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Cell and Tumor Biology |
1 Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University; 2 Department of Pathology, Loyola University Medical Center, Chicago, Illinois; and 3 Dows Institute for Dental Research and Department of Prosthodontics, University of Iowa, Iowa City, Iowa
Requests for reprints: Mary J.C. Hendrix, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, 2300 Children's Plaza, Box 222, Chicago, IL 60614-3394. Phone: 773-755-6528; Fax: 773-755-6534; E-mail: mjchendrix{at}childrensmemorial.org.
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Abstract |
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Introduction |
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Melanoma metastasis is a multistep process involving the movement of an invading melanoma cell through its basement membrane, thus exposing it to different extracellular matrix (ECM) components. Melanoma cells acquire the ability to recognize these ECM components by ectopically expressing different ECM receptors, including integrins (reviewed in ref. 2). The recognition of these new ECM components by receptors (such as integrins) results in the activation of signal transduction cascades within the melanoma cell to further promote migration and invasion. Signal transduction pathways activated by integrin signaling primarily involve focal adhesion kinase (FAK), a 125-kDa cytoplasmic tyrosine kinase responsible for mediating many cellular processes, including cell survival, migration, and invasion. Integrin clustering as trigged by binding to ECM components results in FAK phosphorylation. Initially, phosphorylation of FAK occurs on its major autophosphorylation site, Tyr397. Phosphorylation of this tyrosine initiates a cascade of signal transduction events that results in the phosphorylation of subsequent tyrosine residues, including Tyr576, which is located within the kinase domain of FAK and renders the molecule a fully active kinase (reviewed in ref. 3). Unregulated increases in cell survival mechanisms, migration, and invasion can contribute to a tumor's ability to metastasize to distant sites within the body. Therefore, FAK is often found to be overexpressed and/or constitutively active in numerous cancers, including melanoma, prostate, thyroid, colorectal, ovarian, and oral tumors (4–9).
Our laboratory has been investigating the molecular mechanisms that promote an aggressive melanoma phenotype resulting in an increased metastatic potential. Studies have primarily focused on understanding the migratory and invasive potential of aggressive melanoma cells as well as tumor cell plasticity as shown by vasculogenic mimicry (reviewed in ref. 10). To date, we have identified numerous signal transduction components that seem to play significant roles in mediating the aggressive properties of melanoma cells (reviewed in ref. 10). Although we are beginning to understand the involvement of some of the signaling pathways that regulate cell invasion, migration, and vasculogenic mimicry, the complexity of the coordinated molecular interactions underlying these processes remains to be elucidated. In this study, we focused on the role of FAK as a significant mediator of the aggressive melanoma phenotype.
This study tests the hypothesis that increased FAK activity in aggressive melanoma tumor cells promotes cellular invasion, migration, and ultimately vasculogenic mimicry, all involved in melanoma metastasis. To test this premise, we analyzed the levels of FAK expression and phosphorylation in a panel of aggressive and poorly aggressive human uveal and cutaneous melanoma cell lines. Although we found little difference in the levels of FAK protein among the various cell lines tested, we observed a marked increase in FAK phosphorylation, specifically on Tyr397 and Tyr576, in the aggressive melanoma cells, which correlated with an increase in invasive behavior and vasculogenic mimicry. Additionally, we confirmed the presence of FAK phosphorylated on Tyr397 and Tyr576 in both cutaneous and uveal melanoma tumors in situ. Furthermore, expression of the FAK-related nonkinase (FRNK) in aggressive melanoma cells, which acts to disrupt FAK signaling, resulted in an inhibition of melanoma vasculogenic mimicry concomitant with a decrease in melanoma cell invasion and migration. We found this biological effect to be mediated in part through an Erk1/2 signaling pathway that resulted in a down-regulation of urokinase and matrix metalloproteinase (MMP)-2/membrane type 1-MMP (MT1-MMP) activity. These results indicated that FAK seems to be a key mediator of the aggressive melanoma phenotype as characterized by increased invasion, migration, and vasculogenic mimicry, suggesting that FAK may serve as a new target for therapeutic intervention in treating aggressive melanomas or preventing emergence of melanoma clones with enhanced metastatic capabilities.
