Role of Osteopontin in Adhesion, Migration, Cell

Experimental Oncology 26, 179-184, 2004 (September) 179 Exp Oncol 2004 26, 3, 179-184 ROLE OF OSTEOPONTIN IN ADHESION, MIGRATION, CELL SURVIVAL AND BONE REMODELING Therese Standal*, Magne Borset, Anders Sundan Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway

Osteopontin (OPN) is a secreted adhesive glycophosphoprotein expressed by several cell types It is normally produced in bone, teeth, kidney and epithelial lining tissues and is found in plasma and breast milk It is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, wound healing and tumor metastasis In this review focus will be on OPN in bone and its role in adhesion, migration and cell survival These aspects of OPN biology are important in tumorigenesis

OPN — general properties OPN’s versatile func- coated surfaces are protected against apoptosis induced tions are illustrated by early articles describing this pro- by serum deprivation or by TRAIL [14, 15]* OPN’s surviv- tein* Initially, OPN was described as a major noncollage- al function on endothelial cells is mediated through avb3 nous protein in bone and named bone sialoprotein I [1]* integrin and nuclear factor kappa B (NF-kB) activation The paper by Senger and colleagues [2] describes a pro- [14]* Furthermore, it was recently shown that OPN-in- tein whose secretion was elevated in cultures of trans- duced NF-kB activation in endothelial cells leads to en- formed cells, indicating a function of it in tumor biology* In hanced expression of osteoprotegerin (OPG)* OPG forms addition, OPN is important in immune activity and bacte- a complex with TRAIL which subsequently blocks apop- rial resistance and was named early T-lymphocyte acti- tosis [15, 16]* In another study, soluble OPN was found to vation 1 protein (Eta-1) by Patarca et al [3] in 1989* To- inhibit apoptosis of adherent endothelial cells deprived of day the protein is designated OPN and is known to be growth factors [17]* In contrast to the NF-kB pathway involved in bone resorption, wound repair, immune func- probably involved in immobilized OPN’s anti-apoptotic tion, angiogenesis, cell survival and cancer biology* effect, stimulation by soluble OPN was shown to cause OPN is an acidic protein consisting of about 300 ami- an up-regulation and re-distribution of Bcl-XL* Although no acids* The protein is highly phosphorylated and gly- both immobilized and soluble OPN seem to protect ad- cosylated and has an arginine-glycine-aspartic acid herent endothelial cells, soluble OPN has no anti-apop- (RGD)-binding domain as well as two heparin-binding totic effects on endothelial cells held in suspension [18]* sites, one thrombin cleavage site and a putative calcium However, other cells grown in suspension are pro- binding site [4]* Matrix metalloproteases 3 and 7 also tected from apoptosis by OPN* An example of this is the cleave OPN [5]* Cleavage of OPN by proteases (most non-adherent IL-3-dependent pro-B cell line Ba/F3* notably thrombin) generates two functional fragments, When these cells are stressed (deprived of IL-3), OPN an RGD-containing N-terminal part that binds to inte- protects against apoptosis via CD44 interaction and seems grin receptors and a C-terminal fragment which inter- to involve PI 3K-Akt downstream signaling pathway [19, acts with CD44 variants* The C-terminal fragment also 20]* OPN thus seems to give pro-survival signals both contains the two heparin-binding sites [4]* Both cleaved through integrins and through CD44, and the downstream and native OPN can bind integrins, although some cells signaling pathways seem to differ and depend both on adhere more strongly to cleaved than native OPN [6–9]* which receptors are engaged and on cell type* Cleavage of OPN by thrombin unmasks epitopes that OPN is strongly associated with tumorigenesis* In pa- are hidden in the native protein, and also makes the tients with breast cancer [21–23], multiple myeloma [24] RGD-motif more accessible in some cases* and prostate cancer [25] high plasma levels or tumor ex- OPN is encoded by a single gene, and its promoter pression of OPN are associated with poor prognosis* Thus, is responsive to a number of different transcription fac- not surprisingly, OPN is expressed by several types of can- tors [10, 11]* cer cells [26–29]* Some of them also respond to OPN with Cell survival Both soluble OPN, which works as a enhanced survival and proliferation* A recent study [30] in- cytokine, and immobilized OPN, which function as an dicates that epidermal growth factor (EGF) dependent pro- extracellular matrix protein, protect against apoptosis and liferation of prostate cancer cells is amplified by OPN* This induce survival and proliferation in several cell types* is probably due to an