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Or Tumor Necrosis Factor-Α Differential Effects of Interleu kin 1-a (IL-1a) or Tumor Necrosis Factor-a (TNF-a) on Motility of Human Melanoma Cell Lines on Fibronectin Sybren K. Dekker,* Jacqueline Vink,* Bert Jan Vermeer,t Jan A. Bruijn,:j: Martin C. MihmJr.,* and H. Randolph Byers* 'Dermatopathology Division, Department of Pathology, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts, U.S.A.; and Departments of tDermatology and :j:Pathology, University of Leiden, Leiden, The Netherlands Interleukin-la (IL-la) and tumor necrosis factor-a melanoma cell lines tested; downward shift of the a 2 , a 3 , a4 , (TNF-a) induce a motogenic response in a number of benign and PI integrin subunits was detected among three of the and malignant cells. We examined the chemokinetic effects melanoma cell lines as were upward shifts of the a 4 , as, and of these cytokines on the cell migration of four melanoma a6 integrin subunits among three of the melanoma cell lines. cell lines on fibronectin using modified Boyden chambers IL-la and TNF-a induced enhanced migration on fibronec­ and video-time lapse analysis. Flow cytometry analysis of tin in one of the melanoma cell lines and were related to an IL-l receptors, TNF receptors, and shifts in PI integrin ex­ upward shift in the a 4 and as integrin subunit expression. pression were correlated with the effects of these cytokines Taken together, the findings indicate that expression of a on cell migration on fibronectin. The four melanoma cell particular receptor for IL-l or TNF does not necessarily sig­ lines exhibited heterogeneous expression of types I and II nal a motogenic response in melanoma cells, but induces IL-l receptors as well as p60 TNF receptors. Scant p80 TNF heterogeneous shifts in PI integrin expression. However, up­ receptor expression was detected on only one cell line. Three regulation in a 4 and as integrin subunits appears to relate to of four melanoma cell lines demonstrated type I IL-l recep­ enhanced migration on fibronectin. Key words: migration/ tors by Western blotting. IL-la and TNF-a induced hetero­ tumor necrosis factor/interleukin 1/integrin. ] Invest Dermatol geneous modulation of PI integrin expression in the four 102:898-905, 1994 alignant cells, like many benign cell types during molecules in cell adhesion and motility in normal and malignant embryogenesis, exhibit a capacity for cell migra­ cells [6]. Tumor cell invasion requires attachment to and migration tion. Regulation of cell motility is complex, and through a number of extracellular matrix molecules [7], and inte­ involves an interplay of cytoskeletal proteins, ad­ grins belonging to the very late antigen (VLA) family, those with a hesion molecules, ion fluxes, and cell-surface re­ common P! subunit, are known to exhibit changes in levels of ex­ Mceptors that relay signals to set the cell in motion. Several cytokines pression on neoplastic transformation [B,9] . Cell transformation or that have potent motogenic properties have recently been identified exposure to certain cytokines have in common an alteration in cell [1] . Lymphocytes, fibroblasts, and endothelial or tumor cell produc­ behavior on extracellular matrix (ECM) proteins that is the result of tion of cytokines may have dramatic effects on the motility of ma­ shifts in integrin expression [2,4,9,10]. lignant cells, providing the malignant cells express the appropriate The expression of P! integrins in human melanoma is heteroge­ receptors. Exactly how cytokines signal motility is unclear; how­ neous [11 J and the pattern of expression dictates differential adhe­ ever, recent findings indicate that interleukin (IL)-1P, tumor necro­ sion [4,12] or migration behavior on specific extracellular matrix sis factor (TNF)-a, and transforming growth factor (TGF)-P are molecules [13]. Exposure of melanoma cells to TNF-a has recently able to modulate integrin expression on a variety of cells [2-5]' been reported to result in their increased adhesion to fibronectin [4]. Integrins are a family ofheterodimeric transmembrane receptors Specifically, upregulation of the asP! integrin was reported. This composed of an a and P subunit and are believed to be important integrin, along with a 4P! and a.jJ!, is known to bind the extracellu­ lar matrix protein fibronectin [14 -17]. We hypothesize that a cytokine-induced shift in asP! expression Manuscript received June 2B, 1993; accepted for publication January 14, may relate to motogenic properties of certain cytokines. Therefore, 1994. we tested the effect ofTNF-a as well as another known motogenic Reprint requests to: Dr. H. Randolph Byers, Immunopathology, Massa­ cytokine, IL-1a, on the migration of a number of melanoma cell chusetts General Hospital, 100 Blossom St., Boston, MA 02114. lines using micropore transmembrane and video time-lapse migra­ Abbreviations: (d)BSA, (denatured) bovine