpression of osteopontin in hepatocellular carcinoma. Pathol Int 2002; 52: 19–24.
Agrawal D, Chen T, Irby R et al. Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 2002; 94: 513–21.
Bautista DS, Saad Z, Chambers AF et al. Quantification of osteopontin in human plasma with an ELISA: Basal levels in pre-and postmenopausal women. Clin Biochem 1996; 29: 231–9.
Singhal H, Bautista DS, Tonkin KS et al. Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival. Clin Cancer Res 1997; 3: 605–11.
Hotte SJ, Winquist, EW, Stitt L et al. Plasma osteopontin: Associations with survival and metastasis to bone in men with hormone refractory prostate cancer. Cancer, 2002; 95: 506–512.
Fedarko NS, Fohr B, Robey PG et al. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complementmediated attack. J Biol Chem 2000; 275: 16666–72.
Fedarko NS, Jain A, Karadag A et al. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001; 7: 4060–6.
O’Regan A, Fleming C. Comment on: JAMA 2002, 287: 1671-9. Osteopontin as a biomarker for ovarian cancer. JAMA 2002; 287: 3208–10.
Crawford HC, Matrisian LM, Liaw L. Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res 1998; 58: 5206–15.
Feng F, Rittling SR. Mammary tumor development in MMTV-cmyc/ MMTV-v-Ha-ras transgenic mice is unaffected by osteopontin deficiency. Breast Cancer Res Treat 2000; 63: 71–9.
Wu Y, Denhardt DT, Rittling SR. Osteopontin expression is required for full expression of the transformed phenotype by the Ras oncogene. Br J Cancer 2000; 83: 156–63.
Nemoto H, Rittling SR, Yoshitake H et al. Osteopontin deficiency reduces experimental tumor cell metastasis to bone and soft tissues. J Bone Miner Res 2001; 16: 652–9.
Orphanides G, Reinberg DA. Unified theory of gene expression. Cell 2002; 108: 439–52.
Hunter T. Oncoprotein networks. Cell 1997; 88: 333–46.
Webb CP, Vande Woude GF. Genes that regulate metastasis and angiogenesis. J Neurooncol 2000; 50: 71–87.
Welch DR, Steeg PS, Rinker-Schaeffer CW. Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis. Breast Cancer Res 2000; 2: 408–16.
Denhardt DT, Noda M. Osteopontin expression and function: Role in bone remodeling. J Cell Biochem 1998; Suppl 30/31: 92–102.
Craig AM, Bowden GT, Chambers AF et al. Secreted phosphoprotein mRNA is induced during multistage carcinogenesis in mouse skin and correlates with the metastatic potiential of murine fibroblasts. Int J Cancer 1990; 46: 133–7.
Yoon JW, Kita Y, Frank DJ et al. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 2002; 277: 5548–55.
Davies BR, Barraclough R, Rudland PS. Induction of metastatic ability in a stably diploid benign rat mammary epithelial cell line by transfection with DNA from human malignant breast carcinoma cell lines. Cancer Res 1994; 54: 2785–93.
Oates AJ, Barraclough R, Rudland PS. The identification of osteopontin as a metastasis-related gene product in a rodent mammary tumour model. Oncogene 1996; 13: 97–104.
Chen H, Ke Y, Oates AJ et al. Isolation of and effector for metastasisinducing DNAs from a human metastatic carcinoma cell line. Oncogene 1997; 14: 1581–8.
El-Tanani M, Barraclough R, Wilkinson MC et al. Regulatory region of metastasis-inducing DNA is the binding site for T cell factor-4. Oncogene 2001; 20: 1793–7.
El-Tanani M, Barraclough R, Wilkinson MC et al. Metastasisinducing DNA regulates the expression of the osteopontin gene by binding the transcription factor Tcf-4. Cancer Res 2001; 61: 5619–29.
Wang D, Yamamoto S, Hijiya N et al. Transcriptional regulation of the human osteopontin promoter: Functional analysis and DNA-protein interactions. Oncogene 2000; 19: 5801–9.
Malyankar UM, Hanson R, Schwartz SM et al. Upstream stimulatory factor 1 regulates osteopontin expression in smooth muscle cells. Exp Cell Res 1999; 250:535–47.
Bos JL. Ras oncogenes in human cancer: A review. Cancer Res 1989; 49: 4682–9.
Varghese HJ, Davidson MT, MacDonald IC et al. Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases. Cancer Res 2002; 62: 887–91.
Rak J, Kerbel RS. Ras regulation of vascular endothelial growth factor and angiogenesis. Methods Enzymol 2001; 333: 267–83.
Guo X, Zhang YP, Mitchell DA et al. Identification of a ras-activated enhancer in the mouse osteopontin gene and its interaction with a putative ETS-related transcription factor whose activity correlates with the metastatic potential of the cell. Mol Cell Biol 1995; 15: 476–87.
Craig AM, Denhardt DT. The murine gene encoding secreted phosphoprotein (osteopontin): Promoter structure activity and induction in vivo by estrogen and progesterone. Gene 1991; 100: 163–71.
Zhang Q, Wrana JL, Sodek J. Characterization of the promoter region of the porcine opn (osteopontin secreted phosphoprotein 1) gene. Eur J Biochem 1992; 207: 649–59.
Hijiya N, Setoguchi M, Matsuura K et al. Cloning and characterization of the human osteopontin gene and its promoter. Biochem J 1994; 303: 255–62.
Rafidi K, Simkina I, Johnson E et al. Characterization of the chicken osteopontin-encoding gene. Gene 1994; 140: 163–9.
Ridall AL, Daane EL, Dickinson DP et al. Characterization of the rat osteopontin gene. Evidence for two vitamin D response elements. Ann NY Acad Sci 1995; 760: 59–66.
Webb CP, van Aelst L, Wigler MH et al. Signaling pathways in Rasmediated tumorigenicity and metastasis. Proc Natl Acad Sci USA 1998; 95: 8773–8.
Morishita R, Higaki J, Tomita N et al. Application of transcription factor ‘decoy’ strategy as means of gene therapy and study of gene expression in cardiovascular disease. Circ Res 1998; 82: 1023–8.
Tomita S, Tomita N, Yamada T et al. Transcription factor decoy to study the molecular mechanism of negative regulation of renin gene expression in the liver in vivo. Circ Res 1999; 84: 1059–66.
Van Golen KL, Wu Z-F, Qial T et al. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res 2000; 60: 5832–8.
Tuteja R, Tuteha N. Ku Autoantigen: A multifactorial DNA-binding protein. Crit Rev Biochem Mol Biol 2000; 35: 1–33.
Singh H, Sen R, Baltimore D et al. A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature 1986; 319: 154–8.
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Denhardt, D.T., Mistretta, D., Chambers, A.F. et al. Transcriptional regulation of osteopontin and the metastatic phenotype: Evidence for a Ras-activated enhancer in the human OPN promoter. Clin Exp Metastasis 20, 77–84 (2003). https://doi.org/10.1023/A:1022550721404
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DOI: https://doi.org/10.1023/A:1022550721404