Int J Clin Lab Res 22:69-72, 1992
9 Springer-Verlag 1992
Reviews
Cell adhesion molecules in neoplastic disease Judith P. Johnson
Institute for Immunology, Goethestrasse 31, W-8000 Munich 2, Federal Republic of Germany
Summary, In a variety of human malignancies, tumorigenesis and the development of metastatic disease are accompanied by changes in the expression of cell adhesion molecules. In carcinomas, normally expressed cell adhesion molecules are lost, or expressed in a functionally altered form, events which may help tumor cells to escape from contact-mediated controls and leave the primary tumor. The development of metastatic potential is, in a number of solid tumors, associated with the expression of new cell adhesion molecules by the tumor cells. These newly expressed cell adhesion molecules appear to mediate tumor cell interaction with leukocytes and endothelium, and may direct dissemination of the tumor cells throughout the body. Key words: Metastasis - Cadherin - Selectin - Immunoglobulin superfamily
The development and progression of malignant tumors is accompanied by changes in the expression of a variety of cellular products [35]. While many of these molecules appear to be directly involved in the regulation of cell proliferation, molecules mediating interaction of the cells with their environment are also altered during this process [14]. The interaction of cells with their cellular environment is mediated, in large part, by surface molecules which are known collectively as cell adhesion molecules (CAMs) and which demonstrate specific affinities for molecules on the surface of other cells. Molecules with many different structural motifs can function as CAMs and this is reflected in the fact that they are found in diverse molecular families, including the immunoglobulin supergene family [36], the calcium-dependent cadherins [33], the integrins [1] and carbohydrate differentiation antigens [9]. One can distinguish two general types of adhesive interactions, homophilic, in which the CAM on one cell binds to the same molecule on a second cell, and heterophilic in which a CAM on one cell binds to a different CAM on a second cell. Homophilic interactions seem to
be particularly important in the establishment and maintenance of tissue architecture in epithelial tissue [33]. Heterophilic adhesion frequently involves diverse cell types, and the best known example of this type of interaction is found in the immune system [32]. While T lymphocytes recognize their targets through the interaction of the T cell receptor with antigen presented by major histocompatibility complex molecules of the target cell, the results of this recognition, be it stimulation of the T cell or killing of the target, frequently do not occur unless CAMs on the two cells also interact. CAMs therefore, do, not simply glue cells together but, by holding cells in close proximity, make it possible for a variety of signals to be exchanged between them. One of the earliest events in the formation of metastasis is the separation of single tumor cells or clusters of tumor cells from the primary tumor. There is increasing evidence, particularly in carcinomas, that this is accomplished at least in part through a loss of normal cell-cell adhesion with the consequent loss of contact-mediated regulation (Fig. 1). Epithelial CAMs are frequently altered in carcinomas. Some of these molecules are downregulated, some are over-expressed and at least one is structurally altered. E-cadherin, a member of a large family of molecules mediating calcium-dependent cell adhesion, is strongly expressed by all normal epithelia [33]. In cell lines studied in vitro or transplanted into nude mice, down-regulation of E-cadherin leads to an increase in cell motility and invasion into the extracellular matrix, characteristics which can be reversed by expression of E-cadherin-encoding c D N A clones [10, 34]. A role for the down-regulation of E-cadherin in tumor invasion in spontaneous human tumors is supported by the observation that poorly differentiated human carcinomas examined in situ often lack detectable levels of this molecule [31]. Why E-cadherin is down-regulated in carcinomas remains unknown. However, analyses of E-cadherin-transfected cells transplanted into nude mice indicate that expression of this molecule is exquisitively sensitive to environmental signals, suggesting that microenvironmental
70
J.P.