interaction of OPN with beta1 inte- OPN has a pro-survival and/or proliferative function grins on the surface of the cancer cells, leading to sus- in adherent cell types such as smooth muscle cells [12] tained activation of the epidermal growth factor receptor and epithelial cells [13]* Endothelial cells plated on OPN- (EGFR)* Epidermal growth factor (EGF) is an important Received: July 8, 2004 growth factor for prostate cancer cells and this interaction *Correspondence: Fax: +47 73 59 88 01 thereby promotes proliferation of the cancer cells* Similar- E-mail: theresestandal@medisinntnuno ly, IL-6 is an important growth promoting/survival factor for Abbreviations used: OPN — osteopontin myeloma cells, and OPN has been shown to promote my- 180 Experimental Oncology 26, 179-184, 2004 (September) eloma cell growth in combination with IL-6* Receptors in- spread of breast and prostate cancer* OPN’s role as a volved are a4b1 and avb3 [31] but the precise molecular metastasis-enhancing protein is further emphasized by mechanisms are currently not known* Breast carcinoma the fact that OPN-deficient mice have reduced number cells are protected against apoptosis when they adhere to of metastases to bone and soft tissue [57] and other stud-

OPN via avb3 [32]* Although cancer cells often produce ies linking OPN expression and responsiveness to in-

OPN, they also give rise to enhanced OPN production by creased cancer risk [45, 58, 59]* Although OPN-avb3 in- host cells such as stromal cells/osteoblasts [29, 33] and teraction seem to be of particular importance in breast osteoclasts [31]* OPN effects on tumor cells can thus be and prostate cancer metastases other receptors, such as both autocrine and paracrine* CD44, may be of importance in the malignancy and spread Adhesion and migration OPN’s association with of other cancer cells [27, 43]* cancer can partly be explained by its anti-apoptotic and Recent findings indicate that an intracellular form of proliferative effect on tumor cells* However, OPN’s role OPN (iOPN) exists [60, 61]* In migrating fibroblasts, as an adhesive and migratory factor might be even more macrophages, osteoclasts and metastatic breast can- important in tumorigenesis* Increased adhesion and mi- cer cell lines iOPN co-localizes with CD44 in cell pro- gration may confer metastatic capacity and invasive- cesses and at the cell membrane* Furthermore, iOPN ness to tumor cells* and CD44 associate with ezrin-radixin-moesin pro- Most cells adhere to OPN through integrins* Both teins inducing cytoskeleton rearrangement and signal- av (b1, b3, b5) and (a4, a8, a9)b1 on several cell types ing involved in cell migration, indicating that iOPN plays bind to OPN [7, 34–36]* The binding of avb1, avb3, avb5 an important role in cell movement [61-63]* integrins to OPN is RGD-dependent [6, 37–39], where- OPN in bone Bone remodeling is a regulated pro- as the binding of a4b1 and a9b1 involves other amino cess in which removal of old bone by osteoclasts is acid sequences [40, 41]* Cells can also bind to OPN followed by bone-formation by osteoblasts* OPN in- via some splice forms of CD44* The binding of fluences bone homeostasis both by inhibiting mineral CD44-variants to OPN is RGD-independent [42] but deposition, by promoting differentiation of osteoclasts seems to require b1 containing integrins [43]* and by enhancing osteoclast activity* The chemoattractant property of OPN has been dem- Inhibition of mineral deposition Bone matrix con- onstrated in the migration of monocytic cells/macroph- sists of an inorganic component in the form of hydroxya- ages, T-cells, smooth muscle cells, endothelial cells, epi- patite (HA - [Ca10 (PO4)6 (OH)2]) and an organic com- thelial cells and several malignant cells [8, 39, 42, 44, ponent consisting of proteins and proteoglycans* OPN 45]* Malignant cells often show an increased responsive- is one of the major non-collagenous proteins in bone* ness to OPN as compared to their normal counterparts* Its electronegative glutamic and aspartic acid residues In cancer, integrin expression is often aberrant on malig- as well as the putative Ca2+ binding motif make it bind nant cells [46–48]* Tumorigenic and highly metastatic tightly to HA* OPN is a potent inhibitor of the mineral- mammary epithelial cells migrate toward OPN in an ization process, since binding of OPN to HA inhibits avb3-dependent way whereas non-malignant and less growth of HA crystals [64–66]* malignant epithelial cells do not express avb3 Migration of Differentiation of osteoclasts Osteoclasts devel- the latter cells to OPN is dependent on avb5 and b1 [49, op from precursor cells in the monocyte/macrophage

