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Molecular Biology and Genetics |
Departments of Experimental Pathology [Y. L., J. L., E. S., C. C. H., X. Z.] and Hematopoiesis [M. T., M. K.], Holland Laboratory, American Red Cross, Rockville, Maryland 20855, and Department of Anatomy and Cell Biology, The George Washington University, Washington, D.C. 20037 [X. Z.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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85% higher than that of cells expressing the vector alone, whereas injection of cells overexpressing the mutant deficient in tyrosine phosphorylation induced 74% fewer osteolytic metastases as compared with the control group. Interestingly, the cells expressing either GFP-cortactin or the mutant did not show significant differences in growth in vitro or when injected m.f.p. in vivo. On the other hand, the cells overexpressing GFP-cortactin but not the mutant acquired a >60% enhanced capability for transendothelial invasion and endothelial cell adhesion. These data suggest that cortactin contributes to tumor metastasis by enhancing the interaction of tumor cells with endothelial cells and the invasion of tumor cells into bone tissues. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cortactin is accumulated in peripheral structures of cells, including lamellipodia and membrane ruffles, where cortical actin is enriched (10) . In MDA-MB-231 breast cancer cells plated on extracellular matrix, cortactin is enriched in invadopodia, a type of membrane protrusion that participates in degradation of and invasion into the matrix (11) . The protein sequence of cortactin features six and a half tandem copies of a unique 37-amino acid repeat domain and a SH33 domain at the COOH terminus. Our previous studies have determined that Src-mediated tyrosine phosphorylation occurs primarily at residues Tyr-421, Tyr-466, and Tyr-482, which lie between the repeat and SH3 domains. In vitro, cortactin binds to and cross-links F-actin into meshwork. The F-actin cross-linking activity of cortactin can be reduced on tyrosine phosphorylation mediated by Src (5) . Inhibition of tyrosine phosphorylation of cortactin by a selective Src inhibitor reduces the response of endothelial cells to hydrogen peroxide-mediated cell injury (12) . Likewise, overexpression of a cortactin mutant that is deficient in tyrosine phosphorylation can compromise cell shape changes induced by reactive oxygen species, whereas overexpression of wild-type cortactin results in enhancement of the injury response to hydrogen peroxide (12) . The role of cortactin in cytoskeletal reorganization is further highlighted by the recent finding that cortactin binds to the Arp2/3 complex and activates Arp2/3 complex-mediated actin polymerization (13) . Thus, cortactin appears to act as a signaling molecule in the regulation of the dynamics of actin cytoskeleton in a tyrosine phosphorylation-dependent manner.
Although the biochemical and cellular function of cortactin and its relationship to poor prognosis in a subset of cancers suggest that cortactin may play a role in tumor metastasis, direct evidence is lacking. In this study, we examined the metastatic ability of MDA-MB-231 breast cancer cells overexpressing wild-type cortactin and a cortactin mutant deficient in tyrosine phosphorylation. We report here that overexpression of wild-type cortactin promoted the metastatic potential of tumor cells, whereas overexpression of the phosphorylation-deficient cortactin mutant inhibited metastasis. In addition, we demonstrate that cortactin influences the interaction of tumor cells with endothelial cells. Thus, our study provides, for the first time, direct evidence of the role of cortactin in tumor metastasis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture.
MDA-MB-231 cells were grown in DMEM supplemented with 10% (v/v) FBS. Human BMECs (a gift from Malcolm Moore; Memorial Sloan-Kettering Cancer Center, New York, NY) were maintained in Iscove’s modified Dulbecco’s medium (Life Technologies, Inc.) supplemented with 20% FBS, 1x antibiotic-antimycotic solution, and 2 mM L-glutamine in a 75-cm2 tissue culture flask (Corning).
Construction and Preparation of Cortactin Virus.
Retroviruses encoding GFP-cortactin and GFP-CortF421F466F482 were constructed and prepared as described previously (12)
. The MGIN viral vector was a gift of Robert Hawley (American Red Cross Holland Laboratory, Rockville, MD), and has been described previously (15)
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Viral Infection.
MDA-MB-231 cells were plated on 35-mm dishes at a density of 1 x 105 cells/dish. On the next day, the medium was replaced with 1 ml of viral supernatant containing 8 µg/ml Polybrene. After 48 h of incubation, the culture medium was replaced with DMEM containing 10% FBS. Expression of GFP proteins was monitored by fluorescence microscopy. To increase the efficiency of infection, the cells were reinfected with the virus two or three times, and the infected cells were enriched further by FACS.