Johnson: Cell adhesion molecules in neoplastic disease
PRIMARYTUMOR ( ~
METASTASIS
VASCULARSYSTEM Fig. 1. Possible roles of cell adhesion molecules in tumorigenesis and the development of metastasis
changes during tumor development may be responsible for its down-regulation [34]. The down-regulation of CAM expression observed in tumors can, however, be the result of genetic mutation. Over 70% of colorectat carcinomas demonstrate a mutation in or the deletion of the gene encoding (DCC), a homotypic CAM of the immunoglobulin supergene family expressed by the normal colorectal mucosal cells [8]. The finding that genetic inactivation of DCC appears to be an early event in the development ofcolorectal carcinomas [7] has led to the suggestion that it functions as a tumor suppressor gene. Recent cloning of the Drosophila tumor suppressor genefat has provided evidence that CAMs can indeed function as tumor suppressor genes [25]. Mutations in this gene, shown to encode a novel member of the cadherin family, result in the development of tumors of the larval imaginal discs, presumably by interfering with the normal adhesion-regulated growth control. Loss of normal adhesive interactions between cells is likely to be a prerequisite for tumor development and progression and, like changes in growth regulation, can probably occur in numerous ways. Consistent with this, alterations potentially leading to decreased cell adhesion have been observed for two additional homotypic CAMs of the immunoglobulin superfamily in carcinomas. A highly glycosylated, developmentally regulated form of the neural CAM, high-PSA-NCAM, has not only been shown to be less adhesive than normal N C A M but also to inhibit interactions mediated by other molecules on the cells expressing it [30]. Expression of high-PSA-NCAM is normally limited to cells in certain stages of development and is thought to be important in temporarily freeing these cells from adhesive interactions with their neighbors. Recently it has been found that the N C A M expressed on Wilm's tumor, small cell lung carcinomas and neuroblastomas is the high-PSA-NCAM form [5], sug-
gesting that this contributes to the separation of cells from the primary tumor. Malignant epithelial cells frequently express 10- to 100-fold higher levels of carcinoembryonic antigen (CEA) than their normal counterparts. The cellular distribution of this CAM is altered and large amounts are secreted into the circulation. These characteristics are associated with enhanced tumor growth and metastasis formation in animal models [20], and it is thought that the over-expression and altered distribution of CEA on malignant epithelial cells may disturb the normal intercellular adhesion and lead to disruption of the tissue architecture [4]. The separation of the tumor cells from the primary tumor and their removal from a variety of contact-mediated regulatory processes is an important early step in tumor progression. However, in order to metastasize, the tumor cells also need to interact with a variety of different cell types as they traverse the lymph and blood vessels and establish new foci of growth in foreign environments (Fig. 1). These interactions m a y also be mediated at least in part by CAMs, and in this case, one might expect such CAMs to be heterophilic, directing adhesion to non-tumor cells, and to be newly expressed on the tumor. Indeed such molecules have been identified on a number of human tumors where they often present as tumor- or progression-associated antigens. The cell surface glycoprotein CD44 was first identified in a functional assay as a lymphocyte-homing receptor, i.e., as a molecule involved in the trafficking of lymphocytes from the circulation into lymph nodes [19]. Since then, this molecule has been found to participate in many different aspects of immune cell interaction and cell-matrix adhesion [15]. CD44 is unrelated to either the cadherin or immunoglobulin superfamilies and shows homologies to the cartilage link protein and proteoglycan
J.P. Johnson: Cell adhesion molecules in neoplastic disease monomer. While CD44 is expressed by most cell types, differential m R N A splicing can generate many different "CD44" molecules, and it now seems likely that these different forms have distinct tissue distributions and functions [16]. One particular CD44 isoform, normally found in activated leukocytes, was found to be expressed in a number of different rodent carcinoma cell lines which had been selected in vivo for high metastatic potential [11]. Transfection of e D N A encoding this isoform could convert low metastatic cells into high metastatic cells, presumably by enabling the tumor cells to interact more effectively with the vascular system and/or the