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Tumor Biology |
The First Department of Internal Medicine [T. F., Y. T., K. F., S. M., K. S., S. Y., S. E.] and Department of Immunology [U. Y.], University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu 807-8555, Japan, and Department of Cancer Biology and Molecular Immunology, Faculty of Pharmaceutical Science, University of Tokyo, Tokyo 113-0033, Japan [T. I.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The adhesive capacity of integrins expressed on peripheral leukocytes/leukemic cells is tightly regulated (15) . Although integrins expressed on resting cells do not mediate firm adhesion to endothelial ligands, stimulation of these cells results in a rapid increase in integrin function. Thus, activation of integrin is essential for integrin-mediated adhesion in which a signal transduced to the circulating cells converts the functionally inactive integrin to an active adhesive configuration (8 , 16, 17, 18) . In this regard, we and others have previously reported that chemokines produced in large amounts at the site of inflammation activate integrins on leukocytes and result in their accumulation in the tissues (9 , 11 , 19, 20, 21, 22) . We also proposed that chemokines produced by leukemic cells are involved in triggering integrin LFA-1 through cytoskeletal rearrangement in an autocrine manner (11) . However, the exact mechanisms that enhance the adherence of circulating tumor cells to the endothelium and their subsequent infiltration into the tissues or those regulating integrin adhesiveness to the endothelium are not very clear at present.
CD44, a widely expressed cell surface glycoprotein, serves as an adhesion molecule in cell-substrate and cell-cell interactions, including lymphocyte homing, hemopoiesis, and cell migration (23, 24, 25) . Several isoforms and variants of CD44, particularly those generated by splicing, have been identified and reported to be causally involved in the formation of tumor metastases (14 , 24 , 26) . However, the functional relevance of CD44 on tumor cells to metastasis remains to be explored.
These insights have prompted us to investigate the stimulatory molecules that induce integrins, especially LFA-1, in the present study. Based on a survey of cross-linking of multiple stimulations using colorectal carcinoma cell lines, we found that CD44 was unique in its induction of LFA-1, especially the activation epitope of LFA-1, on the cells. We propose that CD44 stimulation can induce integrin expression as well as integrin activation on tumor cells and can augment integrin-mediated tumor cell adhesion to endothelial cell. This, in turn, leads to the transendothelial migration of tumor cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Reagents and mAbs.
The following mAbs were used as purified immunoglobulin in cell surface analyses and functional assays: (a) CD54 (ICAM-1) mAb 84H10 [kindly provided by Dr. S. Shaw (NIH, Bethesda, MD); Ref. 27
]; (b) CD106 (VCAM-1) mAb 2G7 [kindly provided by Dr. W. Newman (Otsuka America, Rockville, MD)]; (c) CD11a (LFA-1
) mAb TS1/22 (American Type Culture Collection, Manassas, VA); (d) antiactivation epitope of LFA-1 mAb NKI-L16 [kindly provided by Dr. C. Figdor (University Hospital, Nijmegen, the Netherlands); Refs. 28
and 29
]; (e) CD44 mAb NIH44-1 (provided by Dr. S. Shaw; Ref. 25
); (f) CD44v3 mAb BBA11 and CD44v6 mAb BBA13 (both are from Cosmo-Bio, Tokyo, Japan); (g) CD49d (VLA-4) mAb NIH49d-1 (from Dr. S. Shaw); (h) c-Met mAb (Seikagaku, Tokyo, Japan); and (i) control mAb thy1.2 and anti-glycophorin mAb 10F7 (both are from American Type Culture Collection). Fragmented and native hyaluronan were kindly donated by the Tokyo Research Institute of Seikagaku. ICAM-1-transfected COS cells and mock-transfected COS cells were also prepared as reported previously (9)
. Multiple inhibitors of cytoplasmic signaling were applied to each assay system, and all reagents were used at the indicated concentrations. At these concentrations, none of these inhibitors produced cytotoxic effects on LS174T cells, as confirmed by trypan blue staining. We used wortmannin (Wako Pure Chemical, Osaka, Japan), a phosphatidylinositol 3'-kinase inhibitor, H89, an A-kinase inhibitor, H7 and staurosporine (Seikagaku), C-kinase inhibitors, herbimycin A (Sigma, St. Louis, MO), and genistein (Calbiochem, San Diego, CA), a tyrosine kinase inhibitor.
Fluorescence-activated Cell-sorting Analysis.