FACS Analysis.
MDA-MB-231 cells (2 x 106) infected with cortactin viruses were trypsinized, washed, and suspended in PBS supplemented with 2% FBS. The suspended cells were sorted in a FACS system (Becton Dickinson, Franklin Lakes, NJ) according to light scatter and fluorescence intensity. Sorted cells with expression efficiencies from 85–98% were used for further analysis.
Phosphotyrosine Immunoblot Analysis.
Cells were extracted in lysis buffer [50 mM Tris-HCl (pH 7.4) containing 1% NP40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 1 µg/ml aprotinin, 1 µg/ml leupeptin, 1 µg/ml pepstatin, 2 mM Na3VO4, and 1 mM NaF]. The extracts were centrifuged at 14,000 rpm for 10 min at 4°C. The clarified supernatants were immunoprecipitated with 5 µg of polyclonal cortactin antisera (14)
. The immunoprecipitates were resolved by SDS-PAGE (7.5%, w/v), transferred to a nitrocellulose membrane, and further blotted with a monoclonal phosphotyrosine antibody (4G10). To measure the expression levels of cortactin, the blot membrane was stripped and reblotted with monoclonal cortactin antibody (4F11).
Cell Growth Assay.
MDA-MB-231 cells were seeded on day 0 in a 12-well plate at a density of 0.4 x 105 cells/well in DMEM supplemented with 10% FBS and 1x antibiotic-antimycotic solution (Life Technologies, Inc.). At various times from days 1–6, cells were trypsinized and counted with a hemocytometer under a phase-contrast light microscope. Quadrupled samples were analyzed for each time point.
Colony Formation Assay.
Cells were trypsinized and resuspended in DMEM plus 10% FBS. The suspended cells (500) were mixed with 1 ml of 0.4% top agarose (SeaPlaque; FMC BioProducts, Rockland, ME) in DMEM plus 10% FBS. The mixture was plated onto a 35-mm Petri dish containing 1 ml of 0.6% bottom agarose in the same culture medium and incubated at 37°C, 5% CO2. After 2 weeks, colonies were examined under a fluorescence microscope (Olympus 70-S1F2) equipped with a RT Slider digital camera (Diagnostic Instruments, Inc.). To count the colonies, each dish was divided into 18 zones with a marker, and the cell image in each zone was captured by the digital camera. The colonies with diameters of >100 µm were counted and averaged based on the 18 images. For each cell line, four independent dishes were examined.
Tumorigenicity of MDA-MB-231 Cells in the Mammary Fat Pad of Nude Mice.
All animal studies described here were performed according to protocols approved by the Institutional Animal Care and Use Committee of Holland Laboratory. Tumorigenicity of MDA-231 cells was determined based on a modified method (16)
. Briefly, cells (2 x 106) were suspended in 0.2 ml of 50% (v/v) Matrigel (Collaborative Research, Bedford, MA) in PBS. Four-week-old female nude mice were anesthetized with ketamine (30 µg/g) and xylazine (1.5 µg/g). The mammary fat pad of a mouse was exposed by a skin incision in the right lateral thorax, and the cells were inoculated into the tissue using a 23-gauge needle. For each cell sample, eight mice were analyzed. Four weeks after injection, the animals were sacrificed, and the tumors were removed and weighed.
Analysis of Adhesion of MDA-MB-231 Cells to Human BMECs.
The procedure was based on a modified method, as described in Ref. 17
. Briefly, human BMECs were plated on fibronectin-coated 2-well Lab-Tek chamber slides (Nunc, Inc., Naperville, IL) at a density of 2 x 105 cells/well. After cells were confluent, MDA-MB-231 cells expressing GFP-cortactin variants were trypsinized, resuspended in DMEM containing 0.1% BSA and 1 mM CaCl2,, and plated over monolayers of endothelial cells that had been washed twice with PBS immediately before plating. The cells were incubated at 37°C for 4 h in a CO2 incubator. Nonattached cells were removed by three washings with PBS. Attached cells were fixed with 3.7% formaldehyde for 30 min. Cells that adhered to endothelial cells were inspected under a fluorescence microscope equipped with a digital camera and quantified by counting the number of green cells based on five high-power field digital images taken randomly at x200. The average number of adherent cells and the SD were calculated based on three independent experiments.