50]* Transfection of the less malignant cells lacking avb3 family to become giant multinucleated cells capable of with b3 leads to increased adherence, migration and in- resorbing bone* The maturation and differentiation of vasiveness in vitro and also leads to increased tumori- macrophages to osteoclasts are dependent on two fac- genesis in vivo [50]* Cells expressing avb3 are more re- tors secreted or expressed by stromal cells/osteoblasts: sponsive to OPN than cells lacking this integrin and the macrophage colony stimulating factor (M-CSF) and re- increased responsiveness may enhance the malignan- ceptor for activation of NF-kB ligand (RANKL) [67]* En- cy-inducing effect of OPN* Migration induced by OPN gagement of these cytokines with their receptors, c-fms via integrin is dependent on at least two different growth and RANK, on the osteoclast precursor cells induces factor/receptor pathways (HGF/Met and EGF ligands/ maturation of the osteoclast osteoprotegerin (OPG) is a EGF) and multiple signaling pathways [49, 51, 52]* decay receptor for RANKL* It is secreted by osteoblasts/ Increased motility in combination with increased stromal cells and inhibits interaction of RANKL with RANK protease expression may lead to increased invasive- and thereby inhibits osteoclastogenesis* ness* Breast cancer cells invade through basement OPN does not seem to be an essential factor in the membrane in response to OPN [45] and the invasion development of osteoclasts during normal bone develop- seems to be dependent on secretion of uPA [53]* This ment since osteoclast number and distribution are normal important protease is secreted due to OPN signaling in OPN knock-out mice [68, 69]* However, several studies via avb3, and further activating c-Src/EGFR/ERK/AP-1 show that in pathological situations, OPN is of importance and/or PI-3kinase/Akt/NF-kB [54, 55]* Also prostate in osteoclastogenesis* PTH-induced RANKL signaling cancer cells respond to OPN in an avb3-dependent way normally results in either an increase in osteoclast number with increased chemotaxis, invasion and up-regula- and/or activation, but this increase is disrupted in the ab- tion of plasminogen activators [56]* sence of OPN [70]* Similarly, ovariectomy of normal mice The findings discussed above indicate that OPN and (as a model of postemenopausal osteoporosis) results in a + in particular OPN interacting with avb3 is important for the 3-fold increase of TRAP cells whereas ovariectomized Experimental Oncology 26, 179-184, 2004 (September) 181

OPN-/- mice lack the capability to increase osteoclast num- els of OPN in healthy individuals [24, 29] and to corre- ber [71]* Furthermore, loss of mechanical stress normally late to bone disease and prognosis [24]* However, the leads to increased bone resorbtion and an increase in os- correlation to bone disease and prognosis is not con- teoclast number* This effect in not seen in OPN-/- mice, firmed, since Standal et al [29] found no such correla- and OPN thus seems to be required for the effects on me- tions in their patient material (although a significant chanical stress on bone [72]* correlation to serum calcium could indicate a connec- In vitro, neutralization of OPN suppresses osteoclas- tion of OPN to bone disease)* Both studies found that togenesis, whereas addition of OPN enhances osteoclas- MM patients had higher plasma concentration of OPN togenesis in OPN-/- cells [73, 74]* OPN has also been shown than MGUS patients* A major difference between MM to influence osteoclastogenesis by enhancing RANKL and and MGUS patients is the lack of bone affection in decreasing OPG expression on stromal cells [74]* MGUS patients* Taken together, this could indicate that Although both Rittling et al [68] and Liaw et al [69] OPN is implicated in the bone destruction in MM al- found that osteoclast number was normal in OPN-/- mouse, though more studies are needed to confirm this hy- the number of osteoclasts in OPN-/- mice was about 3- pothesis* During the last few years, several reports show fold higher than in normal mice in the study by Yoshitake that bone homeostasis in patients with multiple myelo- et al [71]* This is also reported by Chellaiah et al [75]* The ma is disrupted due to an imbalance in the RANKL/ increase in number of osteoclasts may be compensatory RANK/OPG system [90–94]* OPN appears to be an for the decreased activity of OPN-/- osteoclasts [75]* important downstream factor in RANKL-mediated bone Osteoclast activity In mineralized tissues, OPN is resorption [70] and deregulation of OPN could thus secreted by both osteoblasts and osteoclasts [73, 76, 77]* contribute to the imbalance in bone homeostasis in this OPN is highly concentrated in sites where preexisting and disease* newly formed bone meet (cement lines), and in bone sur- Conclusion OPN is a player in several processes faces interfacing with cells (laminae limitantes) [78–80]* and functions in different ways in different cells in different Several studies suggest that OPN in laminea limitantes systems* In this review, OPN’s role in tumorigenesis has mediate the attachment of osteoclasts to bone* avb3 inte- been exemplified by giving a brief overview over its role in grin is located in the sealing zone of osteoclasts and inter- cell survival, adhesion, migration and bone remodeling* acts with OPN in the bone matrix underneath [78, 79, 81– Other aspects of OPN biology that are important in ma-

