|
Article |
Address correspondence to Ruth J. Muschel, Dept. of Pathology, Rm. 916D ARC, Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104. Tel.: (267) 426-5481. Fax: (267) 426-5483. email: muschel{at}xrt.upenn.edu
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: metastasis; tumor cell; integrin; laminin; vessel
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It has long been supposed that integrins play an important role in metastasis. This supposition is based in part on the role of integrins in motility, and in part on data showing that agents that interrupt integrinligand interaction also inhibit metastasis. For example, peptides containing the motif RGD (Arg-Gly-Asp) that compete for binding of integrins to fibronectin, or peptides that block binding of integrins to laminin (LN) can inhibit metastasis when coinjected with tumor cells (Humphries et al., 1986; Saiki et al., 1989; Yamamura et al., 1993). Antibodies directed against surface integrins that affect LN binding also reduced lung metastasis (Vollmers et al., 1984). Each integrin is a heterodimer composed of both an and a ß subunit. The ligand-binding domain of the integrin heterodimer is a globular region that requires both subunits to engage the ligand. Thus, antibodies specific for either the
or the ß chain can be blocking. Integrins bind to components of ECM such as collagens, fibronectin, and LNs, and can mediate adhesion, spreading, or migration on these substrates (Schwartz, 2001; van der Flier and Sonnenberg, 2001).
Using an attachment assay based on the observation of fluorescent tumor cells in isolated lungs, we have evaluated the involvement of integrins in the arrest of tumor cells in the pulmonary circulation. This report shows for the first time that the 3ß1 integrin is an important (but not exclusive) component in that process. The importance of
3ß1 integrin in pulmonary vascular attachment by tumor cells raised the question of access to its ligands. LN-5, -8, -10, and -11 are ligands for the
3ß1 integrin (Nissinen et al., 1997; Fukushima et al., 1998; Kikkawa et al., 2000; Fujiwara et al., 2001). Each is mainly found in ECM with LN-8/9 and LN-10/11 also present in the stroma of the bone marrow (Siler et al., 2000). How ECM or basement membrane (BM) components could be exposed to tumor cells in pulmonary vessels was not immediately apparent. Unexpectedly, examination of vessels at the sites of tumor cell attachment revealed exposed BM, enabling the binding of
3ß1 integrin.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
HT1080-GFP cells were incubated with blocking antibodies to the 1,
2,
3,
4,
5,
6, or
v integrin subunits. As shown in Table I, blocking antibodies against the
1,
5,
6, or
v integrin subunits did not affect pulmonary attachment. Anti-
3 integrin subunit antibody had the greatest effect with 34% inhibition, whereas slight reductions of 15 and 16% were seen after the treatments with anti-
2 and
4 integrin subunits, respectively. The effect of blocking the
2 integrin subunit was statistically significant; the effect on the
4 integrin subunit was not. Combining these three antibodies increased the inhibition, but was not entirely additive (unpublished data). Blocking antibodies to
3 (but not
6) integrin subunits similarly reduced pulmonary arrest by two metastatic breast carcinoma cell lines, MDA-MB-231 and MDA-MB-435s (Table II). Because the
3 subunit only forms a complete integrin molecule with the ß1 subunit, these data suggest that the
3ß1 integrin plays a critical role in the early lodgment of tumor cells in the lung.