Analysis of Transendothelial Invasion by Tumor Cells.
Transendothelial invasion of MDA-MB-231 cells was analyzed based on a modified method, as described in Ref. 18
. Briefly, human BMECs (3 x 105) were plated on a fibronectin-coated polycarbonate membrane insert (6.5 mm in diameter with 8.0-µm pores) in a Transwell apparatus (Costar, Cambridge, MA) and maintained in Iscove’s modified Dulbecco’s medium containing 20% FBS, 1x antibiotic-antimycotic solution, and 2 mM L-glutamine. After cells reached confluence, MDA-MB-231 cells expressing GFP-cortactin variants were trypsinized and resuspended in DMEM containing 10% FBS. The suspended cells (3 x 104) were seeded on the monolayer of endothelial cells and incubated for 20 h at 37°C in a CO2 incubator. After incubation, the insert was washed with PBS. The cells on the top surface of the insert were removed by wiping with a cotton swab. The cells that migrated to the bottom surface of the insert were fixed with 3.7% formaldehyde and subjected to fluorescence microscopic inspection. Green cells were counted based on five high-power field digital images taken randomly at x200. The average number cell number and SD were calculated based on duplicated experiments.
Intracardiac Injections of MDA-MB-231 Cells in Nude Mice.
Subconfluent MDA-MB-231 cells were fed with DMEM containing 10% FBS 24 h before injection. The cells were trypsinized, immediately suspended in DMEM containing 0.2 mg/ml soybean trypsin inhibitor, and washed twice with PBS. The washed cells were finally resuspended in cold PBS at a density of 2.5 x 106 cells/ml on ice. Female 4–5-week-old BALB/c-nu/nu mice (National Cancer Institute, Frederick, MD) were anesthetized with ketamine (30 µg/g) and xylazine (1.5 µg/g). The suspended cells (5 x 105) were injected into the left cardiac ventricles of animals with a 27-gauge needle. The cell-injected animals were housed in a pathogen-free environment for 5–10 weeks. Body weights of animals were measured using a digital Sartorius weigher (The Scale People, Inc., Beltsville, MD). Experiments were repeated twice, and each experiment involved five animals per cell sample.
Statistical Analysis.
Statistical evaluation of the differences among groups was performed by Mann-Whitney test using GraphPad InStat software. All data shown were the mean ± SD.
Determination of Bone Metastases by X-radiography.
Tumors in bone were examined by X-ray radiographs 5 weeks after injection. Animals were anesthetized and placed on a transparent board in prone and lateral positions. The board was placed against an X-ray film (22 x 27 mm; X-OMAT AR; Kodak, Rochester, NY) and exposed to X-ray at 30 kV for 10 s in a Fixitron radiographic inspection unit (model 43855A). Exposed films were developed using an automatic film processor (Kodak RP X-OMAT). Radiographs of bones were evaluated for the presence of tumor foci.
Histological Examinations.
Animals were sacrificed with CO2. The lung, heart, liver, kidney, spleen, pancreas, forelimbs, and hind limbs were incised and fixed with 10% formalin. The bone tissues were decalcified in Cal-Ex II solution (Fisher Scientific) for 24 h. All tissues were embedded in paraffin. Histological sections were prepared by standard conventional processing and stained with H&E. Micrographs were taken with a Nikon microscope equipped with a digital camera (Cool Snap) and further processed using Adobe Photoshop software.
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RESULTS |
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, both GFP-cortactin and GFP-CortF421F466F482 were expressed at a level nearly 2-fold higher than endogenous cortactin. The epitope GFP did not seem to affect the specificity of tyrosine phosphorylation of cortactin because GFP-cortactin, but not GFP-CortF421F466F482, was able to be phosphorylated in response to a mixture of hydrogen peroxide and sodium vanadate (Fig. 1)
. A similar response was also described with either endogenous cortactin or small epitopes such as Myc-tagged cortactin proteins (19)
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, indicating that cortactin and its tyrosine phosphorylation-deficient mutant have no significant effects on cell growth.
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. In contrast, the average body weight of mice bearing GFP-CortF421F466F482 was about 20% higher than that of the control animals.