83]* OPN stimulate osteoclast migration through avb3 and lignancy are OPN’s role in angiogenesis and immune CD44 [84–86] and also increases CD44 expression on function* A recent review covering these topics was pub- osteoclasts* The expression of CD44 is necessary for os- lished [95]* The transcriptional control of OPN has not been teoclast motility [75]* Osteoclasts deficient in OPN do not mentioned her but are excellently reviewed in [11]* migrate and are unable to resorb bone [86, 87]* The bone- REFERENCES resorbing activity can only partially be restored by exoge- 1 Franzen A, Heinegard D Isolation and characteri- nous OPN, indicating that autocrine OPN is important to zation of two sialoproteins present only in bone calcified osteoclast activity [75]* OPN secreted by the osteoclast is matrix Biochem J 1985; 232: 715–24 present in the resorption lacunae in which exogenously 2 Senger DR, Perruzzi CA, Papadopoulos A, Tenen DG added OPN does not have access* The need for autocrine Purification of a human milk protein closely similar to tumor- OPN to get fully functional osteoclasts could also be due to secreted phosphoproteins and osteopontin Biochim Biophys the need of the expression of intracellular OPN [62]* Acta 1989; 996: 43–8 Osteolysis in myeloma and breast cancer Breast 3 Patarca R, Freeman GJ, Singh RP, Wei F Y, Durfee T, Blattner F, Regnier DC, Kozak CA, Mock BA, cancer cells frequently metastasize to bone and com- Morse HC III Structural and functional studies of the monly give rise to osteolysis* Breast cancer patients early T lymphocyte activation 1 (Eta-1) gene Definition with metastases to the skeleton have higher levels of of a novel T cell-dependent response associated with ge- OPN than patients without such metastases [21]* netic resistance to bacterial infection J Exp Med 1989; Breast cancer and prostate cancer cells that induce 170: 145–61 osteolytic lesions are able to enhance expression of 4 Weber GF The metastasis gene osteopontin: a can- OPN in osteoblasts, whereas cancer cells that induce didate target for cancer therapy Biochim Biophys Acta 2001; 1552: 61–85 osteopetrotic effects have no effect on OPN expres- 5 Agnihotri R, Crawford HC, Haro H, Matrisian LM, sion [33]* This finding indicates that osteolysis induced Havrda MC, Liaw L Osteopontin, a novel substrate for by tumor cells metastasizing to the skeleton could be matrix metalloproteinase-3 (stromelysin-1) and matrix due to enhanced OPN expression by osteoblasts* On metalloproteinase-7 (matrilysin) J Biol Chem 2001; the other hand, breast cancer cells themselves express 276:28261–7 OPN [23, 26, 88], so enhanced osteoclast activity could 6 Senger DR, Perruzzi CA, Papadopoulos-Sergiou A, be due to both tumor cell and host cell OPN* Van de WL Adhesive properties of osteopontin: regula- Osteolysis is also a common complication of multi- tion by a naturally occurring thrombin-cleavage in close proximity to the GRGDS cell-binding domain Mol Biol ple myeloma, and, similarly, myeloma cells express Cell 1994; 5: 565–74 OPN [24, 29, 89] and increases OPN expression in os- 7 Smith LL, Cheung HK, Ling LE, Chen J, Sheppard D, teoblasts/stromal cells [29] and osteoclasts [31]* Lev- Pytela R, Giachelli CM Osteopontin N-terminal domain els of circulating OPN in myeloma patients have re- contains a cryptic adhesive sequence recognized by alpha9beta1 cently been shown to be increased as compared to lev- integrin J Biol Chem 1996; 271: 28485–91 182 Experimental Oncology 26, 179-184, 2004 (September)