|
|
|
|
|
Interaction between tumor cells and vascular BM
We used EM as an alternative means to visualize tumor cellpulmonary vessel interactions. HT1080-GFP-vimentin cells were labeled with ferritin before injection to allow their identification. 38 tumor cells were identified, all within the pulmonary vessels. Of these, nine cells showed distinct attachment to the vessel wall in EM images. In each of these cases, at the point of contact between the tumor cell and the vessel, the vessel was missing the expected endothelial covering of the basal lamina (Fig. 4, ac). When the tumor cells were pretreated with a blocking anti-ß1integrin subunit antibody, no points of contact were identified (0 out of 33 tumor cells; P = 0.001). Rare patches of exposed BM could be found in the absence of tumor cells (Fig. 4 d). These observations lead to the hypothesis that the foci of exposed BM between endothelial cells may be a prerequisite for tumor cell vascular attachment in the lung.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The observation that antibodies to components of LN-5 stained foci in pulmonary vessels and that anti-LN 3 chain antibodies block pulmonary arrest provided evidence for LN-5 as a vascular ligand for the tumor cell
3ß1 integrins. A potential role for LN-6 is not addressed by these analyses. The structural basis for this staining was shown in EM indicating sporadic absence of overlying endothelial cells in small patches in the pulmonary vessels. Menter et al. (1987) also found EM evidence for direct contact between tumor cells and pulmonary BM. One might expect that these absences could lead to loss of the fluid barrier. However, in the lung fluid integrity is in fact maintained by the tight junctions of the alveolar cells, not the endothelium (Schneeberger-Keeley and Karnovsky, 1968). One might also have expected platelet aggregation. However, the exposure of the surface of the basal lamina or the BM might not expose collagens, or more specifically, their helical domains. In some BMs, the collagens appear to be beneath the basal lamina (Nguyen et al., 2000a). Consistent with this possibility, anti-collagen IV antibody only stained poorly in our hands (unpublished data). This would also explain why the exposed BM regions do not have associated platelet aggregation. Metastasis may favor the lung because of this unique feature of its vessels. Whether arrest in the bone marrow is influenced by the
3ß1 integrin binding with LN-8/9 or LN-10/11 remains to be studied. Other organs may also use different adhesion factors. For example, expression of the
5 integrin subunit enhances the arrest of tumor cells in the kidney glomeruli, but does not affect cell attachment in the lung or the liver (Tani et al., 2003).
The 6ß4 integrin also binds to LN-5, yet anti-
6 integrin subunit antibody failed to alter attachment in vivo in our experiments. There are other situations in which the
6ß4 integrin and the
3ß1 integrin function differently. Antibodies to the
3 integrin subunit blocked migration of pancreatic carcinoma cell lines and inhibited adhesion of keratinocytes to LN-5, whereas antibodies to the
6 subunit failed to have these effects (Tani et al., 1997; Hintermann et al., 2001). The signaling pathways through these two integrins are distinct in keratinocytes (Hintermann et al., 2001; Mercurio et al., 2001b). The
6ß4 integrin is critical for the formation of hemidesmosomes, whereas the
3ß1 integrin regulates adhesion, spreading, and migration in association with the ECM (Borradori and Sonnenberg, 1999). Nonetheless, the
6ß4 integrin clearly plays a role in metastasis, if not a demonstrable role in the early arrest of tumor cells in the lung (Mercurio et al., 2001a; Jauliac et al., 2002). Metastasis to the mouse lung is inhibited both by pretreatment of the lung with anti-
6 integrin subunit antibody and treatment of the tumor cells with the antibody (Ruiz et al., 1993). Furthermore,
6 integrin was shown to contribute to survival of breast carcinoma cells as they formed metastatic colonies (Wewer et al., 1997). The
6ß1 can also bind LN-5. Some of the actions attributed to the
6 subunit may involve this integrin. Thus, the
6 integrin subunit may augment metastasis, not through enhancing pulmonary arrest, but by facilitating survival or proliferation. Pauli's group has shown that the ß4 integrin subunit on tumor cells can ligate to endothelial-bound CLCA1, mediating a signaling cascade that includes FAK activation (Abdel-Ghany et al., 2002). Although they have postulated that this interaction initiates vascular arrest, their data are equally comparable with a model synthesizing our data in which the tumor cell
3ß1 integrin interacts with exposed LN-5, allowing subsequent interactions that then signal for intravascular survival and proliferation. CLCA1 may be one of the factors that contribute to pulmonary arrest in addition to the
3ß1 integrin.
