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Tumor Biology |
Departments of Medical Oncology (D.B., J.C.R., M.J.B.T., E.E.V.), Neurology (D.B., J.C.R., M.J.B.T.), Pulmonary Diseases (L.U., L.K.), and Haematology (M.F.B.G.), University Medical Center Utrecht, Utrecht; and Department of Pharmaco-epidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, University Medical Center Utrecht, Utrecht (M.B.); Department of Haematology, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.Z.); Sanquin Research, Amsterdam (J.J.Z.); and Department of Nephrology, Leiden University Medical Center, Leiden (H.D.); The Netherlands
2 Address correspondence to Dieta Brandsma, Department of Neurology, University Medical Center Utrecht, P.O. Box 85500, 3584 CX Utrecht, The Netherlands (d.brandsma{at}umcutrecht.nl).
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Abstract |
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Key Words: adhesion • integrin activation • L1210 • leptomeningeal metastases • mouse
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Integrins have been identified as principal mediators of tumor cell intravasation, arrest in the blood vessel, extravasation, and infiltration in the target tissue (Ruoslahti, 1999). Integrins comprise a family of at least 24 transmembrane adhesion receptors composed of noncovalently linked 
and ß subunits, which interact with cellular adhesion molecules (e.g., intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) or extracellular matrix proteins like collagen, fibronectin, and vitronectin (Hynes, 1992). Integrins are known to exist in distinct activation states, being regulated by inside-out signaling pathways: Extracellular stimuli (e.g., chemokines) induce intracellular signal transduction pathways that subsequently activate integrins (Hynes, 1992; Schwartz et al., 1995). An increase in activation state is determined by two processes: a change in conformation of the integrin (affinity) and/or clustering of integrins on the cell membrane (avidity). Both integrin expression and activation on tumor cells have been linked to tumor progression (Chan et al., 1991; Felding-Habermann et al., 2001; Gosslar et al., 1996). In LM, in vitro studies pointed out a role for integrins in tumor cell adhesion to the leptomeninges. Giese et al. (1998) showed that static adhesion of glioma cells to human arachnoidea could be blocked by antibodies against 2, 3, and ß1 integrin subunits. We demonstrated that the interaction of 4ß1 integrin on tumor cells and VCAM-1 on leptomeningeal cells mediates initial melanoma cell tethering to the leptomeninges under flow conditions (Brandsma et al., 2002).
To study the role of integrin expression and activation on tumor cells in LM in vivo, we used a mouse acute lymphocytic leukemic suspension cell line (L1210) and generated a derivative, adherent leukemic cell line. Using this model, we show that constitutive integrin activation on leukemic cells contributes to increased in vitro leukemic cell adhesion to the leptomeninges and rapid progression of leptomeningeal leukemia in vivo. Our findings point to an abberantly regulated integrin inside-out signaling pathway in tumor cells as a mechanism of LM progression.
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Materials and Methods |
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v chain (CD51, clone RMV7) were all purchased from Pharmingen (San Diego, Calif.). Purified rat monoclonal IgG against mouse IIb chain (CD41, clone MWReg30) was obtained from Santa Cruz Biotechnology (Santa Cruz, Calif.). Purified hamster monoclonal IgGs against mouse ICAM-1 (CD54, clone 3E2) and mouse integrin ß3 chain (CD61, clone 2C9.G2) and purified fluorescein isothiocyanate (FITC)-conjugated mouse anti-rat IgG2a (clone G28-5) and anti-hamster and anti-rat IgG1/2b (clone G70-204 and G94-56) were also obtained from Pharmingen. R-phycoerythrin-conjugated goat F(ab')2 antihamster IgG (H + L) mouse/rat adsorbed second-step reagent was obtained from Southern Biotechnology Associates, Inc. (Birmingham, Ala.). Antibody concentrations were used as recommended by the manufacturer. Vitronectin was purified according to the method described by Yatohgo et al. (1988). Fibronectin was obtained from Harbor BioProducts (Norwood, Mass.). Collagen type I was obtained from Sigma (St. Louis, Mo.). Recombinant mouse ICAM-1 Fc chimera was purchased from R&D Systems (Minneapolis, Minn.).