extracellular matrix. While little is presently known about the functions of the various CD44 isoforms, it is interesting to note that many human carcinomas also express distinct CD44 variants [16]. Molecules mediating the adhesion of leukocytes to activated endothelia are important for directing migration of these cells into sites of inflammation [27]. The recent discovery that leukocyte ligands of some of these endothelial molecules are expressed by non-lymphoid tumor cells, suggests that tumor cells may use normal leukocyte trafficking mechanisms to move between the tissues and the vascular system. Expression of the/~t-integrin VLA-4 is normally limited to lymphocytes where it mediates their adherence both to fibronectin and to the CAM VCAM-1, expressed by activated endothelia [6]. VLA-4-VCAM-1 interaction is important in directing lymphocyte migration into inflamed tissues. Some malignant non-lymphoid tumors have also been found to express VLA-4, and in malignant melanoma it is found preferentially on advanced tumors with a high probability of metastasizing [2]. Studies in vitro indicate that the adhesion of melanoma cells to activated endothelium is mediated almost entirely by VLA-4VCAM-1 interaction [29], strongly suggesting that melanoma cells may indeed use this molecule to traverse the vascular endothelium in vivo. The carbohydrate epitope, sialyated Lewis • was identified a number of years ago as a tumor-associated antigen broadly expressed on carcinomas derived from the gastrointestinal tract [18]. Although normally only detectable on fetal colon epithelium, its presence on the surface of carcinoma cells is thought to reflect disturbances in glycosyl-transferase regulation which are common in malignant cells [12]. This oligosaccharide has been identified as a normal differentiation antigen on granulocytes and monocytes and recently was shown to be the ligand for a second inducible endothelial adhesion molecule, ELAM-1 [28]. Thus, like melanomas, colon carcinoma cells also appear to use leukocyte trafficking molecules. In cutaneous melanoma, the search for molecules whose expression in situ change during tumor progression and correlate with the development of metastatic potential, revealed de novo expression of two immunoglobulin family CAMs. One of these is ICAM-1, a cytokine-inducible molecule which was first identified as the melanoma-associated antigen P3.58 [17]. ICAM-1 mediated leukocyte adhesion through its interaction with the /32-integrins LFA-1 and Mac-1 and functions to strengthen immune cell-target cell interactions [32]. Ex-
71 pression of this CAM by malignant melanomas in situ correlates with the development of metastatic potential in these tumors [22] and with a reduced survival time [26]. While the reason for this enigmatic association remains unknown, it may be related to the presence of a soluble form of ICAM-1 which is able to block tumor-leukocyte interactions [3, 13]. MUC18 is a second cell surface glycoprotein whose expression in melanomas correlates with the development of metastatic potential [23]. Molecular cloning of MUC18 revealed that it is a novel member of the immunoglobulin supergene family [24] and that it is most closely related to the CAMs DCC, CEA and NCAM, suggesting that it also mediates cell adhesion [21]. While studies with MUC18 transfectants suggest that this molecule cannot mediate homotypic adhesion, its expression on smooth muscle cells of some blood vessels [23] might indicate that its normal ligand is found in the vasculature. If true than the expression of MUC 18 by melanoma cells may promote intra- and extravasation of the tumor cells. The function of CAMs in directing cell-cell interactions makes them attractive candidates for molecules which play decisive roles in malignant transformation and metastasis formation. The observation that changes in their expression do accompany the development and progression of a variety of spontaneous human tumors supports such roles. While the direct demonstration of the role of CAMs in these processes remains difficult, it is also unclear why their expression is altered. There is no evidence that the genetic alteration observed in the case of DCC is a common mechanism. CAMs are developmentally and environmentally regulated molecules, and it seems likely that their expression pattern during tumor progression reflects a disturbance at the level of the microenvironmental signals and the molecular elements normally controlling their expression. For the majority of CAMs these elements remain undefined. The identification of these mechanisms may shed light not only on the normal expression of these molecules but also on the changes which occur during the development and progression of human tumors.