This model is consistent with the observation that pulmonary metastasis is enhanced by endothelial damage. Both hyperoxia and bleomycin or other chemotherapeutic drugs induce endothelial injury and lead to exposure of the BM (Nicolson and Custead, 1985; Orr et al., 1986; Lichtner and Nicolson, 1987). Orr et al. (1986) demonstrated that endothelial damage with bleomycin promoted pulmonary metastasis, and most of the arrested cells were found attached to the endothelial BM. It has been proposed that tumor cells induce the retraction of endothelial cells, enhancing metastasis (Honn et al., 1989, 1994). Our results suggest that LN-5 is available before interaction with tumor cells, but they do not preclude further retraction after arrest.
These analyses put forward a new model for pulmonary metastasis in which tumor cells use the 3ß1 integrin to bind to LN-5 in exposed BM. Colony formation was decreased more extensively than attachment by blockage of the
3ß1 integrin subunits, suggesting that in addition to mediating adhesion, the
3ß1 integrin may also provide important signaling for other steps required for metastasis.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Monoclonal antibodies
All antibodies used for the tumor cell attachment in vivo assay were purchased from CHEMICON International. The blocking anti-integrin antibodies were as follows: anti-ß1 from clone 6S6 (Shang et al., 2001); anti-ß3, clone B3A; anti-ß4[CD104], clone ASC-3; anti-vß5, clone P1F6; anti-
v, clone AV1; anti-
1 I domain, clone FB12; anti-
2, clone P1E6; anti-
3, clone P1B5 and anti-
3, clone ASC (Wayner et al., 1988; Wagner et al., 1991); anti-
4, clone P1H4; anti-
5, clone P1D6; and anti-
6, clone NK1-GoH3. The anti-ß1 integrin nonblocking stimulating antibody is clone 21C8.
MIG-1 and CM6 are mouse mAbs raised against different domains of the 3 chain of LN-5. Both antibodies react with rat, but not murine LN-5 (Plopper et al., 1998; Shang et al., 2001). Anti-LN
2 chain antibody was purchased from CHEMICON International. Antibodies against LNs, or collagen II, were freshly labeled with Zenon mouse IgG labeling kits; Alexa Fluor® 647 (Molecular Probes, Inc.) in a ratio of 10 µg antibody:50 µl labeling reagent:50 µl blocking reagent.
Treatment of cells with antibodies
Cells were harvested, washed with serum-free medium, and resuspended in the same medium containing 0.1% BSA. The suspensions were incubated with antibodies (10 µg/ml) at 4°C for 30 min on a rotator, followed by dilution with equal volume of the same medium. Although some reports have indicated that treatment with anti-3 integrin subunit antibody can lead to aggregation of keratinocytes (Nguyen et al., 2001), to ensure that aggregation was not occurring in our experiments, we verified that the cells were in single-cell suspension before injection. As additional confirmation, we point out that we did not see cells in aggregates in the lung after injection.
Intravital attachment test
Tumor cells were labeled by either stable GFP expression (HT1080-GFP and HT1080-GFP-vimentin) or vital fluorescence dyes. ESb cells and derivatives were incubated in 100 µM CellTrackerTM Green CMFDA (Molecular Probes, Inc.) in a medium containing 10% FBS at 37°C for 30 min. K562 cells, MK cells, and MDA-MB-231 or -435s cells were labeled with the vital dye MitoTracker® Red CMXRos (200 nM; Molecular Probes, Inc.) by 5 min exposure in culture medium. Experiments using CMFDA or MitoTracker® Red on HT1080-GFP cells gave the same results as monitoring GFP. Male rats (250 g; Sprague-Dawley) were injected into the renal vein with 3 x 105 cells unless otherwise indicated. For colony assays, female mice (CD-1 nude; Charles River Laboratories) received 5 x 105 cells in the lateral tail vein. 30 min after injection for the attachment assays or 1 wk after injection for the colony assays, the lungs were ventilated, perfused, and isolated under physiological pressures as described previously (Al-Mehdi et al., 1998, 2000). Fluorescent tumor cells were observed in the isolated lungs using an inverted fluorescent research microscope (model DMIRB; Leica), and images were recorded with a camera (Orca; Hamamatsu Photonics) with OpenLab software (Improvision). The quantitative assays were based on counting cells in 60 consecutive and nonoverlapping fields with a 10x/1x lens (1.1 mm2 field/picture). Rats and mice were matched by weight, and each antibody was tested in matched pairs of animals. The results were obtained from at least three independent experiments in all cases.