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Materials and Methods |
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Three-dimensional cultures. Three-dimensional type I collagen matrices were used to evaluate the vasculogenic mimicry potential of the tumor cells and were prepared as described previously (13). C8161 cells either untransfected or transfected with FRNK were seeded onto the three-dimensional type I collagen matrices and cultured for 6 days. C8161, MUM-2B, and C918 cells were either left untreated (DMSO; control) or treated with the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 inhibitor, U0126 (1 or 10 µmol/L final concentration in DMSO; Cell Signaling Technologies, Beverly, MA), and seeded onto the three-dimensional type 1 collagen matrices and cultured for a period of 6 days (C8161) or 4 days (MUM-2B and C918). Fresh medium containing inhibitor was added every 48 hours.
Electrophoresis and immunoblotting. Whole-cell lysates were collected from cells cultured on three-dimensional type I collagen matrices as described previously (13). Protein concentrations were determined using a BCA Protein Assay Reagent kit (Pierce Corp., Rockford, IL). Whole-cell lysates (20 µg) were separated by 10% or 12% SDS-PAGE and transferred to nitrocellulose (Schleicher & Schuell, Keene, NH). Blots were blocked with either 5% nonfat milk in TBS-TB [0.05% Tween 20, 0.05% bovine serum albumin (BSA)] or 5% nonfat milk in TBS-B (0.05% BSA; for anti-FRNK analysis) for 1 hour at room temperature. Blots were incubated with anti-FAK[pY397] (1:1,000; BioSource, Camarillo, CA), anti-FAK[pY576] (1:1,000; BioSource), anti-FAK (clone 77; 1:1,000; BD Biosciences, Lexington, KY), anti–FAK/FRNK (1:500; BC3; Upstate Biotechnology, Lake Placid, NY), anti-Erk1/2[pTpY185/187] (1:1,000; BioSource), or anti-Erk1/2 pan (1:1,000; BioSource) followed by incubation with horseradish peroxidase (HRP)–conjugated anti-mouse or anti-rabbit secondary (1:5,000; Bio-Rad, Hercules, CA). Blots were developed using the SuperSignal West Pico Chemiluminescent Substrate (Pierce).
Immunohistochemistry. Formalin-fixed, paraffin-embedded archival tissue was obtained from patients classified as having radial growth-phase cutaneous melanoma or vertical growth-phase cutaneous melanoma (Loyola University, Chicago, IL) or aggressive uveal melanoma xenografts obtained by injecting 1 x 106 C918 tumor cells into the subretinal space of nude mice as described previously (14) and grown for 4 weeks. Following deparaffinization and antigen retrieval using citrate buffer (Richard-Allan Scientific, Kalamazoo, MI), slides were washed in TBS with Tween 20 (Richard-Allan Scientific), and three blocking steps were applied: 0.03% hydrogen peroxide followed by avidin and biotin blocks (avidin/biotin blocking kit, Vector Laboratories, Inc. Burlingame, CA). Lastly, serum-free protein block (Richard-Allan Scientific) was applied, after which slides were incubated in primary antibodies, anti-FAK[pY397] (1:100) or anti-FAK[pY576] (1:50; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), for 1 hour, and staining was detected using the Multispecies HRP/3,3'-Diaminobenzidine (DAB) Detection System kit (Richard-Allan Scientific). Slides were counterstained using Meyer's hematoxylin. Negative control slides were prepared by incubating the tissue with an appropriate concentration of rabbit IgG (DAKO Cytomation, Inc., Carpinteria, CA). Images were captured using an Axioskop 2 (Carl Zeiss, Inc., Thornwood, NY) and Spot 2 camera (Diagnostic Instruments, Inc., Sterling Heights, MI) using the Zeiss Axiovision 2.0.5 software (Carl Zeiss).