Reagents
Tissue culture supplies (culture media, antibiotics, and trypsin) were obtained from Gibco Biocult (Grand Island, N.Y.). Ethylenediaminetetraacetic acid (EDTA) was purchased from Riedel de Haen (Seelze, Germany). Ethylene glycol-bis tetraacetic acid (EGTA) was and phorbol 12-myristate 13-acetate (PMA) were obtained from Sigma. Magnesium (II) chloride and manganese (II) chloride hexahydrate were obtained from Merck Biosciences (Bad Soden, Germany).
Mouse L1210 Leukemia Cells
The L1210 mouse lymphocytic leukemia cell line was obtained from the Netherlands Cancer Institute (Amsterdam). As the majority of cells are grown in suspension, this leukemic cell line is called L1210-S (suspension) cell line. We developed an adherent leukemic cell line—named the L1210-A (adherent) cell line (see Results)—by selectively culturing the few adherent cells from the L1210-S line. Both the L1210-S and the L1210-A cell lines were cultured in noncoated flasks in RPMI, supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin-L-glutamine (PSG), and 60 µM ß-mercaptoethanol. Cells were incubated in 5% CO2-95% air at 37°C. L1210-A cells were treated with 10 mM EDTA (pH = 7.5) for 5 min, centrifuged at 1500 rpm for 5 min, and resuspended in the culture medium for cell passaging. The L1210-S cell line was maintained as a suspension culture.
Mouse Leptomeningeal Cells
Primary cultures of mouse leptomeningeal cells were obtained as described previously (Brandsma et al., 2002). Briefly, leptomeninges were dissected from the cortical surface of two-day-old neonatal DBA/2 cortex and treated with 0.25% trypsin for 30 min at 37°C. After trypsin was neutralized, cells were centrifuged (1250 rpm, 5 min, room temperature), resuspended, and plated on poly-L-lysine-coated plates. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing sodium pyruvate and nonessential amino acids (Gibco), supplemented with 10% fetal bovine serum, 1% PSG, and 0.1% amphotericin. Cells were incubated in 5% CO2-95% air at 37°C and passaged two or three times before use.
Cerebrospinal Fluid
We obtained fresh CSF samples from a single patient with a normal pressure hydrocephalus who had CSF drained via an external lumbar drain (Department of Neurosurgery, University Medical Center Utrecht). Cell count, protein, and glucose levels were within normal limits in these CSF samples.
Immunofluorescence
Immunofluorescence flow cytometry was used to measure expression levels of surface adhesion molecules. L1210 cells were treated with 10 mM EDTA (pH 7.5; 5 min), centrifuged, and washed twice in phosphate-buffered saline (PBS) at 4°C. Cells were resuspended in PBS/1% bovine serum albumin (BSA) (4°C) and distributed in a concentration of 1-2 x 105 cells/sample in a 96-well plate. They were centrifuged (1250 rpm, 3 min, 4°C) and incubated in 35 µl of appropriately diluted antibody in PBS-1% BSA (60 min, 4°C). Subsequently, cells were washed three times in PBS-1% BSA and incubated for another 30 min in 35 µl of the appropriately diluted, FITC-labeled, second-step antibody (4°C). After washing twice with PBS-1% BSA, stained cells were analyzed on a FACScalibur flow cytometer (Becton Dickinson, San Jose, Calif.). The mean fluorescence intensity was measured for each sample. Samples that were first incubated with isotype control antibodies and subsequently with FITC-labeled antibodies served as negative controls.