Acknowledgements. This work was supported by grants from the Deutsche Krebshilfe, Mildred-Scheel-Stiftung and the Deutsche Forschungsgemeinschaft, SFB217 (A3) Bonn, FRG
References
1. Albeda SM, Buck CA, Integrins and other cell adhesion molecules. FASEB J 4:2868, 1990 2. Albeda SM, Mette SA, Elder DE, Stewart R, Damjanovich L. Herlyn M, Buck CA, Integrin distribution in malignant melanoma: association of the/33 subunit with tumor progression. Cancer Res 50:6757, 1990 3. BeckerJC, Dummer R, Hartmann AA, Burg G, Schmidt RE, Sheeding of ICAM-1 from human melanoma cell lines induced by IFN. gamma and tumor necrosis factor-alpha: functional consequences on cell-mediating cytotoxicity. J Immunol 147:4398, 1991 4. Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K, Stanners CD, Carcinoembryonic antigen, a human tumor
J.P. Johnson: Cell adhesion molecules in neoplastic disease
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marker, functions as an intercellular adhesion molecule. Cell 57: 327, 1989 Edelman GM, Crossin KL, Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem 60: 155, 1991 Elices M J, Osborn L, Takada Y, Crouse C, Luhowsky S, Hemler M, Lobb R, VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60: 577, 1990 Fearon ER, Vogelstein B, A genetic model for colorectal tumorigenesis. Cell 61: 759, 1990 Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Tupert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, Vogelstein B, Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247:49, 1990 Feizi T, Carbohydrate differentiation antigens: probable ligands for cell adhesion molecules. Trends Biochem 16: 84, 1991 Frixen U, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W, E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 111:173, 1991 Gfinthert U, Hoffmann M, Rudy W, Reber S, Zrller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P, A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65: 13, 1991 Hakomori SI, Aberrant glycosylation in cancer cell membranes as focused on glycolipids: overview and persepctives. Cancer Res 45:2405, 1985 Harning RE, Mainolfi E, Bystryn JC, Henn M, Merluzzi VJ, Rothlein R, Serum levels of circulatory intercellular adhesion molecule-1 in human malignant melanoma. Cancer Res 51: 5003, 1991 Hart IR, Goode NT, Wilson RE, Molecular aspects of the metastatic cascade. Biochim Biophys Acta 989: 65, 1989 Haynes BF, Telen M J, Hale LP, Denning SM, CD44, a molecule involved in leukocyte adherence and T cell activation. Immunol Today 10:423, 1989 Hoffmann M, Rudy W, Zrller M, Trig C, Ponta H, Herrlich P, Gfinthert U, CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res 51:5292, 1991 Holzmann B, Johnson JP, Kaudewitz P, Riethmiiller G, In situ analysis of antigens on malignant and benign cells of the melanocyte lineage: differential expression of 2 surface molecules, gp75 and gp89. J Exp Med 161: 366, 1985 Itzkowitz SH, Yuan M, Fukushi Y, Palekar A, Phelps PC, Shamsuddin AM, Trump BF, Hakomori S, Kim YS, Lewis" and sialylated Lewis'-related antigen expression in human malignant and non-malignant colonic tissues. Cancer Res 46: 2627, 1986 Jalkanen ST, Bargatze RF, Herron LR, Butcher EC, A lymphoid cell surface glycoprotein involved in endothelial cell recognition and lymphocyte homing in man. Eur J Immunol 16: 1195, 1986 Jessup JM, Giavazzi R, Campbell D, Cleary K, Morikawa K, Fidler IJ, Growth potential of human colorectal carcinomas in nude mice: association with the preoperative serum concentra-
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9 Springer-Verlag 1992
Reviews
Cell adhesion molecules in neoplastic disease Judith P. Johnson
Institute for Immunology, Goethestrasse 31, W-8000 Munich 2, Federal Republic of Germany