serum albumin; DOC, deoxy­ tion assays. Heterogeneity of response among the cell lines could cholic acid; FN, fibronectin; IL-1a, interleukin 1-alpha; IL-1R, interleukin- relate to differential expression of cytokine receptors. Therefore, we 1 receptor; MFI, mean fluorescence intensity; MM-AN, metastatic mela­ noma cell line-code; MM-RU, metastatic melanoma cell line-code; p60 used indirect immunofluorescence and flow cytometry utilizing TNF-R, p60 tumor necrosis factor receptor; pBO TNF-R, pBO tumor necro­ monoclonal antibodies against the two recently described types of sis factor receptor; PM-WK, primary melanoma cell line-code; RPM-EP, TNF receptors-p60 and pBO TNF-R [1B-21]-and the two recurrent primary melanoma cell line-code; TRIS, tris-hydroxymethyl types ofIL-l receptors-types I and II IL-1R [22,23]. In addition, amino methane; VLA, very late antigen. Western blotting with type I IL-l R was performed on the four cell 0022-202X/94/S07.00 Copyright © 1994 by The Society for Investigative Dermatology, Inc. 898 VOL. 102, NO.6 JUNE 1994 IL-la OR TNF-a AND MOTILITY IN MELANOMA 899 40~--------------------------~1 14.-----------------------------. • Control (Fibronectin coated) • Control (Fibronectin coated) ..... 1'21 + TNF-a. 12 -­..c II +TNF-a. 1IIIII+IL-1a. 30 (/) III + IL-1 a. E c 10 ~ <l> -C 8 20 6 Ol <l> 4 10 c 2 o o PM-WK RPM-EP MM-AN MM-RU PM-WK RPM-EP MM-AN MM-RU Figure 1. Representative video time-lapse migration assay of the four mel­ Figure 2. Representative modified Boyden chamber transmembrane mi­ anOIna cell lines on fibronectin following exposure to TNF-a and IL-1a. gration assay of the four melanoma cell lines on double-sided fibronectin­ Whereas the PM-WK, RPM-EP, and MM-AN cell lines exhibit no signifi­ coated micropore filters after exposure to TNF-a and IL-1a. No significant cant increase in motility, a significant increase in mean migration rate of the effects are seen with either cytokines on the migration of the PM-WK. MM-RU cell line is observed with both TNF-a ("p < 0.005) and IL-1a RPM-EP. or MM-AN cell lines; however, both TNF-a and IL-la signifi­ incubation (' p < 0.001). cantly enhance the transmembrane migration of MM-RU melanoma cells ('p < 0.001). lines tested. Finally, TNF-a- and IL-la-treated melanoma cell lines were examined by quantitative flow cytometry to determine control MoAb anti-human leukocyte antigen (HLA) class I (W6/32) was whether cytokine-induced motogenic effects related to specific obtained from American Type Culture Collection. Negative control MoAb shifts in integrin expression. included an anti-Fe receptor antibody [26], fluorescein-conjugated anti­ mouse (or anti-rat) immunoglobulin (Ig)G alone [27], Fe fragment (Rock­ land Inc.), or unrelated mouse IgG isotype-matched fluorescein-conjugated MATERIALS AND METHODS antibodies (Becton-Dickinson, Mountain View, CAl. Melanoma Cell Lines and Culture Conditions The primary mela­ noma cell line PM-WK, isolated from the radial growth phase, the recurrent Transmembrane Cell Migration Through Double-Sided Fibronec­ melanoma cell line, RPM-EP, from the vertical growth phase, and the tin-Coated Micropore Membranes Both sides of the modified Boyden metastatic cell lines, MM-AN and MM-RU, from lymph nodes. were iso­ chamber po~ycarbonate membranes (Transwell 24, 8-,um pore, 3422; Co­ lated in permanent culture and maintained using standard culture media star, Cambndge, MA) were coated and washed three times with PBS as with 2% fetal bovine serum and 8% newborn bovine serum as previously described above. Cells of each melanoma cell line culture were added to each s described [24]. upper chamber unit of the transwell plate at 1 X 10 cells and cultured for 24-48 h with or without IL-1a (1000 U/ml) or TNF-a (5 ng/ml; 100 Extracellular-Matrix Coating Procedure Microcover glasses used in U/ml). Each membrane was then washed with PBS. fixed for 10 min inl0% the cell migration assay (see below) were coated with fibronectin (FN) or formalin. and incubated for 5 min with 0.5% Triton X-I00. After cotton larninin (LN) (Collaborative Research Inc .• Bedford. MA) diluted in phos­ swab removal of upper chamber melanoma cells. the cells on the bottom side phate-buffered saline (PBS) to 10,ug/ml for 1 hat 37'C following estab­ were stained with Gill's hematoxylin. All membranes were analyzed with an lished techniques [25]. Overnight coating with 20 mg/ml heat-denatured Image analYSIS system (Microcomp. Southern Micro, Atlanta. GA), which bovine serum albumin (dB SA) at 4 'C was performed to block nonspecific was used to obtain densitometry readings of four different 7-mm2 areas binding sites. The upper and bottom side of the micro pore membranes in mcorporatmg nearly the entire membrane, using the 2 X objective. Stained modified Boyden chambers (see below) were similarly coated with FN and ~ells r ~du~e pixel intensity; therefore.
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