Static Adhesion Assays
For in vitro adhesion assays on matrix proteins, mouse ICAM-1, or leptomeningeal cells, L1210-A and L1210-S cells were washed with PBS, treated with 10 mM EDTA (pH 7.5, 5 min), and washed with PBS again. Cells were resuspended in DMEM without phenol red and sodium pyruvate (Gibco Biocult) and labeled fluorescently by incubation with 5 µM calcein (Molecular Probes, Leiden, The Netherlands) for 15 min at 37°C. Cells were centrifuged (1250 rpm, 5 min, room temperature) after labeling, washed two times with PBS, and resuspended in DMEM without phenol red and sodium pyruvate. Adhesion assays were performed in triplicate by administering 5 x 105 L1210 cells (>95% viability) per well in a 96-well plate coated with matrix proteins or recombinant mouse ICAM-1. Coating with matrix proteins (vitronectin, 10 µg/ml; collagen, 5 µg/ml) or recombinant mouse ICAM-1 (5 µg/ml) was performed overnight at 4°C. Subsequently, wells were incubated with 2.5% BSA-PBS for 1 h at room temperature. Noncoated wells that were incubated with 2.5% BSA-PBS served as controls. Static adhesion assays were performed for 30 min at 37°C, whereafter the fluorescence per well was measured with a Cytofluor II fluorometer (PerSeptive Biosystems, Framingham, Mass.). Wells were washed three times with washing buffer (20 mM HEPES, 140 mM NaCl, 2 mg/ml glucose, 1 mM EGTA, and 1 mM Mg2+, pH 7.4), and the fluorescence per well was measured again. The ratio of the latter fluorescent signal and the initial fluorescent signal was calculated, representing the percentage of adhered cells per well. The effect of PMA stimulation, integrin-blocking monoclonal antibodies (MoAbs), or dRGD-w peptide on leukemic cell adhesion was determined by preincubation of leukemic cells with PMA (100 ng/ml), MoAbs (10 µg/ml), or dRGD-w peptide (100 µM) for 30 min at 37°C, before static adhesion assays were performed. The divalent cations Mg2+ (5 mM) or Mn2+ (0.5 mM) were added to the leukemic cell suspension, just prior to performing the adhesion assay.
For adhesion assays of leukemic cells on a leptomeningeal cell layer, adhered leukemic cells were fixed with 2% paraformaldehyde. Five FITC images (1.3 mm2/image) of the central area of the leptomeningeal cell layer were obtained by using a fluorescence microscope (Leica DM IRHC; Leica Microsystems, Rijswijk, The Netherlands). The confluence of the leptomeningeal cell layer was confirmed by light microscopy. The number of adhered L1210 cells per FITC image was determined by quantitative analysis using Leica WIN software (Leica Microsystems), and high-magnification light microscopic pictures were made.
Proliferation Assays
For proliferation assays, L1210-S and L1210-A cells were seeded at a density of 2 x 104 cells per noncoated well in a 48-well plate. Cells were cultured in either normal culture medium (RPMI, 10% fetal calf serum, PSG) or fresh CSF supplemented with 60 µM ß-mercaptoethanol for 72 h. At 24, 48, and 72 h, the number of leukemic cells was counted by using a cell counter (Coulter particle counter, Becton Dickinson). For counting, cells were incubated with 10 mM EDTA (5 min, 37°C) and resuspended in 10 ml Isoton (Baker-Mallincrodt, Deventer, The Netherlands). The absence of residual adherent cells on the culture plates was confirmed by light microscopy. The mean number of cells of six wells (for culture medium) or three wells (for CSF) was calculated for each culture condition. Cell viability was determined by trypan blue dye exclusion in a separate well.
Induction of Leptomeningeal Metastases
Eight-week-old male DBA/2 mice were purchased from the Central Laboratory Animal Institute (Utrecht, The Netherlands). Leptomeningeal leukemia was induced as described previously for melanoma LM (Reijneveld et al., 1999). Briefly, L1210 leukemia cells were washed twice with PBS and suspended in Hanks Balanced Salt Solution (Gibco). Cell viability was determined by trypan blue exclusion (>95% for all experiments). For survival studies of L1210-A and L1210-S leptomeningeal leukemia, 2 x 105 leukemic cells were injected in a volume of 10 µl into the cisterna magna. Neurological symptoms and survival were recorded every 24 h. Mice were defined as symptomatic when they showed more than 10% weight loss in combination with either (1) lethargy, (2) an arched back with a stretched neck, or (3) rotatory movements when lifted by the tail. For histologic studies, mice injected with L1210-A or L1210-S cells were sacrificed three or eight days after tumor inoculation. The brains, livers, spleens, and femurs were excised and directly fixed in 4% paraformaldehyde for at least 24 h. Formalin-fixed and paraffin-embedded 5-µm brain and femur sections were stained with hematoxylin-eosin for morphological studies.
Statistical Analysis
Statistical analysis of data obtained by immunofluorescence flow cytometry and static adhesion assays was performed using the Student's t-test for independent samples. For comparison of survival data, a log-rank analysis of Kaplan-Meier curves was performed. P values of <0.05 were considered significant.