Stable transfections. To express the FRNK (pcDNA3.1-FRNK; a generous gift provided by Dr. Michael Schaller, University of North Carolina, Chapel Hill, NC) in C8161 cells, the cells were transfected with 350 ng DNA using LipofectAMINE Plus reagent (Invitrogen Life Technologies) following the manufacturer's protocol. Twenty-four hours after transfection, the cells were replated in normal growth medium. Twenty-four hours after plating, G418 (600 µg/mL) was added to the growth medium. Colonies were selected and screened by Western blot analysis to identify FRNK-expressing cells. As a control, cells were transfected with empty pcDNA3.1 vector.
Invasion and migration assays. The invasive potential of the cells was analyzed using the membrane invasion culture system (MICS) as described previously (15). For invasion, an equal number of cells were seeded into the upper wells of the MICS chamber, which is separated from the lower wells by 10-µm polycarbonate membrane (Osmonics Co., Livermore, CA) coated with a defined matrix consisting of 50 µg/mL each of human laminin and human collagen IV (Sigma Chemical) in 2 mg/mL gelatin-10 mmol/L acetic acid/PBS base or coated with gelatin for migration assays. Chambers were incubated for 24 hours (invasion) or 6 hours (migration) at 37°C, 5% CO2, after which cells in the lower chamber wells were collected and counted. Samples were analyzed in triplicate and the statistical significance of the observed differences was determined using the Student's t test (Sigma Plot for Windows, SPSS, Inc., Chicago, IL). For invasion or migration assays where the MEK inhibitor U0126 was used, cells were either left untreated or treated with 1 or 10 µmol/L U0126 for 24 hours before seeding into the chamber in the presence of inhibitor.
Zymography and membrane type 1-matrix metalloproteinase activity assays. Conditioned medium was collected from C8161, MUM-2B, or C918 cells left untreated (DMSO; control) or treated with 1 or 10 µmol/L U0126 or from C8161 cells untransfected, transfected with empty vector, or transfected with FRNK cultured on three-dimensional type I collagen matrices for 24 and 48 hours. Cell debris was removed from the samples by centrifugation at 4,000 rpm for 5 minutes. Active urokinase was detected using casein/plasminogen zymography as follows: conditioned medium (10 µL) was loaded onto a 10% polyacrylamide gel containing 1 mg/mL casein and 5 units/mL plasminogen (American Diagnostica, Stamford, CT); after electrophoresis, the gel was developed as described previously (16). Gelatin zymography was used to detect the levels of active MMP-2 as follows: serum-free conditioned medium was collected and subjected to SDS-PAGE using 0.1% (w/v) gelatin containing 10% polyacrylamide gels as described previously (17). For MT1-MMP activity assays, C8161, MUM-2B, and C918 cells were cultured on three-dimensional type I collagen matrices and either left untreated (DMSO; control) or treated with 1 or 10 µmol/L U0126 for 48 hours. The level of MT1-MMP activity was determined in the samples using an immunoabsorbed Biotrak assay kit (Amersham Biosciences, Piscataway, NJ) following the manufacturer's protocol and as described previously (17). The experiments were done in triplicate, and the samples were analyzed in duplicate. The values are reported as a percentage of control and statistical significance of the observed differences was determined using the Student's t test (Sigma Plot for Windows).