Summary, In a variety of human malignancies, tumorigenesis and the development of metastatic disease are accompanied by changes in the expression of cell adhesion molecules. In carcinomas, normally expressed cell adhesion molecules are lost, or expressed in a functionally altered form, events which may help tumor cells to escape from contact-mediated controls and leave the primary tumor. The development of metastatic potential is, in a number of solid tumors, associated with the expression of new cell adhesion molecules by the tumor cells. These newly expressed cell adhesion molecules appear to mediate tumor cell interaction with leukocytes and endothelium, and may direct dissemination of the tumor cells throughout the body. Key words: Metastasis - Cadherin - Selectin - Immunoglobulin superfamily
The development and progression of malignant tumors is accompanied by changes in the expression of a variety of cellular products [35]. While many of these molecules appear to be directly involved in the regulation of cell proliferation, molecules mediating interaction of the cells with their environment are also altered during this process [14]. The interaction of cells with their cellular environment is mediated, in large part, by surface molecules which are known collectively as cell adhesion molecules (CAMs) and which demonstrate specific affinities for molecules on the surface of other cells. Molecules with many different structural motifs can function as CAMs and this is reflected in the fact that they are found in diverse molecular families, including the immunoglobulin supergene family [36], the calcium-dependent cadherins [33], the integrins [1] and carbohydrate differentiation antigens [9]. One can distinguish two general types of adhesive interactions, homophilic, in which the CAM on one cell binds to the same molecule on a second cell, and heterophilic in which a CAM on one cell binds to a different CAM on a second cell. Homophilic interactions seem to
be particularly important in the establishment and maintenance of tissue architecture in epithelial tissue [33]. Heterophilic adhesion frequently involves diverse cell types, and the best known example of this type of interaction is found in the immune system [32]. While T lymphocytes recognize their targets through the interaction of the T cell receptor with antigen presented by major histocompatibility complex molecules of the target cell, the results of this recognition, be it stimulation of the T cell or killing of the target, frequently do not occur unless CAMs on the two cells also interact. CAMs therefore, do, not simply glue cells together but, by holding cells in close proximity, make it possible for a variety of signals to be exchanged between them. One of the earliest events in the formation of metastasis is the separation of single tumor cells or clusters of tumor cells from the primary tumor. There is increasing evidence, particularly in carcinomas, that this is accomplished at least in part through a loss of normal cell-cell adhesion with the consequent loss of contact-mediated regulation (Fig. 1). Epithelial CAMs are frequently altered in carcinomas. Some of these molecules are downregulated, some are over-expressed and at least one is structurally altered. E-cadherin, a member of a large family of molecules mediating calcium-dependent cell adhesion, is strongly expressed by all normal epithelia [33]. In cell lines studied in vitro or transplanted into nude mice, down-regulation of E-cadherin leads to an increase in cell motility and invasion into the extracellular matrix, characteristics which can be reversed by expression of E-cadherin-encoding c D N A clones [10, 34]. A role for the down-regulation of E-cadherin in tumor invasion in spontaneous human tumors is supported by the observation that poorly differentiated human carcinomas examined in situ often lack detectable levels of this molecule [31]. Why E-cadherin is down-regulated in carcinomas remains unknown. However, analyses of E-cadherin-transfected cells transplanted into nude mice indicate that expression of this molecule is exquisitively sensitive to environmental signals, suggesting that microenvironmental
70
J.P.