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Adhesion Molecule Expression on L1210-A and L1210-S cells
To find the cellular mechanism or mechanisms that underlie the increased adhesive capacity of L1210-A cells as compared to that of L1210-S cells, we studied the expression levels of a number of adhesion molecules on the two leukemic cell lines by using immunofluorescence flow cytometry. Both cell types showed similar, low expression levels of ß2 integrin subunits (CD18) and ICAM-1 (CD54). Similar high expression levels of CD44 (hyaluronate receptor, phagocyte glycoprotein, or Pgp-1) were found on both leukemic cell lines. L-selectin (CD62L) was not expressed on either cell line. The ß1 integrin subunit (CD29) and ß3 integrin subunit (CD61) expression levels were low in both cell lines, but slightly higher in L1210-A cells than in L1210-S cells (Table 1). Furthermore, low expression levels of the v integrin subunits were found in the L1210-A cells (mean fluorescence intensity = 7.8 ± 0.4) as compared to the L1210-S cells (mean fluorescence intensity = 4.9 ± 1.2; n = 2), whereas no expression of the iib integrin subunit was found on either leukemic cell type (data not shown).
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Constitutively Active ß1, ß2, and ß3 Integrins on L1210-A Cells
Not the integrin expression level but in particular the integrin activation state determines cell adhesion (Diamond and Springer, 1993; Lum et al., 2002). Therefore, we studied the activation state of ß1, ß2, and ß3 integrins in the two leukemic cell lines. We performed static adhesion assays using wells coated with ligands for ß1 integrin (collagen), ß2 integrin (mouse ICAM-1), and ß3 integrin (vitronectin) in the presence of extracellular factors that activate integrins (Mg2+, Mn2+, or PMA) or agents blocking integrin-ligand interactions (integrin-blocking MoAbs, dRGD-w peptide, or EDTA). Levels of L1210-A cell binding to collagen (Fig. 4A), mouse ICAM-1 (Fig. 4B), and vitronectin (Fig. 4C) were significantly higher than L1210-S cell binding levels; 47% ± 2% of the L1210-A cells versus 18% ± 4% of the L1210-S cells adhered to collagen, 38% ± 1% of the L1210-A cells versus 23% ± 4% of the L1210-S cells adhered to mouse ICAM-1, and 47% ± 2% of the L1210-A cells versus 12% ± 1% of the L1210-S cells adhered to vitronectin after 30 min of static adhesion. Leukemic cell binding on all matrix proteins was blocked completely by 10 mM EDTA, which prevents integrin-ligand interaction by capturing divalent cations. ß1 integrin-blocking MoAb completely blocked leukemic cell binding to collagen. Leukemic cell binding to mouse ICAM-1 was fully prevented by ß2 integrin-blocking MoAb. Finally, both dRGD-w peptide and ß3 integrin-blocking MoAb completely prevented leukemic cell binding to vitronectin. No effect on leukemic cell binding to collagen, mouse ICAM-1, or vitronectin was seen for the isotype controls of the integrin-blocking MoAbs. Levels of L1210-S cell binding to collagen, mouse ICAM-1, and vitronectin were significantly increased by PMA and Mn2+. Moreover, L1210-S cell binding to collagen was also significantly increased by Mg2+. Both Mg2+ and Mn2+ are known to force the integrin in a high-affinity state (Hogg and Leitinger, 2001; Mould et al., 1995), whereas PMA can induce integrin clustering on the cell membrane (avidity change) in a protein kinase C-dependent way (Peter and O'Toole, 1995; van Kooyk and Figdor, 2000). However, the extracellular factors Mg2+, Mn2+, or PMA did not further enhance L1210-A cell binding to collagen, mouse ICAM-1, or vitronectin.
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1ß1 and 2ß1 integrins, since these integrins are known to be expressed on leukocytes and interact with collagen in a non-RGD-dependent way, as was found for the L1210-A cells (Ben Horin and Bank, 2004; Gendron et al., 2003). Lß2 integrins on the leukemic cells most likely recognize ICAM-1, because these integrins are expressed on lymphocytes, whereas Mß2 integrins are present only on leukocytes of the myeloid lineage (Li, 1999; van Kooyk and Figdor, 2000). Several integrins (vß5, vß3, vß1, 8ß1, and iibß3) potentially interact with vitronectin (Hynes, 2002). We consider it most likely that for the L1210 cells vß3 integrins mediate the adhesion to vitronectin, as leukemic cell adhesion was largely ß3 integrin dependent, and low expression levels of the v integrin subunit but not iib integrin subunit were found on the L1210-A cells.