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Results |
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50% of the tumor staining positive for either antibody as determined by a pathologist (B.J.N.)]. A representative slide is shown in Fig. 2, which shows an aggressive cutaneous melanoma stained with anti-FAK[pY397] (Fig. 2A) or anti-FAK[pY576] (Fig. 2C) antibodies. Closer examination of the radial (Fig. 2A-1 and C-3) and vertical (Fig. 2A-2 and C-4) growth phases at higher magnification revealed strong cytoplasmic as well as some nuclear staining of FAK phosphorylated on both Tyr397 and Tyr576. These primary cutaneous melanomas included numerous cases in which a wide basal incision was done such that normal-appearing skin was included in the specimen. This normal skin allowed us to evaluate the immunoreactivity of normal, nonneoplastic melanocytes. As noted in Fig. 2B, the entire basal epidermal layer was negative for FAK[pY397] or FAK[pY576] (data not shown), including numerous normal melanocytes (arrows). A table summarizing the degree of immunoreactivity of both anti-FAK[pY397] and anti-FAK[pY576] for all 14 cases analyzed is presented in Supplementary Table S2. Likewise, Fig. 2D and E shows aggressive C918 primary uveal melanoma xenograft stained with anti-FAK[pY397] (Fig. 2D) or anti-FAK[pY576] (Fig. 2E) antibodies. Analyses of the tissue samples at higher magnification (Fig. 2D-5 and E-6) also revealed strong cytoplasmic and focal membrane staining of FAK phosphorylated on Tyr397 and Tyr576. It is noteworthy that we did not observe the same kind of nuclear staining for phosphorylated FAK in the aggressive uveal melanoma xenograft as we did with the aggressive cutaneous melanoma tissues. These immunohistochemical staining results confirmed the finding of phosphorylated FAK in melanoma tumor tissues similar to that seen in aggressive melanoma tumor cells in vitro.
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Erk1/2 regulates urokinase and matrix metalloproteinase-2/membrane type 1-matrix metalloproteinase activity, thus promoting melanoma invasion and vasculogenic mimicry. To determine if urokinase activity was regulated by the Erk1/2 signaling pathway in the melanoma cells, we used the MEK1/2 inhibitor U0126, which functions to decrease the levels of phosphorylated Erk1/2. For these studies, conditioned media from C8161, MUM-2B, and C918 cells cultured on three-dimensional type I collagen matrices and left untreated (DMSO; control) or treated with 1 or 10 µmol/L U0126 (Fig. 4A) were analyzed for urokinase activity. Figure 4A shows that treatment of all three cell lines with 10 µmol/L U0126 diminishes the level of both the 55-kDa proform and the 35-kDa active form of urokinase, which correlates with the reduction of urokinase activity in the FRNK-expressing C8161 cells (compare Fig. 3E with Fig. 4A, top). Western blot analyses of whole-cell lysates showed that treatment with 10 µmol/L U0126 also inhibited Erk1/2 phosphorylation to the same extent as expression of FRNK protein in the C8161 cells (compare Fig. 3F with Fig. 4A, bottom). Furthermore, treatment with the MEK inhibitor U0126 decreased the levels of active MMP-2 (Fig. 4B) and MT1-MMP (Fig. 4C) in the C8161, MUM-2B, and C918 cells.