Staining and flow cytometric analysis of colon cancer cell lines were carried out with a FACScan (Becton Dickinson, Mountain View, CA) using standard procedures, as described previously (8
, 10)
. Briefly, cells (2 x 105) were incubated with negative control mAb thy1.2., ICAM-1 mAb 84H10, VCAM-1 mAb 2G7, LFA-1 mAb TS1/22, activation epitope of LFA-1 mAb NKI-L16, CD44 mAb NIH44-1, CD44v3 mAb, CD44v6 mAb, CD49d mAb NIH49d-1, and c-Met mAb in fluorescence-activated cell-sorting media consisting of HBSS (Nissui, Tokyo, Japan), 0.5% HSA (Green-Cross, Osaka, Japan), and 0.2% NaN3 (Sigma Aldrich) for 30 min at 4°C. After washing, the cells were further incubated with FITC-conjugated goat antimouse IgG Ab for 30 min at 4°C. Amplification of mAb binding was provided by a three-decade logarithmic amplifier. Quantification of the cell surface antigens on each cell was performed using QIFKIT beads (Dako Japan, Kyoto, Japan) as reported previously (11
, 30
, 31)
.
F-Actin Polymerization Assay.
For microscopic analysis, LS174T cells were allowed to settle for 30 min at 4°C on fibronectin-coated slides. After incubation for 1 min at 37°C, the cells were fixed with 1% formaldehyde. F-actin was stained with rhodamine-phalloidin (1 unit/slide; Molecular Probes, Inc., Eugene, OR) and analyzed later with a confocal laser microscope system (model LSM 410UV; LD Achroplan 20 objective lens; Carl Zeiss, Juna, Germany).
Adhesion Assay.
The adhesion assay of colon cancer cell lines to HUVECs was performed as described previously (9)
. HUVECs were applied to 48-well culture plates (Costar Corp., Cambridge, MA) coated with 2% gelatin and cultured to confluence in DMEM containing 100 units/ml penicillin G, 100 units/ml streptomycin, 20% heat-inactivated FCS, 20 µg/ml endothelial mitogen (Biomedical Technologies, Stoughton, MA), and 10 units/ml heparin. After washing with PBS, HUVECs were stimulated with 1 ng/ml IL-1ß (Otsuka, Tokyo, Japan) for 8 h at 37°C. COS cells were plated onto 96-well plates (Costar) and cultured to confluence. Plates were washed three times with PBS before the addition of 51Cr (DuPont New England Nuclear, Wilmington, DE)-labeled LS174T cells (2 x 105); with or without stimulation of CD44-cross-linking, second goat antimouse IgG, or hyaluronan to each well in a final volume of 100 µl of PBS/0.5% HSA. LFA-1 mAb and VLA-4 mAb were used at a saturating concentration of 10 µg/ml, which was shown in previous studies to maximally inhibit the relevant adhesive interaction (9)
. After a settling phase of 30 min at 4°C, which also allowed mAb binding, plates were warmed rapidly to 37°C for 30 min and then gently washed twice with RPMI 1640 at room temperature to remove nonadherent cells. The contents of each well containing adherent cells were lysed with 250 µl of 1% Triton X-100 (Sigma), and 
-emission of the content of each well was determined. Data were expressed as the mean percentage of binding of indicated cells from a representative experiment.
Transendothelial Migration Assay.
LS174T cells that had reached subconfluence were harvested and used for the transendothelial migration assay (32)
. For this purpose, HUVECs were incubated on the membrane filter in Transwell (Costar) chambers with tissue culture-treated 12-µm-pore filters for 3 days. The cell suspensions of 51Cr -labeled LS174T cells (500 µl) in serum-free DMEM containing 0.1% HSA were then placed into the upper compartment of the chamber in the presence or absence of 20 ng/ml rHGF, and the lower well of the chamber was filled with serum-free medium. Cells adhering to the upper side of the filter (after a 30-min incubation at 37°C) and cells adhering to the lower side of the filter and cells in the lower chamber (after a 24-h incubation at 37°C) were collected separately, and the -emission of each component was determined. The mean percentage of cells adhering to the upper side of the filter relative to the added cells represented cells adherent to HUVECs, and the mean percentage of cells adhering to the lower side of the filter and in the lower chamber represented the cells that migrated to the endothelium.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, VLA-4, and CD44 and its variants (CD44v3 and CD44v6) on eight colon cancer cell lines using flow cytometry. Among these molecules, CD44 was highly and consistently expressed on all but one colon cancer cell line (HCT-115). In contrast, integrins LFA-1 and VLA-4 were not expressed on any of the eight cell lines (Fig. 1A)
. CD44 possesses 10 exons subjected to alternative splicing, resulting in the generation of variable regions, and CD44v6 is known to be involved in the metastatic process of certain cancer cells (24)
. HT-29 and HCT-116 slightly expressed CD44v3 and CD44v6, but other cell lines did not express these variant forms of CD44 (Fig. 1B)
. The level of CD44 and the expression of variant forms of CD44 on the surface did not depend on the differentiation pattern of cancer cell lines.