Several studies suggest that the inside-out signaling of integrins in tumor cells can be dysregulated, which can lead both to adhesion defects due to integrin inactivity and to increased adhesion caused by constitutive integrin activation. Geijtenbeek et al. (1999) demonstrated Lß2 integrin and 4ß1 integrin-mediated adhesion defects in leukemic cells isolated from bone marrow of patients with B-lineage acute lymphoblastic leukemia. Trusolino et al. (1998) found that vß3 integrins on thyroid carcinoma were highly active and enriched at focal contacts, mediating tight adhesion, whereas these integrins were in a latent state on normal thyroid cells, which could not form cytoskeletal connections and promote cell adhesion. An autocrine loop of the hepatocyte growth factor/scatter factor and a constitutively tyrosine phosphorylated receptor were thought to be responsible for the high vß3 integrin-activated state in the thyroid carcinoma cells. Felding-Habermann et al. (2001) showed that constitutively activated vß3 integrins, but not the nonactivated form, promoted distant metastases of mammary carcinoma. This finding was attributed to vß3 integrin-mediated interaction of tumor cells with platelets, which supports tumor cell arrest to the blood vessel wall.
Here we show that constitutive integrin activation on leukemic cells contributes to leptomeningeal leukemia. We attribute this finding to an increased integrin-mediated leukemic cell adhesion to the leptomeninges, which was mostly ß3 integrin dependent as determined in in vitro assays to determine the adhesion of leukemic cells to a primary leptomeningeal cell layer. Three hypotheses were formulated to explain integrin-mediated LM progression: (I) direct integrin-ligand interactions between adhered cells and leptomeningeal cells/matrix proteins lead to survival or proliferation signaling, (II) adhered cells proliferate faster than cells in suspension, because the leptomeningeal vasculature provides nutrients, growth factors, and oxygen to the adhered cells more efficiently, and (III) proliferating, adhered leukemic cells can form tumor masses that induce angiogenesis. Our finding that leukemic cells do not proliferate in the CSF underscores the relevance of tumor cell adhesion to the leptomeninges in LM progression. No data were found to support the first hypothesis, because binding of leukemic cells to either collagen or vitronectin could not induce leukemic cell proliferation in CSF (data not shown). The second and third hypotheses are therefore more likely to explain integrin-mediated LM progression.
Integrin activation is a combination of integrin affinity and avidity changes. The constitutively activated state of ß1, ß2, and ß3 integrins on L1210-A cells is likely to be caused by an increase in both integrin affinity and integrin avidity, since Mn2+ (affinity change) as well as PMA (avidity change) significantly increased adhesion of L1210-S cells to collagen, mouse ICAM-1, and vitronectin. Only L1210-S cell binding to collagen was induced by Mg2+, known to be less potent in changing the affinity state of integrins than is Mn2+. Surprisingly, L1210-S cell binding to mouse leptomeningeal cells was induced only by Mn2+ and not by PMA, which suggests that integrin affinity is more important than integrin avidity for tumor cell adhesion to the leptomeninges.
It is tempting to speculate about the intracellular factor(s) being dysregulated in tumor cells with constitutively active integrins. R-ras, a member of the Ras family of small GTP-binding proteins, and its downstream effector, Raf-1, are interesting proteins in this respect, because they are involved in both integrin activation and oncogenesis (Hughes et al., 1997; Sethi et al., 1999). The Ras-related GTPase protein, Rap-1, a protein that has been shown to be a key regulator of integrin activation in leukocytes, may be another interesting candidate (Katagiri et al., 2000; Reedquist et al., 2000; Shimonaka et al., 2003). Future research will focus on unraveling the intracellular inside-out signaling defects that lead to constitutively activated integrins on tumor cells. Ultimately, this research should lead to the development of agents that efficiently block tumor cell adhesion in order to prevent LM progression.
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3 These authors contributed equally to this article.
4 Abbreviations used are as follows: BSA, bovine serum albumin; CSF, cerebrospinal fluid; DMEM, Dulbecco's modified Eagle's medium; EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene glycol-bis tetraacetic acid; FITC, fluorescein isothiocyanate; ICAM-1, intercellular adhesion molecule-1; IgG, immunoglobulin G; LM, leptomeningeal metastases; MoAb, monoclonal antibody; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; PSG, penicillin-streptomycin-L-glutamine; VCAM-1, vascular cell adhesion molecule 1.
Received for publication July 15, 2005. Accepted for publication December 19, 2005.
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