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40% to 60% reduction in invasion, which is similar to the decreases seen with the C8161-FRNK cells. Furthermore, a complete inhibition of vasculogenic mimicry occurred after culturing the C8161 cells on three-dimensional type I collagen for 6 days or the MUM-2B and C918 cells on three-dimensional type I collagen for 4 days in the presence of 10 µmol/L U0126 (Fig. 4E). Similarly, inhibition of vasculogenic mimicry was seen when C8161 cells were treated for 6 days with 1 µmol/L PD98059 as shown in Supplementary Fig. S3B. Contrary to what we observed in the C8161 cells expressing FRNK protein, there was no change in the ability of the cells to migrate after treatment with either 1 or 10 µmol/L U0126 (Supplementary Fig. S4). These results suggest that FAK may promote an aggressive melanoma phenotype by up-regulating invasion and vasculogenic mimicry through an Erk1/2-mediated signal transduction pathway, although migration seems to be regulated through a separate FAK-mediated signal transduction pathway. |
Discussion |
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Deciphering the molecular signature of an aggressive melanoma phenotype is key to understanding and predicting the metastatic potential within the tumor. Therefore, the purpose of this study was to further identify key signal transduction events that underlie the aggressive melanoma phenotype as characterized by increased invasion, migration, and vasculogenic mimicry potential. We hypothesized that FAK could play a key role in promoting the aggressive melanoma phenotype because its increased expression has already been linked to tumor cell aggressiveness in other tumors (4–9). The data presented throughout this study indicate that, although FAK expression is relatively equal among normal melanocytes, poorly aggressive and aggressive melanoma cells, consistent with other reports for melanoma (23), FAK is phosphorylated on its key tyrosine residues, Tyr397 and Tyr576, in only the most aggressive melanoma cells, which correlates with increased invasion, migration, and vasculogenic mimicry. Furthermore, we showed that FAK is phosphorylated on Tyr397 and Tyr576 in aggressive cutaneous and uveal melanoma tissues in situ. Interestingly, although we observed some nuclear staining for phosphorylated FAK in the cutaneous melanoma tissue samples analyzed, we failed to observe the same phenomenon in the uveal melanoma xenografts. This disparity could be attributed to the different location of these melanomas; uveal melanomas arise in the choroid, iris, and ciliary body of the eye, whereas cutaneous melanomas arise in the skin. It is noteworthy that phosphorylated FAK associated with the nucleus (in our study) has not been reported previously and may represent a significant new finding that should be pursued. Collectively, these results suggest that FAK-mediated signal transduction pathways are important for promoting the aggressive melanoma phenotype. As proof of principle, disruption of FAK-mediated signaling pathways by overexpressing FRNK, which acts as a dominant-negative protein, resulted in a decrease in all three of these cellular events associated with a more aggressive phenotype.
Signaling events downstream of FAK are complex and result in the activation of many cellular pathways affecting cell survival, cell growth, angiogenesis, cellular invasion, and cellular migration (3, 24). Our findings indicate that disruption of FAK signaling by overexpression of FRNK has a significant effect on invasion, migration, and vasculogenic mimicry by aggressive melanoma cells used in this study. To better understand a mechanism for how these processes could be regulated by FAK, we first examined the proteolytic enzymes known to be important for invasion in several tumor cell types, including melanoma. In particular, there have been reports linking both uPA/uPAR and MMP with FAK signaling (21, 25–27). We found urokinase activity to be greatly reduced by FRNK expression in the aggressive melanoma cells. However, we did not see an effect on MMP-2 activity or MT1-MMP activity in the FRNK-transfected C8161 melanoma cells (data not shown). To identify the signaling pathways downstream of FAK that were responsible for urokinase secretion in the aggressive melanoma cells, we turned our attention to the MAPK pathways, specifically the MEK1/2-Erk1/2 pathway, because it has been linked to urokinase activity in aggressive breast cancer (20, 21). We found Erk1/2 phosphorylation to be significantly decreased in the FRNK-expressing C8161 cells compared with the untransfected C8161 cells. Moreover, we found that treatment with two different MEK inhibitors, both of which reduced Erk1/2 phosphorylation to the level seen with FRNK expression, decreased urokinase activity concomitant with a decrease in invasion and vasculogenic mimicry in the aggressive melanoma cells. These results coincide with those found with overexpression of the FRNK protein in the C8161 cells and suggest that FAK signals through an Erk1/2-mediated pathway to promote urokinase secretion.