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. On the other hand, cross-linking of CD44 with a subsequent 6-h culture markedly induced the expression of the three molecules on all colon cancer cell lines, with the exception of HCT-15, which expressed less CD44 on the surface (Fig. 2B)
. These results indicate that CD44 cross-linking markedly induces the expression of integrins LFA-1 as well as HGF-receptor c-Met on colon cancer cell lines, although such expression does not occur without stimulation. In addition, the observation that after CD44 cross-linking, HCT-116 cells bearing CD44v6 showed properties similar to those of the other cells suggests that the expression of a variant form of CD44 is not relevant to the induction of LFA-1 and c-Met by CD44 stimulation.
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-chain of LFA-1 (11
, 28 , 30)
. We next assessed the biological activities of hyaluronan on the expression of the activation epitope of LFA-1 and c-Met on LS174T cells. Expression of the activation epitope of LFA-1, as recognized by the NKI-L16 mAb, was significantly induced by the addition of the Mr 6,900 fragment of hyaluronan (1 nM). In contrast, native hyaluronan, a Mr 1,700 fragment of hyaluronan, and a Mr 40,000 fragment of hyaluronan (all 1 nM) failed to induce its expression (Fig. 3A)
. Furthermore, the expression of c-Met was also increased by the Mr 6,900 fragment of hyaluronan, but not by others, including native hyaluronan (Fig. 3B)
. These data suggest that hyaluronan, especially when fragmented, is a possible ligand involved in CD44-mediated LFA-1 expression and/or activation and c-Met expression on LS174T cells.
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. These results indicated that CD44 induced an immediate polymerization and rearrangement of F-actin, which might lead to active configuration of LFA-1.
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. Thus, these data indicate that although the up-regulation of the activation epitope of LFA-1 induced by hyaluronan was mediated by a number of signaling pathways, it depended mainly on the activation of protein kinase C.
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. These results suggest that CD44 cross-linking induces not only the expression of LFA-1 but also the active configuration of LFA-1. Furthermore, HGF is also involved in the expression of the activation epitope of LFA-1 through the c-Met receptor induced by CD44 cross-linking as an alternate pathway.
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. The adhesion of LS174T cells to IL-1-activated HUVECs was also markedly augmented after stimulation by CD44 cross-linking or by the Mr 6,900 hyaluronan fragment. Furthermore, fragmented hyaluronan-induced adhesion of LS174T was inhibited by the addition of anti-LFA-1 and VLA-4 mAbs (Fig. 7B)
. These results indicate that CD44 stimulation by mAbs or fragmented hyaluronan induces integrin expression as well as integrin activation, which results in an enhancement of integrin-mediated adhesion to their ligands on endothelial cells.
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. These results suggest that c-Met induction on colon cancer cells by CD44 cross-linking results in a further enhancement of their adhesion and migration in response to HGF.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It is well known that the expression and function of adhesion molecules are regulated through cytoplasmic signaling induced by several cellular stimuli, a process known as "inside-out signaling" (15)
. Among these stimuli, cytokines including IL-1ß or tumor necrosis factor up-regulate the immunoglobulin superfamily of adhesion molecules, such as ICAM-1 and VCAM-1 (35
, 36)
. The present study is the first to show that one particular adhesion molecule, CD44, is involved in the up-regulation of expression of LFA-1. In this regard, the function of LFA-1 is tightly regulated through the inside-out signaling stimulated by several other cellular stimuli; namely, the activation of integrin is essential for integrin-mediated adhesion in which a signal converts the functionally inactive integrin to an active adhesive configuration. It is noteworthy in the current study that CD44 cross-linking or fragmented hyaluronan appears to induce not only a quantitative change of LFA-1 expression but also induces a qualitative change of LFA-1 on the colon cancer cells and amplified integrin-mediated adhesion of the cells. We observed that expression of the activation epitope of LFA-1, as recognized by NKI-L16 mAb, was induced by the addition of the fragmented hyaluronan, which was decreased by staurosporin or H7, protein kinase C inhibitors. Also, we and others (11
, 15
, 30
, 32)
have proposed that higher affinity and/or avidity of LFA-1 are induced by conformational change and/or multimerization of LFA-1 on the cell surface, and that polymerization of F-actin filaments, which are associated with the endodomain of integrins, is involved in the induction of the active configuration of LFA-1. Here we observed that CD44 cross-linking resulted in the polymerization and rearrangement of F-actin in the cell cortex within a minute using confocal microscopy.