Confocal scanning laser microscopy
5 min after injection of HT1080-GFP-vimentin cells (106) into the left renal vein, antibodyAlexa Fluor® complexes were introduced through the inferior vena cava. Lungs were isolated as described above. The pulmonary vasculature was labeled by perfusion with tetramethylrhodamine dextran (Molecular Probes, Inc.). The images were captured using a laser scanning system (Radiance 2000; Bio-Rad Laboratories) and a microscope (Eclipse TE300; Nikon). The 2-line Argon/kryotin laser (wavelength 488 nm/568 nm) and the red laser diode (wavelength 638 nm) were used for observation.
Transmission EM observation
HT1080-GFP-vimentin cells were labeled with the electron-dense marker ferritin at 4°C for 10 min. 5 or 30 min after i.v. injection (2 x 106 cells) into rats, the lung was dissected as described above. Afterwards, the lung was washed with PBS, followed by perfusion with 5% glutaraldehyde. Samples were collected from the upper region of the left lung and fixed in 2.5% glutaraldehyde at 4°C. The images were photographed with a transmission electron microscope, 80 kV (JEM-1010; JEOL USA, Inc.)
![]() |
Acknowledgments |
---|
The authors are grateful for support from the National Cancer Institute (National Institutes of Health; grants CA46830 and CA89188).
Submitted: 18 September 2003
Accepted: 10 February 2004
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Abdel-Ghany, M., H.C. Cheng, R.C. Elble, and B.U. Pauli. 2001. The breast cancer b4 integrin and endothelial human CLCA2 mediate lung metastasis. J. Biol. Chem. 276:2543825446.
Abdel-Ghany, M., H.-C. Cheng, R.C. Elble, and B.U. Pauli. 2002. Focal adhesion kinase activated by ß4 integrin ligation to mCLCA1 mediates early metastasis growth. J. Biol. Chem. 277:3439134400.
Abdel-Ghany, M., H.C. Cheng, R.C. Elble, H. Lin, J. DiBiasio, and B.U. Pauli. 2003. The interacting binding domains of the b4 integrin and calcium-activated chloride channels (CLCAs) in metastasis. J. Biol. Chem. 278:4940649416.
Adair-Kirk, T.L., J.J. Atkinson, T.J. Broekelmann, M. Doi, K. Tryggvason, J.H. Miner, R.P. Mecham, and R.M. Senior. 2003. A site on laminin a5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis. J. Immunol. 171:398406.
Al-Mehdi, A.B., G. Zhao, C. Dodia, K. Tozawa, K. Costa, V. Muzykantov, C. Ross, F. Blecha, M. Dinauer, and A.B. Fisher. 1998. Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+. Circ. Res. 83:730737.
Al-Mehdi, A.B., K. Tozawa, A.B. Fisher, L. Shientag, A. Lee, and R.J. Muschel. 2000. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat. Med. 6:100102.[CrossRef][Medline]
Borradori, L., and A. Sonnenberg. 1999. Structure and function of hemidesmosomes: more than simple adhesion complexes. J. Invest. Dermatol. 112:411418.
Burger, S.R., M.M. Zutter, S. Sturgill-Koszycki, and S.A. Santoro. 1992. Induced cell surface expression of functional 2ß1 integrin during megakaryocytic differentiation of K562 leukemic cells. Exp. Cell Res. 202:2835.[Medline]
Colognato, H., and P.D. Yurchenco. 2000. Form and function: the laminin family of heterotrimers. Dev. Dyn. 218:213234.[CrossRef][Medline]
Coraux, C., G. Meneguzzi, P. Rousselle, E. Puchelle, and D. Gaillaer. 2002. Distribution of laminin 5, integrin receptors, and branching morphogenesis during human fetal lung development. Dev. Dyn. 225:176185.[CrossRef][Medline]
DiPersio, C.M., K.M. Hodivala-Dilke, R. Jaenisch, J.A. Kreidberg, and R.O. Hynes. 1997. 3ß1 integrin is required for normal development of the epidermal basement membrane. J. Cell Biol. 137:729742.