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. As summarized in Fig. 3B
, the mice bearing GFP-cortactin cells developed an average of 7 tumors/animal, whereas the mice bearing GFP only developed an average of <4 tumors/animal. In contrast, the mice injected with GFP-CortF421F466F482 cells showed much less potential for bone metastasis and developed only 1 tumor/animal. This result is consistent with our previous finding that the mutant acts in a dominant negative manner within cells (12)
. Tumors grown in other tissues were also examined by histological analysis. Most tumor metastases were found within bone tissues, a few in were found in the lung, and one was found in the adrenal gland (Table 1)
. No tumors were found in the heart, kidney, spleen, liver, and pancreas.
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, GFP-cortactin cells exhibited a motility 70% higher than that of the control cells, whereas the motility of GFP-CortF421F466F482 cells was 45% lower than that of the control cells (Fig. 4A)
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, GFP-cortactin cells enhanced the adhesive affinity for endothelial cells by 62% compared with cells expressing the viral vector alone, whereas GFP-CortF421F466F482 cells adhered to human BMECs with an efficiency that was 40% lower than that of the control cells. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. This result was consistent with reports that overexpression of cortactin via gene amplification is often associated with poor prognosis of cancer patients (9
, 25) .
Cortactin could play a role in early stages of tumor progression because its phosphorylation level is known to be up-regulated by oncogenes and growth factors (26
, 27)
. However, cells overexpressing either wild-type or tyrosine phosphorylation-deficient cortactin variants had a growth rate similar to that of control cells expressing the vector only as analyzed by growth curve, colony formation in soft agarose, and growth in the mammary fat pad (Fig. 2)
. This result agrees with our previous finding (6)
that Src(-/-) cells, in which tyrosine phosphorylation of cortactin is impaired, exhibit a response similar to that of normal cells to fibroblast growth factor for cell growth. Thus, overexpression of cortactin via gene amplification may serve as a pathogenic mechanism in the late stages of tumor development rather than contribute directly to the primary tumor progression, which is known to involve many genes responsible for cell cycle regulation (28)
. However, the pathological function of cortactin may be implemented in concert with oncogenes that are involved in cell growth. In this regard, it is worth noting that cortactin is frequently coamplified in cancers with cyclin D1, an important regulator of the cell cycle (4)
.
Overexpression of cortactin can increase by 62–70% in transendothelial invasion as well as adhesion to endothelial cells (Fig. 4)
. Adhesion of tumor cells to endothelial cells is known to be an important step in tumor metastasis and may determine the rate of cell transendothelial invasion (29)
. Indeed, highly metastatic colorectal cancer cells also tend to have higher affinities for endothelial cells than do poorly metastatic cells (30)
. However, the mechanism by which overexpression of cortactin facilitates the interaction of tumor cells with endothelial cells is not clear. It may involve the activation of cell surface proteins implicated in cell adhesions via alteration of the actin cytoskeleton underneath the plasma membrane, which is required for the function of cell-to-cell or cell-to-extracellular matrix interactions (31)
. The actin cytoskeleton is a dynamic structural entity and constantly undergoes assembly or disassembly (32)
. The assembled actin filaments can be further cross-linked to form either actin bundles or actin meshwork. Cortactin may alter the cytoskeleton by its ability to promote actin assembly via activation of Arp2/3, a protein complex that plays a vital role in the nucleation of actin assembly (13)
, and to cross-link actin filaments in a reversible manner dependent on its tyrosine phosphorylation (5)
. Cortactin also contains a COOH-terminal SH3 domain, which is known to bind to various membrane-associated proteins including ZO1, a junction-associated protein (33)
. Thus, cortactin may link a cell adhesion molecule either directly or indirectly via its SH3 domain.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by NIH Grant RO1 HL52753-07, Department of Defense Grant DAMD 17-98-18278, and American Heart Association Established Investigator Grant 0040135N (to X. Z.). 
2 To whom requests for reprints should be addressed, at Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Phone: (301) 738-0568; Fax: (301) 517-0352; E-mail: zhanx{at}usa.redcross.org
3 The abbreviations used are: SH3, Src homology 3; FBS, fetal bovine serum; GFP, green fluorescence protein; GFP-cortactin, green fluorescence protein-tagged cortactin; BMEC, bone marrow endothelial cell; FACS, fluorescence-activated cell sorting.
Received 11/30/00. Accepted 7/12/01.
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