Johnson: Cell adhesion molecules in neoplastic disease
PRIMARYTUMOR ( ~
METASTASIS
VASCULARSYSTEM Fig. 1. Possible roles of cell adhesion molecules in tumorigenesis and the development of metastasis
changes during tumor development may be responsible for its down-regulation [34]. The down-regulation of CAM expression observed in tumors can, however, be the result of genetic mutation. Over 70% of colorectat carcinomas demonstrate a mutation in or the deletion of the gene encoding (DCC), a homotypic CAM of the immunoglobulin supergene family expressed by the normal colorectal mucosal cells [8]. The finding that genetic inactivation of DCC appears to be an early event in the development ofcolorectal carcinomas [7] has led to the suggestion that it functions as a tumor suppressor gene. Recent cloning of the Drosophila tumor suppressor genefat has provided evidence that CAMs can indeed function as tumor suppressor genes [25]. Mutations in this gene, shown to encode a novel member of the cadherin family, result in the development of tumors of the larval imaginal discs, presumably by interfering with the normal adhesion-regulated growth control. Loss of normal adhesive interactions between cells is likely to be a prerequisite for tumor development and progression and, like changes in growth regulation, can probably occur in numerous ways. Consistent with this, alterations potentially leading to decreased cell adhesion have been observed for two additional homotypic CAMs of the immunoglobulin superfamily in carcinomas. A highly glycosylated, developmentally regulated form of the neural CAM, high-PSA-NCAM, has not only been shown to be less adhesive than normal N C A M but also to inhibit interactions mediated by other molecules on the cells expressing it [30]. Expression of high-PSA-NCAM is normally limited to cells in certain stages of development and is thought to be important in temporarily freeing these cells from adhesive interactions with their neighbors. Recently it has been found that the N C A M expressed on Wilm's tumor, small cell lung carcinomas and neuroblastomas is the high-PSA-NCAM form [5], sug-
gesting that this contributes to the separation of cells from the primary tumor. Malignant epithelial cells frequently express 10- to 100-fold higher levels of carcinoembryonic antigen (CEA) than their normal counterparts. The cellular distribution of this CAM is altered and large amounts are secreted into the circulation. These characteristics are associated with enhanced tumor growth and metastasis formation in animal models [20], and it is thought that the over-expression and altered distribution of CEA on malignant epithelial cells may disturb the normal intercellular adhesion and lead to disruption of the tissue architecture [4]. The separation of the tumor cells from the primary tumor and their removal from a variety of contact-mediated regulatory processes is an important early step in tumor progression. However, in order to metastasize, the tumor cells also need to interact with a variety of different cell types as they traverse the lymph and blood vessels and establish new foci of growth in foreign environments (Fig. 1). These interactions m a y also be mediated at least in part by CAMs, and in this case, one might expect such CAMs to be heterophilic, directing adhesion to non-tumor cells, and to be newly expressed on the tumor. Indeed such molecules have been identified on a number of human tumors where they often present as tumor- or progression-associated antigens. The cell surface glycoprotein CD44 was first identified in a functional assay as a lymphocyte-homing receptor, i.e., as a molecule involved in the trafficking of lymphocytes from the circulation into lymph nodes [19]. Since then, this molecule has been found to participate in many different aspects of immune cell interaction and cell-matrix adhesion [15]. CD44 is unrelated to either the cadherin or immunoglobulin superfamilies and shows homologies to the cartilage link protein and proteoglycan
J.P. Johnson: Cell adhesion molecules in neoplastic disease monomer. While CD44 is expressed by most cell types, differential m R N A splicing can generate many different "CD44" molecules, and it now seems likely that these different forms have distinct tissue distributions and functions [16]. One particular CD44 isoform, normally found in activated leukocytes, was found to be expressed in a number of different rodent carcinoma cell lines which had been selected in vivo for high metastatic potential [11]. Transfection of e D N A encoding this isoform could convert low metastatic cells into high metastatic cells, presumably by enabling the tumor cells to interact more effectively with the vascular system and/or the extracellular matrix. While little is presently known about the functions of the various CD44 isoforms, it is interesting to note that many human carcinomas also express distinct CD44 variants [16]. Molecules mediating the adhesion of leukocytes to activated endothelia are important for directing migration of these cells into sites of inflammation [27]. The recent discovery that leukocyte ligands of some of these endothelial molecules are expressed by non-lymphoid tumor cells, suggests that tumor cells may use normal leukocyte trafficking