DiPersio, C.M., M. Shao, L.D. Costanzo, J.A. Kreidberg, and R.O. Hynes. 2000. Mouse keratinocytes immortalized with large T antigen acquire 3ß1 integrin-dependent secretion of MMP-9/gelatinase B. J. Cell Sci. 113:29092921.
Fujiwara, H., Y. Kikkawa, N. Sanzen, and K. Sekiguchi. 2001. Purification and characterization of human laminin-8. Laminin-8 stimulates cell adhesion and migration through 3ß1 and
6ß1 integrins. J. Biol. Chem. 276:1755017558.
Fukushima, Y., T. Ohnishi, N. Arita, T. Hayakawa, and K. Sekiguchi. 1998. Integrin 3ß1-mediated interaction with laminin-5 stimulates adhesion, migration and invasion of malignant glioma cells. Int. J. Cancer. 76:6372.[CrossRef][Medline]
Hintermann, E., M. Bilban, A. Sharabi, and V. Quaranta. 2001. Inhibitory role of 6ß4-associated erB-2 and phosphoinositide 3-kinase in keratinocyte haptotactic migration dependent on
3ß1 integrin. J. Cell Biol. 153:465478.
Honn, K.V., I.M. Grossi, C.A. Diglio, M. Wojtukiewicz, and J.D. Taylor. 1989. Enhanced tumor cell adhesion to the subendothelial matrix resulting from 12(S)-HETE-induced endothelial cell retraction. FASEB. J. 3:22852293.
Honn, K.V., D.G. Tang, I. Grossi, Z.M. Duniec, J. Timar, C. Renaud, M. Leithauser, I. Blair, C.R. Johnson, C.A. Diglio, et al. 1994. Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Res. 54:565574.[Abstract]
Humphries, M.J., K. Olden, and K.M. Yamada. 1986. A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells. Science. 233:467470.[Medline]
Jauliac, S., C. Lopez-Rodriguez, L.M. Shaw, L.F. Brown, A. Rao, and A. Toker. 2002. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat. Cell Biol. 4:540544.[CrossRef][Medline]
Kikkawa, Y., N. Sanzen, H. Fujiwara, A. Sonnenberg, and K. Sekiguchi. 2000. Integrin binding specificity of laminin-10/11: laminin-10/11 are recognized by 3ß1,
6ß1 and
6ß4 integrins. J. Cell Sci. 113:869872.
Lichtner, R.B., and G.L. Nicolson. 1987. Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions. Clin. Exp. Metastasis. 5:219231.[Medline]
Menter, D.G., J.S. Hatfield, C. Harkins, B.F. Sloane, J.D. Taylor, J.D. Crissman, and K.V. Honn. 1987. Tumor cell-platelet interactions in vitro and their relationship to in vivo arrest of hematogenously circulating tumor cells. Clin. Exp. Metastasis. 5:6578.[Medline]
Mercurio, A.M., R.E. Bachelder, I. Rabinovitz, K.L. O'Connor, T. Tani, and L.M. Shaw. 2001a. The metastatic odyssey: the integrin connectin. Surg. Oncol. Clin. N. Am. 10:313328.[Medline]
Mercurio, A.M., I. Rabinovitz, and L.M. Shaw. 2001b. The 6ß4 integrin and epithelial migration. Curr. Opin. Cell Biol. 13:541545.[CrossRef][Medline]
Mizushima, H., N. Koshikawa, K. Moriyama, H. Takamura, Y. Nagashima, F. Hirahara, and K. Miyazaki. 1998. Wide distribution of laminin-5 2 chain in basement membranes of various human issues. Horm. Res. 50:714.[CrossRef][Medline]
Morini, M., M. Mottolese, N. Ferrari, F. Ghiorzo, S. Buglioni, R. Mortarini, D.M. Noonan, P.G. Natali, and A. Albini. 2000. The 3ß1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int. J. Cancer. 87:336342.[CrossRef][Medline]
Nguyen, B.P., S.G. Gil, and W.G. Carter. 2000a. Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling. J. Biol. Chem. 275:3189631907.