In order for aggressive melanoma cells to engage in vasculogenic mimicry, they must have the ability to migrate and invade the ECM to form vasculogenic-like networks (see video at http://www.childrensmrc.org/hendrix/supplemental/quicktime/). Although blocking the phosphorylation of Erk1/2 using specific inhibitors diminished invasion and vasculogenic mimicry in the aggressive melanoma cells, we saw no effect on migration in these cells. Subsequently, we explored specific proteolytic enzymes that are important for invasion and vasculogenic mimicry. Using the MEK1/2 inhibitor U0126 to down-regulate Erk1/2 phosphorylation, we found decreases in both MMP-2 and MT1-MMP activity, which could result in the decreases seen in invasion and vasculogenic mimicry. Given our previous observations concerning the role of MMP-2 and MT1-MMP in melanoma vasculogenic mimicry (17, 28), we suggest that Erk1/2 signaling may regulate the proteolytic enzymes secreted by the aggressive melanoma cells, which results in the observed decreases in invasion and vasculogenic mimicry and a result of significant decrease in urokinase, MMP-2, and MT1-MMP activities—all necessary components enabling these tumor cells to remodel the ECM and invade and engage in vasculogenic mimicry.
Although we found a decrease in urokinase activity mediated in part through an Erk1/2 signal transduction pathway, FRNK expression in the C8161 cells resulted in no effect on MMP-2 and MT1-MMP activity. These results suggest that there could be another signal transduction pathway independent of FAK signaling, which is responsible for Erk1/2 phosphorylation in the aggressive melanoma cells. One possibility for such a signaling pathway is the RAS-RAF-MEK-ERK-MAPK pathway. Mutations in N-Ras or B-Raf are very common in cutaneous melanoma and often result in increased phosphorylation of Erk1/2 (reviewed in ref. 29). Sumimoto et al. showed that disruption of the B-Raf signaling pathway in melanoma cell lines using RNA interference technology resulted in a down-regulation of invasion concomitant with a decrease in Erk1/2 phosphorylation and MMP-2 activity (30). In spite of a large body of evidence supporting a role for N-Ras and/or B-Raf mutations in cutaneous melanoma, these mutations are not typically associated with uveal melanoma, although these tumors also have constitutive activation of the MAPK pathway (31).
A second potential role for FAK signaling in the aggressive melanoma cells is by promoting migration. In this regard, Haskell et al. investigated the role of FAK in mediating angiogenesis in malignant astrocytic tumors (24). These investigators found that FAK is phosphorylated on Tyr397 in endothelial cells of the highest-grade tumors. Furthermore, they reported that expression of FRNK in brain microvascular endothelial cells inhibited tube formation in three-dimensional collagen gels and haptotatic migration toward collagen and fibronectin ECMs. These results suggested that FAK promotes endothelial angiogenesis in part through the regulation of endothelial cell migration.
Cellular migration is a complex process that requires the precise cooperation of various signal transduction pathways, which facilitate the formation of new focal adhesions, lamellipodia, and filopodia at the leading edge of the cell in conjunction with retraction of the cell's posterior processes. FAK has been found to be a key regulator of cellular migration by initiating many of the signal transduction pathways necessary for this process to occur. In melanoma specifically, there has been a correlation between expression of FAK and increased migration potential (32, 33). Using the K1735 murine mouse model for melanoma, Li et al. found that expressing FRNK in these cells resulted in a decrease in FAK phosphorylation on Tyr397 concomitant with a 90% decrease in the migration capability of these cells (33). Together, these results support our observations that signal transduction pathways initiated by FAK play an important role in mediating melanoma cell migration and offer a new potential mechanism for the effects shown on melanoma invasion and vasculogenic mimicry.
These studies have added yet another important signaling component, FAK, as a key mediator of the aggressive behavior of melanoma cells. As we develop a better understanding of the signal transduction pathways at work in regulating melanoma invasion, migration, and vasculogenic mimicry, we may identify new avenues for the therapeutic intervention of aggressive melanoma.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. Meenhard Herlyn for his generosity in providing the WM278 and 1205Lu cutaneous melanoma cell lines and Dr. Michael Schaller for his generosity in providing the FRNK construct used in these studies.
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Footnotes |
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Received 6/21/05. Revised 8/22/05. Accepted 8/26/05.
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References |
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2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res 2001;61:6322–7.
vß3 mediates K1735 murine melanoma cell motility in vivo and in vitro. J Cell Sci 2001;114:2665–72.
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