mechanisms to move between the tissues and the vascular system. Expression of the/~t-integrin VLA-4 is normally limited to lymphocytes where it mediates their adherence both to fibronectin and to the CAM VCAM-1, expressed by activated endothelia [6]. VLA-4-VCAM-1 interaction is important in directing lymphocyte migration into inflamed tissues. Some malignant non-lymphoid tumors have also been found to express VLA-4, and in malignant melanoma it is found preferentially on advanced tumors with a high probability of metastasizing [2]. Studies in vitro indicate that the adhesion of melanoma cells to activated endothelium is mediated almost entirely by VLA-4VCAM-1 interaction [29], strongly suggesting that melanoma cells may indeed use this molecule to traverse the vascular endothelium in vivo. The carbohydrate epitope, sialyated Lewis • was identified a number of years ago as a tumor-associated antigen broadly expressed on carcinomas derived from the gastrointestinal tract [18]. Although normally only detectable on fetal colon epithelium, its presence on the surface of carcinoma cells is thought to reflect disturbances in glycosyl-transferase regulation which are common in malignant cells [12]. This oligosaccharide has been identified as a normal differentiation antigen on granulocytes and monocytes and recently was shown to be the ligand for a second inducible endothelial adhesion molecule, ELAM-1 [28]. Thus, like melanomas, colon carcinoma cells also appear to use leukocyte trafficking molecules. In cutaneous melanoma, the search for molecules whose expression in situ change during tumor progression and correlate with the development of metastatic potential, revealed de novo expression of two immunoglobulin family CAMs. One of these is ICAM-1, a cytokine-inducible molecule which was first identified as the melanoma-associated antigen P3.58 [17]. ICAM-1 mediated leukocyte adhesion through its interaction with the /32-integrins LFA-1 and Mac-1 and functions to strengthen immune cell-target cell interactions [32]. Ex-
71 pression of this CAM by malignant melanomas in situ correlates with the development of metastatic potential in these tumors [22] and with a reduced survival time [26]. While the reason for this enigmatic association remains unknown, it may be related to the presence of a soluble form of ICAM-1 which is able to block tumor-leukocyte interactions [3, 13]. MUC18 is a second cell surface glycoprotein whose expression in melanomas correlates with the development of metastatic potential [23]. Molecular cloning of MUC18 revealed that it is a novel member of the immunoglobulin supergene family [24] and that it is most closely related to the CAMs DCC, CEA and NCAM, suggesting that it also mediates cell adhesion [21]. While studies with MUC18 transfectants suggest that this molecule cannot mediate homotypic adhesion, its expression on smooth muscle cells of some blood vessels [23] might indicate that its normal ligand is found in the vasculature. If true than the expression of MUC 18 by melanoma cells may promote intra- and extravasation of the tumor cells. The function of CAMs in directing cell-cell interactions makes them attractive candidates for molecules which play decisive roles in malignant transformation and metastasis formation. The observation that changes in their expression do accompany the development and progression of a variety of spontaneous human tumors supports such roles. While the direct demonstration of the role of CAMs in these processes remains difficult, it is also unclear why their expression is altered. There is no evidence that the genetic alteration observed in the case of DCC is a common mechanism. CAMs are developmentally and environmentally regulated molecules, and it seems likely that their expression pattern during tumor progression reflects a disturbance at the level of the microenvironmental signals and the molecular elements normally controlling their expression. For the majority of CAMs these elements remain undefined. The identification of these mechanisms may shed light not only on the normal expression of these molecules but also on the changes which occur during the development and progression of human tumors.
Acknowledgements. This work was supported by grants from the Deutsche Krebshilfe, Mildred-Scheel-Stiftung and the Deutsche Forschungsgemeinschaft, SFB217 (A3) Bonn, FRG
References
1. Albeda SM, Buck CA, Integrins and other cell adhesion molecules. FASEB J 4:2868, 1990 2. Albeda SM, Mette SA, Elder DE, Stewart R, Damjanovich L. Herlyn M, Buck CA, Integrin distribution in malignant melanoma: association of the/33 subunit with tumor progression. Cancer Res 50:6757, 1990 3. BeckerJC, Dummer R, Hartmann AA, Burg G, Schmidt RE, Sheeding of ICAM-1 from human melanoma cell lines induced by IFN. gamma and tumor necrosis factor-alpha: functional consequences on cell-mediating cytotoxicity. J Immunol 147:4398, 1991 4. Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K, Stanners CD, Carcinoembryonic antigen, a human tumor
J.P. Johnson: Cell adhesion molecules in neoplastic disease
72
5.
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7. 8.
9. 10.
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16.
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