8 O’Regan AW, Chupp GL, Lowry JA, Goetschkes M, Katada Y, Asaoku H, Kitano M, Nishimoto N, Yoshizaki K, Mulligan N, Berman JS Osteopontin is associated with T Maeda M, Kon S, Kinoshita N, Uede T, Kawase I En- cells in sarcoid granulomas and has T cell adhesive and cyto- hanced production of osteopontin in multiple myeloma: clin- kine-like properties in vitro J Immunol 1999; 162: 1024–31 ical and pathogenic implications Br J Haematol 2003; 9 Helluin O, Chan C, Vilaire G, Mousa S, DeGrado WF, 123:263–70 Bennett JS The activation state of alphavbeta 3 regulates 25 Hotte SJ, Winquist EW, Stitt L, Wilson SM, platelet and lymphocyte adhesion to intact and thrombin- Chambers AF Plasma osteopontin: associations with sur- cleaved osteopontin J Biol Chem 2000; 275: 18337–43 vival and metastasis to bone in men with hormone-refrac- 10 Denhardt DT, Noda M Osteopontin expression tory prostate carcinoma Cancer 2002; 95: 506–12 and function: role in bone remodeling J Cell Biochem 26 Gillespie MT, Thomas RJ, Pu ZY, Zhou H, Mar- Suppl 1998; 30–31: 92–102 tin TJ, Findlay DM Calcitonin receptors, bone sialopro- 11 Denhardt DT, Mistretta D, Chambers AF, tein and osteopontin are expressed in primary breast can- Krishna S, Porter JF, Raghuram S, Rittling SR Transcrip- cers Int J Cancer 1997; 73: 812–5 tional regulation of osteopontin and the metastatic pheno- 27 Ue T, Yokozaki H, Kitadai Y, Yamamoto S, Yasui W, type: evidence for a Ras-activated enhancer in the human Ishikawa T, Tahara E Co-expression of osteopontin and OPN promoter Clin Exp Metastasis 2003; 20: 77–84 CD44v9 in gastric cancer Int J Cancer 1998; 79: 127–32 12 Weintraub AS, Schnapp LM, Lin X, Taubman MB 28 Kim JH, Skates SJ, Uede T, Wong KK, Schorge JO, Osteopontin deficiency in rat vascular smooth muscle cells Feltmate CM, Berkowitz RS, Cramer DW, Mok SC Os- is associated with an inability to adhere to collagen and teopontin as a potential diagnostic biomarker for ovarian can- increased apoptosis Lab Invest 2000; 80: 1603–15 cer JAMA 2002; 287: 1671–9 13 Elgavish A, Prince C, Chang PL, Lloyd K, Lind- 29 Standal T, Hjorth-Hansen H, Rasmussen T, Dahl IM, sey R, Reed R Osteopontin stimulates a subpopulation of Lenhoff S, Brenne AT, Seidel C, Baykov V, Waage A, Bor- quiescent human prostate epithelial cells with high prolifer- set M, Sundan A, Hjertner O Osteopontin is an adhesive ative potential to divide in vitro Prostate 1998; 35: 83–94 factor for myeloma cells and is found in increased levels in 14 Scatena M, Almeida M, Chaisson ML, Fausto N, plasma from patients with multiple myeloma Haematologica Nicosia RF, Giachelli CM NF-kappaB mediates alpha v 2004; 89: 174–82 beta 3 integrin-induced endothelial cell survival J Cell 30 Angelucci A, Festuccia C, Gravina GL, Muzi P, Biol 1998; 141: 1083–93 Bonghi L, Vicentini C, Bologna M Osteopontin enhances 15 Pritzker LB, Scatena M, Giachelli CM The role the cell proliferation induced by the epidermal growth factor of osteoprotegerin and tumor necrosis factor-related apop- in human prostate cancer cells Prostate 2004; 59: 157–66 tosis-inducing ligand in human microvascular endothelial 31 Abe M, Hiura K, Wilde J, Shioyasono A, Moriya- cell survival Mol Biol Cell 2004; 15: 2834–41 ma K, Hashimoto T, Kido S, Oshima T, Shibata H, 16 Malyankar UM, Scatena M, Suchland KL, Yun TJ, Ozaki S, Inoue D, Matsumoto T Osteoclasts enhance Clark EA, Giachelli CM Osteoprotegerin is an alpha v myeloma cell growth and survival via cell-cell contact: a beta 3-induced, NF-kappa B-dependent survival factor for vicious cycle between bone destruction and myeloma ex- endothelial cells J Biol Chem 2000; 275: 20959–62 pansion Blood 2004 17 Khan SA, Lopez-Chua CA, Zhang J, Fisher LW, 32 Noti JD Adherence to osteopontin via alpha v beta3 Sorensen ES, Denhardt DT Soluble osteopontin inhibits suppresses phorbol ester-mediated apoptosis in MCF-7 apoptosis of adherent endothelial cells deprived of growth breast cancer cells that overexpress protein kinase C-alpha factors J Cell Biochem 2002; 85: 728–36 Int J Oncol 2000; 17: 1237–43 18 Rittling SR, Chen Y, Feng F, Wu Y Tumor-de- 33 Hullinger TG, Taichman RS, Linseman DA, Som- rived osteopontin is soluble, not matrix associated J Biol erman MJ Secretory products from PC-3 and MCF-7 Chem 2002; 277: 9175–82 tumor cell lines upregulate osteopontin in MC3T3-E1 cells 19 Lin YH, Huang CJ, Chao JR, Chen ST, Lee SF, J Cell Biochem 2000; 78: 607–16 Yen JJ, Yang-Yen HF Coupling of osteopontin and its 34 Liaw L, Skinner MP, Raines EW, Ross R, cell surface receptor CD44 to the cell survival response Cheresh DA, Schwartz SM, Giachelli CM The adhesive elicited by interleukin-3 or granulocyte-macrophage colo- and migratory effects of osteopontin are mediated via dis- ny-stimulating factor Mol Cell Biol 2000; 20: 2734–42 tinct cell surface integrins Role of alpha v beta 3 in smooth 20 Lin YH, Yang-Yen HF The osteopontin-CD44 muscle cell migration to osteopontin in vitro J Clin Invest survival signal involves activation of the phosphatidyli- 1995; 95: 713–24 nositol 3-kinase/Akt signaling pathway J Biol Chem 2001; 35 Bayless KJ, Meininger GA, Scholtz JM, Davis GE 276: 46024–30 Osteopontin is a ligand for the alpha4beta1 integrin J Cell 21 Singhal H, Bautista DS, Tonkin KS, O’Malley FP, Sci 1998; 111: 1165–74 Tuck AB, Chambers AF, Harris JF Elevated plasma 36 Denda S, Reichardt LF, Muller U Identification osteopontin in metastatic breast cancer associated with of osteopontin as a novel ligand for the integrin alpha8 