Second, certain adhesion molecules not only function as a glue but also transduce extracellular information to the cytoplasmic organelle through "outside-in signaling," resulting in cell activation and cytokine production (15) . LFA-1, VLA-4, CD2, CD28, and CD154 are the best known molecules that induce costimulatory signals in T-cell-antigen-presenting cell binding, which are essential to T-cell activation and cytokine production (27 , 37, 38, 39) . Studies from our laboratories have also shown that ICAM-1 on rheumatoid synoviocytes induces cytokine gene transcription in synoviocytes through the activation of nuclear factor activating protein (AP)-1 (33) . Recent studies have also identified CD44 as a signaling molecule (23 , 25 , 40) . Stimulation of CD44 transmits the signal into the cells, which leads to the activation of T cells and cytokine release from monocytes or chondrocytes (41, 42, 43) . Although CD44 is up-regulated in colon cancers, and its expression as well as that of its variant form is thought to be relevant to cancer metastasis (14 , 24 , 26 , 44 , 45) , the precise functional role of CD44 in metastasis is still unclear. Our results showed that CD44 cross-linking or fragmented hyaluronan induced LFA-1 expression and activation. It is of interest that CD44 stimulation failed to induce LFA-1 and c-Met expression on one cell line, HCT-15, which bears little CD44 on the surface. Furthermore, another cell line, HCT-116, bearing higher levels of CD44v6, expressed adhesive properties similar to those of other cell lines lacking CD44v6 after CD44 cross-linking. These results suggest that a variant form of CD44 is not relevant to the induction of LFA-1 and c-Met by CD44 stimulation and that the amount of CD44 on the cell surface appears to be important for signaling. Furthermore, it is noteworthy that integrin activation through outside-in signaling induced by CD44 stimulation possesses two differential pathways. Namely, CD44 stimulation alone satisfactorily induced the activation epitope of LFA-1 and its mediated adhesion. In addition, our results also indicated that CD44 stimulation further induced the expression of c-Met, a major receptor for HGF. CD44 also stimulated responsiveness to HGF, which in turn augmented LFA-1-mediated adhesion induced by CD44 stimulation.
The principal ligand of CD44 is hyaluronan. Hyaluronan is a high molecular weight digosacchahide bearing linear repeats of disaccharide-ß-D-glucuronyl-ß-D-N-acetylglucosamine (46) . Several studies have examined the biological activities of hyaluronan and shown that its high molecular weight fragments inhibit the proliferation of endothelial cells, fibrocytes, and mitogen-stimulated lymphocytes, whereas the low molecular fragments exert a stimulatory effect (47) . The functional role of hyaluronan in metastasis is virtually unknown. Our results showed that fragmented hyaluronan up-regulated LFA-1, activated LFA-1, and induced the integrin-mediated adhesion of colon cancer cells to endothelial cells. In this regard, several studies have shown that the stroma of various tumors is hyaluronan-rich compared to the supporting connective tissue of normal parenchyma (48) . Recent studies have also shown that certain malignant cells secrete or present membrane-bound hyaluronan in adjacent fibroblasts and that high concentrations of hyaluronan in turn stimulate cancer cell motility (48 , 49) . Hyaluronan also stimulates angiogenesis, a vital process for tumor growth, and low molecular weight hyaluronan fragments strongly stimulate tumor growth (48) . For human colon carcinoma, tumor cells show hyaluronidase activity, thus enhancing the generation of fragmented hyaluronan (50 , 51) . Based on the above findings, both the synthesis and degradation of hyaluronan seem to support tumor invasion and growth. Furthermore, the present results indicate that fragmented hyaluronan is more effective in up-regulating LFA-1 than native HA. These results demonstrate that fragmented hyaluronan, far from being an inert space filler, plays an important biological role, including qualitative and quantitative regulation of adhesion molecules in cancer cells.