Nguyen, B.P., M.C. Ryan, S.G. Gil, and W.G. Carter. 2000b. Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion. Curr. Opin. Cell Biol. 12:554562.[CrossRef][Medline]
Nguyen, B.P., X.D. Ren, M.A. Schwartz, and W.G. Carter. 2001. Ligation of integrin 3ß1 by laminin 5 at the wound edge activates Rho-dependent adhesion of leading keratinocytes on collagen. J. Biol. Chem. 276:4386043870.
Nicolson, G.L., and S.E. Custead. 1985. Effects of chemotherapeutic drugs on platelet and metastatic tumor cell-endothelial cell interactions as a model for assessing vascular endothelial integrity. Cancer Res. 45:331336.[Abstract]
Nishimura, S.L., K.P. Boylen, S. Einheber, T.A. Milner, D.M. Ramos, and R. Pytela. 1998. Synaptic and glial localization of the integrin 8 in mouse and rat brain. Brain Res. 791:271282.[CrossRef][Medline]
Nissinen, L., L. Pirila, and J. Heino. 1997. Bone morphogenetic protein-2 is a regulator of cell adhesion. Exp. Cell Res. 230:377385.[CrossRef][Medline]
Orr, F.W., I.Y.R. Adamson, and L. Young. 1986. Promotion of pulmonary metastasis in mice by bleomycin-induced endothelial injury. Cancer Res. 46:891897.[Abstract]
Petermann, A., H. Fees, H. Grenz, S.L. Goodman, and R.B. Sterzel. 1993. Polymerase chain reaction and focal contact formation indicate integrin expression in mesangial cells. Kidney Int. 44:9971005.[Medline]
Plopper, G.E., S.Z. Domanico, V. Cirulli, W.B. Kiosses, and V. Quaranta. 1998. Migration of breast epithelial cells on laminin-5: differential role of integrins in normal and transformed cell types. Breast Cancer Res. Treat. 51:5769.[CrossRef][Medline]
Ruiz, P., D. Dunon, A. Sonnenberg, and B.A. Imhof. 1993. Suppression of mouse melanoma metastasis by EA-1, a monoclonal antibody specific for 6 integrins. Cell Adhes. Commun. 1:6781.[Medline]
Saiki, I., J. Murata, J. Iida, T. Sakurai, N. Nishi, K. Matsuno, and I. Azuma. 1989. Antimetastatic effects of synthetic polypeptides containing repeated structures of the cell adhesive Arg-Gly-Asp (RGD) and Tyr-Ile-Gly-Ser-Arg (YIGSR) sequences. Br. J. Cancer. 60:722728.[Medline]
Scherberich, A., S. Moog, G. Haan-Archipoff, D.O. Azorsa, F. Lanza, and A. Beretz. 1998. Tetraspanin CD9 is associated with very late-acting integrins in human vascular smooth muscle cells and modulates collagen matrix reorganization. Arterioscler. Thromb. Vasc. Biol. 18:16911697.
Schneeberger-Keeley, E.E., and M.J. Karnovsky. 1968. The ultrastructural basis of alveolar-capillary membrane permeability to peroxidase used as a tracer. J. Cell Biol. 37:781793.[Medline]
Schwartz, M.A. 2001. Integrin signaling revisited. Trends Cell Biol. 11:466470.[CrossRef][Medline]
Shang, M., N. Koshikawa, S. Schenk, and V. Quaranta. 2001. The LG3 module of laminin-5 harbors a binding site for integrin 3ß1 that promotes cell adhesion, spreading, and migration. J. Biol. Chem. 276:3304533053.