increased tumor burden and decreased survival Clin Can- beta1 and potential roles for this integrin-ligand interaction cer Res 1997; 3: 605–11 in kidney morphogenesis Mol Biol Cell 1998; 9: 1425–35 22 Tuck AB, O’Malley FP, Singhal H, Harris JF, 37 Bayless KJ, Davis GE, Meininger GA Isolation Tonkin KS, Kerkvliet N, Saad Z, Doig GS, Chambers AF and biological properties of osteopontin from bovine milk Osteopontin expression in a group of lymph node negative Protein Exp Purif 1997; 9: 309–14 breast cancer patients Int J Cancer 1998; 79: 502–8 38 Miyauchi A, Alvarez J, Greenfield EM, Teti A, 23 Rudland PS, Platt-Higgins A, El Tanani M, Grano M, Colucci S, Zambonin-Zallone A, Ross FP, De Silva RS, Barraclough R, Winstanley JH, Howitt R, Teitelbaum SL, Cheresh D Recognition of osteopontin West CR Prognostic significance of the metastasis-asso- and related peptides by an alpha v beta 3 integrin stimu- ciated protein osteopontin in human breast cancer Cancer lates immediate cell signals in osteoclasts J Biol Chem Res 2002; 62: 3417–27 1991; 266: 20369–74 24 Saeki Y, Mima T, Ishii T, Ogata A, Kobayashi H, 39 Liaw L, Almeida M, Hart CE, Schwartz SM, Gi- Ohshima S, Ishida T, Tabunoki Y, Kitayama H, Mizuki M, achelli CM Osteopontin promotes vascular cell adhesion Experimental Oncology 26, 179-184, 2004 (September) 183 and spreading and is chemotactic for smooth muscle cells 55 Das R, Mahabeleshwar GH, Kundu GC Osteopon- in vitro Circ Res 1994; 74: 214–24 tin induces AP-1-mediated secretion of urokinase-type plas- 40 Bayless KJ, Davis GE Identification of dual al- minogen activator through c-Src-dependent epidermal pha 4 beta 1 integrin binding sites within a 38 amino acid growth factor receptor transactivation in breast cancer cells domain in the N-terminal thrombin fragment of human J Biol Chem 2004; 279: 11051–64 osteopontin J Biol Chem 2001; 276: 13483–9 56 Angelucci A, Festuccia C, D’Andrea G, Teti A, 41 Yokosaki Y, Matsuura N, Sasaki T, Murakami I, Bologna M Osteopontin modulates prostate carcinoma Schneider H, Higashiyama S, Saitoh Y, Yamakido M, invasive capacity through RGD-dependent upregulation Taooka Y, Sheppard D The integrin alpha(9)beta(1) binds of plasminogen activators Biol Chem 2002; 383: 229–34 to a novel recognition sequence (SVVYGLR) in the throm- 57 Nemoto H, Rittling SR, Yoshitake H, Furuya K, bin-cleaved amino-terminal fragment of osteopontin J Biol Amagasa T, Tsuji K, Nifuji A, Denhardt DT, Noda M Chem 1999; 274: 36328–34 Osteopontin deficiency reduces experimental tumor cell 42 Weber GF, Ashkar S, Glimcher MJ, Cantor H metastasis to bone and soft tissues J Bone Miner Res Receptor-ligand interaction between CD44 and osteopon- 2001;16: 652–9 tin (Eta-1) Science 1996; 271: 509–12 58 Oates AJ, Barraclough R, Rudland PS The iden- 43 Katagiri YU, Sleeman J, Fujii H, Herrlich P, Hotta H, tification of osteopontin as a metastasis-related gene prod- Tanaka K, Chikuma S, Yagita H, Okumura K, Murakami M, uct in a rodent mammary tumour model Oncogene 1996; Saiki I, Chambers AF, Uede T CD44 variants but not CD44s 13: 97–104 cooperate with beta1-containing integrins to permit cells to 59 Urquidi V, Sloan D, Kawai K, Agarwal D, Wood- bind to osteopontin independently of arginine-glycine-aspartic man AC, Tarin D, Goodison S Contrasting expression of acid, thereby stimulating cell motility and chemotaxis Cancer thrombospondin-1 and osteopontin correlates with absence Res 1999; 59: 219–26 or presence of metastatic phenotype in an isogenic model 44 Senger DR, Perruzzi CA Cell migration promoted of spontaneous human breast cancer metastasis Clin Can- by a potent GRGDS-containing thrombin-cleavage fragment cer Res 2002; 8: 61–74 of osteopontin Biochim Biophys Acta 1996; 1314: 13–24 60 Zohar R, Lee W, Arora P, Cheifetz S, McCul- 45 Tuck AB, Arsenault DM, O’Malley FP, Hota C, loch C, Sodek J Single cell analysis of intracellular os- Ling MC, Wilson SM, Chambers AF Osteopontin in- teopontin in osteogenic cultures of fetal rat calvarial cells duces increased invasiveness and plasminogen activator J Cell Physiol 1997; 170: 88–100 expression of human mammary epithelial cells Oncogene 61 Zohar R, Suzuki N, Suzuki K, Arora P, Glogauer M, 1999; 18: 4237–46 McCulloch CA, Sodek J Intracellular osteopontin is an 46 Nesbit M, Herlyn M Adhesion receptors in hu- integral component of the CD44-ERM complex involved in man melanoma progression Invasion Metastasis 1994; cell migration J Cell Physiol 2000; 184: 118–30 14:131–46 62 Suzuki K, Zhu B, Rittling SR, Denhardt DT, 47 Felding-Habermann B, O’Toole TE, Smith JW, Goldberg HA, McCulloch CA, Sodek J Colocalization Fransvea E, Ruggeri ZM, Ginsberg MH, Hughes PE, of intracellular osteopontin with CD44 is associated with Pampori N, Shattil SJ, Saven A, Mueller BM Integrin