HGF is a pleiotropic growth factor with various biological activities, including mitogenic, motogenic, and/or morphogenic properties, in a variety of epithelial tissues, and its ligand for a tyrosine kinase cell surface receptor is encoded by the Met proto-oncogene c-Met (52 , 53) . Recent studies have shown the importance of mutual interactions between carcinoma cells and these cells (as the inducer of HGF within the supporting stroma of tumors) in the invasion and metastasis of carcinoma cells. Thus, HGF derived from these cells stimulates the motility and invasiveness of various carcinoma cell types in vitro (54 , 55) . Furthermore, overexpression of c-Met in gastric and hepatocellular carcinoma is associated with poor prognosis (56 , 57) . Recent studies have also shown that NIH3T3 fibroblasts transfected with both HGF and c-Met genes exhibit tumorigenic capacity in nude mice (58) . Furthermore, HGF/c-Met has been shown to be involved in the adhesion of tumor cells; specifically, HGF follows the initial adhesion of cancer cells via selectins and increases the adhesion of c-Met-positive cancer cells to the extracellular matrix via integrins (59 , 60) . Our early findings that HGF activates integrins and induces integrin-mediated adhesion of lymphocytes and leukocytes, as chemokines do (32 , 61) , were followed by several studies that demonstrated activation of VLA-4 and VLA-5 of lymphoma cells by HGF (59 , 62) . Based on this background work, we investigated in the present study whether HGF is involved in the activation of integrin LFA-1 and adhesion of colon carcinoma cells. Our results showed that HGF further augmented the expression of the activation epitope of LFA-1 and its dependent adhesion as well as the transendothelial migration of colorectal carcinoma cells that was mediated by c-Met induced by CD44 stimulation.
Although colorectal carcinoma cells did not express sufficient LFA-1 and VLA-4, taken together, our results showed that stimulation of these cells by CD44 cross-linking or fragmented hyaluronan resulted in the expression of LFA-1 and the activation epitope of LFA-1. This allows the adhesion of cancer cells to endothelial cells, followed by transendothelial migration. Furthermore, CD44 not only acted directly via integrins but induced c-Met expression and enhanced the response to HGF, and HGF further augmented the integrin-mediated adhesion and migration of CD44-stimulated colon cancer cells. Based on the findings presented here, we postulate that cellular functions are regulated by cross-talk between two distinctive adhesion molecules on the same cell. Thus, stimulation by CD44 cross-linking or ligation with fragmented hyaluronan induces outside-in signaling, which augments integrin expression and triggers integrin function by inside-out signaling. Furthermore, the outside-in signaling in colon cancer cells appears to consist of at least two pathways, a direct pathway through CD44 and an alternate pathway through the induction of c-Met expression involved by HGF, both of which cooperatively play a pivotal role in the integrin-mediated adhesion of colon cancer cells to the vascular wall. We believe that the concept of the adhesion cascade described in leukocyte adhesion to endothelial cells can also be applied to tumor cell extravasation and metastasis. Induction of expression and activation of integrins on the cells induced by CD44 stimulation could explain the transendothelial migration of tumor cells, especially with regard to colon cancer cells,. Recent studies have suggested that CD44 receptor globulin, anti-CD44 mAb, native hyaluronan, and hyaluronan oligomers efficiently inhibit tumor growth, metastasis, and invasion in in vivo and in vitro (63 , 64) . Our findings using colorectal carcinoma cells warrant additional studies to unravel the mechanisms of integrin activation in other types of cells and the pathogenesis of tumor metastasis. Such studies may potentially lead to the design of novel pharmacological approaches to control these diseases.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan. 
2 To whom requests for reprints should be addressed, at The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Phone: 81-93-603-1611, ext. 2426; Fax: 81-93-691-9334; E-mail: tanaka{at}med.uoeh-u.ac.jp
3 The abbreviations used are: LFA, lymphocyte function-associated antigen; HGF, hepatocyte growth factor; HUVEC, human umbilical vein-derived endothelial cell; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; VLA, very late antigen; mAb, monoclonal antibody; HSA, human serum albumin; Ab, antibody; IL, interleukin; rHGF, recombinant HGF.
Received 2/23/99. Accepted 7/ 1/99.
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REFERENCES |
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and is mediated by intercellular adhesion molecule 1 (ICAM-1). J. Exp. Med., 167: 1323-1340, 1988.4ß1 and 5ß1 integrins. Blood, 89: 990-1000, 1997.This article has been cited by other articles:
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, mock-transfected COS cells; 
, ICAM-1-transfected COS cells) or (B) IL-1-ß-activated HUVECs was carried out by a 30-min incubation in the presence or absence of the indicated adhesion-blocking mAbs (in 10 µg/ml). 