Siler, U., M. Seiffert, S. Puch, A. Richards, B. Torok-Storb, C.A. Muller, L. Sorokin, and G. Klein. 2000. Characterization and functional analysis of laminin isoforms in human bone marrow. Blood. 96:41944203.
Stroeken, P.J., E.A. van Rijthoven, M.A. van der Valk, and E. Roos. 1998. Targeted disruption of the ß1 integrin gene in a lymphoma cell line greatly reduces metastatic capacity. Cancer Res. 58:15691577.[Abstract]
Takenaka, K., M. Shibuya, Y. Takeda, S. Hibino, A. Gemma, Y. Ono, and S. Kudoh. 2000. Altered expression and function of ß1 integrins in a highly metastatic human lung adenocarcinoma cell line. Int. J. Oncol. 17:11871194.[Medline]
Tani, N., S. Higashiyama, N. Kawaguchi, J. Madarame, I. Ota, Y. Ito, Y. Ohoka, S. Shiosaka, Y. Takada, and N. Matsuura. 2003. Expression level of integrin 5 on tumour cells affects the rate of metastasis to the kidney. Br. J. Cancer. 88:327333.[CrossRef][Medline]
Tani, T., A. Lumme, A. Linnala, E. Kivilaakso, T. Kiviluoto, R.E. Burgeson, L. Kangas, I. Leivo, and I. Virtanen. 1997. Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane. Am. J. Pathol. 151:12891302.[Abstract]
Testa, J.E., P.C. Brooks, J.M. Lin, and J.P. Quigley. 1999. Eukaryotic expression cloning with an antimetastatic monoclonal antibody identifies a tetraspanin (PETA-3/CD151) as an effector of human tumor cell migration and metastasis. Cancer Res. 59:38123820.
van der Flier, A., and A. Sonnenberg. 2001. Function and interaction of integrins. Cell Tissue Res. 305:285298.[CrossRef][Medline]
Vollmers, H.P., B.A. Imhof, S. Braun, C.A. Waller, V. Schirrmacher, and W. Birchmeier. 1984. Monoclonal antibodies which prevent experimental lung metastases. Interference with the adhesion of tumour cells to laminin. FEBS Lett. 172:1720.[CrossRef][Medline]
Wagner, E.A., R.A. Orlando, and D.A. Cheresh. 1991. Integrins vß3 and
vß5 contribute to cell attachment to vitronectin but differentially distribute on the cell surface. J. Cell Biol. 113:919929.[Abstract]
Wayner, E.A., W.G. Carter, R.S. Piotrowicz, and T.J. Kunicki. 1988. The function of multiple extracellular matrix receptors in mediating cell adhesion to extracellular matrix: preparation of monoclonal antibodies to the fibronectin receptor that specifically inhibit cell adhesion to fibronectin and react with platelet glycoproteins Ic-IIa. J. Cell Biol. 107:18811891.[Abstract]
Wei, Y., J.A. Eble, Z. Wang, J.A. Kreidberg, and H.A. Chapman. 2001. Urokinase receptors promote ß1 integrin function through interactions with integrin 3ß1. Mol. Biol. Cell. 12:29752986.
Weitzman, J.B., C. Pujades, and M.E. Hemler. 1997. Integrin chain cytoplasmic tails regulate "antibody-redirected" cell adhesion, independently of ligand binding. Eur. J. Immunol. 27:7884.[Medline]
Wewer, U.M., L.M. Shaw, R. Albrechtsen, and A.M. Mercurio. 1997. The integrin 6ß1 promotes the survival of metastatic human breast cells in mice. Am. J. Pathol. 151:11911198.[Abstract]
Yamamura, K., M.C. Kibbey, S.H. Jun, and H.K. Kleinman. 1993. Effect of matrigel and laminin peptide YIGSR on tumor growth and metastasis. Semin. Cancer Biol. 4:259265.[Medline]
Zhang, X.A., A.L. Bontrager, and M.E. Hemler. 2001. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific ß1 integrins. J. Biol. Chem. 276:2500525013.
Related Article