migration, cell fusion, and resorption in osteoclasts J Bone activation controls metastasis in human breast cancer Proc Miner Res 2002; 17: 1486–97 Natl Acad Sci USA 2001; 98: 1853–8 63 Zhu B, Suzuki K, Goldberg HA, Rittling SR, Den- 48 Cooper CR, Chay CH, Pienta KJ The role of hardt DT, McCulloch CA, Sodek J Osteopontin modulates alpha(v)beta(3) in prostate cancer progression Neoplasia CD44-dependent chemotaxis of peritoneal macrophages through 2002; 4: 191–4 G-protein-coupled receptors: evidence of a role for an intracel- 49 Tuck AB, Elliott BE, Hota C, Tremblay E, Cham- lular form of osteopontin J Cell Physiol 2004; 198: 155–67 bers AF Osteopontin-induced, integrin-dependent migra- 64 Steitz SA, Speer MY, McKee MD, Liaw L, Almei- tion of human mammary epithelial cells involves activa- da M, Yang H, Giachelli CM Osteopontin inhibits min- tion of the hepatocyte growth factor receptor (Met) J Cell eral deposition and promotes regression of ectopic calcifi- Biochem 2000; 78: 465–75 cation Am J Pathol 2002; 161: 2035–46 50 Furger KA, Allan AL, Wilson SM, Hota C, Van- 65 Hunter GK, Hauschka PV, Poole AR, Rosen- tyghem SA, Postenka CO, Al Katib W, Chambers AF, berg LC, Goldberg HA Nucleation and inhibition of hy- Tuck AB Beta(3) integrin expression increases breast car- droxyapatite formation by mineralized tissue proteins Bio- cinoma cell responsiveness to the malignancy-enhancing chem J 1996; 317: 59–64 effects of osteopontin Mol Cancer Res 2003; 1: 810–9 66 Pampena DA, Robertson KA, Litvinova O, Lajoie G, 51 Tuck AB, Hota C, Wilson SM, Chambers AF Os- Goldberg HA, Hunter GK Inhibition of hydroxyapatite for- teopontin-induced migration of human mammary epithelial mation by osteopontin phosphopeptides Biochem J 2004; cells involves activation of EGF receptor and multiple signal 378: 1083–7 transduction pathways Oncogene 2003; 22: 1198–205 67 Teitelbaum SL Bone resorption by osteoclasts 52 Zhang G, He B, Weber GF Growth factor signal- Science 2000; 289: 1504–8 ing induces metastasis genes in transformed cells: molecu- 68 Rittling SR, Matsumoto HN, McKee MD, Nanci A, lar connection between Akt kinase and osteopontin in breast An XR, Novick KE, Kowalski AJ, Noda M, Denhardt DT cancer Mol Cell Biol 2003; 23: 6507–19 Mice lacking osteopontin show normal development and 53 Tuck AB, Hota C, Chambers AF Osteopontin(OPN)- bone structure but display altered osteoclast formation induced increase in human mammary epithelial cell invasive- in vitro J Bone Miner Res 1998; 13: 1101–11 ness is urokinase (uPA)-dependent Breast Cancer Res Treat 69 Liaw L, Birk DE, Ballas CB, Whitsitt JS, David- 2001; 70: 197–204 son JM, Hogan BL Altered wound healing in mice lack- 54 Das R, Mahabeleshwar GH, Kundu GC Osteopon- ing a functional osteopontin gene (spp1) J Clin Invest tin stimulates cell motility and nuclear factor kappaB-medi- 1998; 101: 1468–78 ated secretion of urokinase type plasminogen activator through 70 Ihara H, Denhardt DT, Furuya K, Yamashita T, phosphatidylinositol 3-kinase/Akt signaling pathways in breast Muguruma Y, Tsuji K, Hruska KA, Higashio K, Enom- cancer cells J Biol Chem 2003; 278: 28593–606 oto S, Nifuji A, Rittling SR, Noda M Parathyroid hor- 184 Experimental Oncology 26, 179-184, 2004 (September) mone-induced bone resorption does not occur in the ab- 83 McHugh KP, Hodivala-Dilke K, Zheng MH, Nam- sence of osteopontin J Biol Chem 2001; 276: 13065–71 ba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, 71 Yoshitake H, Rittling SR, Denhardt DT, Noda M Teitelbaum SL Mice lacking beta3 integrins are osteo- Osteopontin-deficient mice are resistant to ovariectomy-induced sclerotic because of dysfunctional osteoclasts J Clin In- bone resorption Proc Natl Acad Sci USA 1999; 96: 8156–60 vest 2000; 105: 433–40 72 Ishijima M, Rittling SR, Yamashita T, Tsuji K, 84 Faccio R, Grano M, Colucci S, Zallone AZ, Quar- Kurosawa H, Nifuji A, Denhardt DT, Noda M Enhance- anta V, Pelletier AJ Activation of alpha v beta 3 integrin ment of osteoclastic bone resorption and suppression of on human osteoclast-like cells stimulates adhesion and osteoblastic bone formation in response to reduced me- migration in response to osteopontin Biochem Biophys chanical stress do not occur in the absence of osteopontin Res Commun 1998; 249: 522–5 J Exp Med 2001; 193: 399–404 85 Faccio R, Grano M, Colucci S, Villa A, Giannelli G, 73 Yamate T, Mocharla H, Taguchi Y, Igietseme JU, Quaranta V, Zallone A Localization and possible role of two Manolagas SC, Abe E Osteopontin expression by osteoclast different alpha v beta 3 integrin conformations in resting and and osteoblast progenitors in the murine bone marrow: dem- resorbing osteoclasts J Cell Sci 2002; 115: 2919–29 onstration of its requirement for osteoclastogenesis and its in- 86 Chellaiah MA, Hruska KA The integrin alpha(v) crease after ovariectomy Endocrinology 1997; 138: 3047–55 beta(3) and CD44 regulate the actions of osteopontin on 74 Ishii T, Ohshima S, Ishida T, Mima T, Tabunoki Y, osteoclast motility Calcif Tissue Int 2003; 72: 197–205 Kobayashi H, Maeda M, Uede T, Liaw L, Kinoshita N, 87 Tani-Ishii N, Tsunoda A, Umemoto T Osteopontin Kawase I, Saeki Y Osteopontin as a positive regulator in antisense deoxyoligonucleotides inhibit bone resorption by the osteoclastogenesis of arthritis Biochem Biophys Res mouse osteoclasts in vitro J Periodontal Res 1997; 32: 480–6 Commun 2004; 316: 809–15 88 Sharp JA, Sung V, Slavin J, Thompson EW, Hen- 75 Chellaiah MA, Kizer N, Biswas R, Alvarez U, derson MA Tumor cells are the source of osteopontin and Strauss-Schoenberger J, Rifas L, Rittling SR, Denhardt DT, bone sialoprotein expression in human breast cancer Lab Hruska KA Osteopontin deficiency produces osteoclast dys- Invest 1999; 79: 869–77 function due to reduced CD44 surface expression Mol Biol 89 Croonquist PA, Linden MA, Zhao F, Van Ness BG Cell 2003; 14: 173–89 Gene profiling of a myeloma cell line reveals similarities 76 Dodds RA, Connor JR, James IE, Rykaczewski EL, and unique signatures among IL-6 response, N-ras-activat- Appelbaum E, Dul E, Gowen M Human osteoclasts, not ing mutations, and coculture with bone marrow stromal osteoblasts, deposit osteopontin onto resorption surfaces: an cells Blood 2003; 102: 2581–92 in vitro and ex vivo study of remodeling bone J Bone Miner 90 Seidel C, Hjertner O, Abildgaard N, Heickendorff L, Res 1995; 10: 1666–80 Hjorth M, Westin J, Nielsen JL, Hjorth-Hansen H, Waage A, 77 Merry K, Dodds R, Littlewood A, Gowen M Ex- Sundan A, Borset M Serum osteoprotegerin levels are re- pression of osteopontin mRNA by osteoclasts and osteoblasts duced in patients with multiple myeloma with lytic bone dis- in modelling adult human bone J Cell Sci 1993; 104: 1013–20 ease Blood 2001; 98: 2269–71 78 Flores ME, Norgard M, Heinegard D, Reinholt FP, 91 Standal T, Seidel C, Hjertner O, Plesner T, San- Andersson G RGD-directed attachment of isolated rat derson RD, Waage A, Borset M, Sundan A Osteopro- osteoclasts to osteopontin, bone sialoprotein, and fibronec- tegerin is bound, internalized, and degraded by multiple tin Exp Cell Res 1992; 20: 526–30 myeloma cells Blood 2002; 100: 3002–7 79 Reinholt FP, Hultenby K, Oldberg A, Heinegard D 92 Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Osteopontin — a possible anchor of osteoclasts to bone Liau DF, Colman N, Michaeli J, Epstein J, Choi Y Mul- Proc Natl Acad Sci USA 1990; 87: 4473–5 tiple myeloma disrupts the TRANCE/ osteoprotegerin cy- 80 McKee MD, Nanci A Osteopontin: an interfacial tokine axis to trigger bone destruction and promote tumor extracellular matrix protein in mineralized tissues Con- progression Proc Natl Acad Sci USA 2001; 98: 11581–6 nect Tissue Res 1996; 35: 197–205 93 Croucher PI, Shipman CM, Lippitt J, Perry M, Asos- 81 Ross FP, Chappel J, Alvarez JI, Sander D, But- ingh K, Hijzen A, Brabbs AC, van Beek EJ, Holen I, Skerry TM, ler WT, Farach-Carson MC, Mintz KA, Robey PG, Dunstan CR, Russell GR, Van Camp B, Vanderkerken K Teitelbaum SL, Cheresh DA Interactions between the Osteoprotegerin inhibits the development of osteolytic bone dis- bone matrix proteins osteopontin and bone sialoprotein ease in multiple myeloma Blood 2001; 98: 3534–40 and the osteoclast integrin alpha v beta 3 potentiate bone 94 Giuliani N, Bataille R, Mancini C, Lazzaretti M, resorption J Biol Chem 1993; 268: 9901–7 Barille S Myeloma cells induce imbalance in the osteopro- 82 Engleman VW, Nickols GA, Ross FP, Horton MA, tegerin/osteoprotegerin ligand system in the human bone Griggs DW, Settle SL, Ruminski PG, Teitelbaum SL A marrow environment Blood 2001; 98: 3527–33 peptidomimetic antagonist of the alpha(v)beta3 integrin 95 Denhardt DT, Giachelli CM, Rittling SR Role of inhibits bone resorption in vitro and prevents osteoporosis osteopontin in cellular signaling and toxicant injury Ann in vivo J Clin Invest 1997; 99: 2284–92 Rev Pharmacol Toxicol 2001; 41: 723–49

ÐÎËÜ ÎÑÒÅÎÏÎÍÒÈÍÀ Â ÀÄÃÅÇÈÈ, ÌÈÃÐÀÖÈÈ È ÂÛÆÈÂÀÍÈÈ ÊËÅÒÎÊ È ÂÎÑÑÒÀÍÎÂËÅÍÈÈ ÊÎÑÒÍÎÉ ÒÊÀÍÈ

Îñòåîïîíòèí, ñåêðåòèðóåìûé àäãåçèâíûìè ãëèêîôîñôîïðîòåèíàìè, ýêñïðåññèðóåòñÿ íåêîòîðûìè òèïàìè êëåòîê  íîðìå îí ïðîäóöèðóåòñÿ â òêàíè êîñòåé, çóáîâ, ïî÷åê è ýïèòåëèÿ è îáíàðóæèâàåòñÿ â ïëàçìå êðîâè è ãðóäíîì ìîëîêå Îñòåîïîíòèí ïðèíèìàåò ó÷àñòèå â íåêîòîðûõ ôèçèîëîãè÷åñêèõ è ïàòîëîãè÷åñêèõ ïðîöåññàõ, â òîì ÷èñëå àíãèîãåíåçå, àïîïòîçå, âîñïàëåíèè, çàæèâëåíèè ðàí è ìåòàñòàçèðîâàíèè îïóõîëåé  îáçîðå ðàññìàòðèâàåòñÿ ðîëü îñòåîïîíòèíà â êîñòíîé òêàíè, àäãåçèè, ìèãðàöèè è âûæèâàíèè êëåòîê, òàê êàê ýòè àñïåêòû èìåþò âàæíîå çíà÷åíèå â áèîëîãèè îïóõîëåé Copyright © Experimental Oncology, 2004