INTERACTION OF TUMOR AND HOST CELLS WITH ADHESION AND EXTRACELLULAR MATRIX MOLECULES IN THE DEVELOPMENT OF MULTIPLE MYELOMA

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Adhesion molecules mediate functional interactions among cells, the extracellular matrix (ECM), and the extracellular fluid, and they play a central role in the normal immune response. Cell surface α4β1 and α5β1 integrins on natural killer (NK) cells, for example, bind to the ECM fibronectin and transduce signals intracellularly by induction of tyrosine phosphorylation of paxillin.44 The interaction of adhesion molecules with ligands on target cells may alter their cell surface phenotype and functional repertoire, including migration, cytokine secretion, and growth.35, 67 Exogenous stimuli can similarly alter adhesion molecule expression and cellular function. For example, both hydroxy-3-nitrophenyl acetate and ezrin upregulate adhesion molecules on NK cells, and ezrin also enhances interleukin (IL)-2–mediated NK cell killing.18, 28 Finally, the functional significance of adhesion molecules is confirmed by clinical conditions that arise when they are lacking. For example, the “leukocyte adhesion deficiencies” are characterized by recurrent severe infections in children and are either type 1, resulting from lack of lymphocyte function–associated antigen (LFA)-1 and Mac-1, or type 2, with deficiency of Sialyl-Lewis X ligand for E selectin.13

In the setting of malignancies, adhesion molecules play a role in homotypic adhesion of tumor cells, as well as in tumor cell homing, local invasion, and distant metastases. In addition, the pattern of expression of adhesion molecules on tumor cells has been correlated with disease course and prognosis. For example, intercellular adhesion molecule (ICAM)-1 is expressed on hematologic malignancies, such as acute lymphoblastic leukemia (ALL) and Hodgkin"s disease (HD) cells, as well as on solid tumors, such as sarcoma. Increased expression of ICAM-1 correlates with stage of disease in HD as well as Ewing"s sarcoma, and with relapse in HD.42 Within multiple myeloma (MM), LFA-1 expression is correlated with tumor cell growth.1 Moreover, in MM as well as in B-cell chronic lymphocytic leukemia (CLL), tumor cells bearing adhesion molecules are correlated with advanced-stage disease and poor prognosis.11, 24, 52 In addition, different epitopes on adhesion molecules often mediate different biologic functions,32, 43 and variations in their genetic and/or molecular structure may correlate with phenotypic variations of the tumor cell and disease course.17, 19, 47 In MM, for example, different CD44 splice variants define prognostic subgroups of patients.56 Finally, levels of circulating adhesion molecules in some cases have clinical importance. For example, serum neural cell adhesion molecule (eNCAM, CD56) expression is associated with malignant, rather than benign, paraproteinemia.37

Section snippets

CLASSES OF ADHESION MOLECULES

Cell adhesion molecules that mediate cell-cell and cell-matrix interactions belong to at least five families: the immunoglobulin superfamily, cadhedrins, integrins, selectins, and cell surface proteoglycans (Table 1).58 The molecules of the immunoglobulin superfamily are characterized by various numbers of immunoglobulin domains, consisting of two sheets of anti-parallel β–pleated strands of 90 to 100 amino acids and an interdomain disulfide bond. Most members of this family are involved in

Normal Versus Neoplastic Cells

Adhesion molecules mediate cell-cell interactions that result in homing and activation of cells; conversely, alterations and/or loss of various adhesion molecules result in changes of biologic function. Many of the observed differences in localization and growth of cancer cells versus their normal cellular counterparts have been associated with differences in expression of specific adhesion molecules. Expression of adhesion molecules may be lost, acquired, or altered on tumor cells, thereby

CELL—ECM/BASEMENT MEMBRANE INTERACTION

Besides intercellular interactions, adhesion molecules also mediate cell binding to ECM components including fibronectin, vitronectin, laminin, fibrin, and collagen.9, 10, 15, 27, 49 For example, MM cells bind to fibronectin via VLA-4 as well as to the RGD binding site,59, 66 whereas binding of MM cells to collagen is mediated via syndecan. Conversely, as noted earlier, failure to express adhesion molecules, such as syndecan-1 in ARH-77 MM cells, prevents cell adhesion to ECM type I collagen

OTHER BIOLOGIC SEQUELAE

Adhesion molecules can also regulate cytokine secretion. For example, the binding of MM cells to bone marrow SCs—for example, via VLA-4 and VCAM-1, induces IL-6 transcription and secretion, with related IL-6–mediated paracrine growth of MM cells.60 This has been shown to be regulated through the NF-κB motif in the IL-6 promoter.8 In addition, human MM cell lines secrete fibronectin, which may further augment their growth.64 CD40L upregulates IL-6 secretion and autocrine IL-6–mediated MM cell

Regulation by Cytokines

Cytokines are well-known regulators of adhesion molecule expression, and Table 4 illustrates examples of the complex cytokine network. Moreover, adhesion itself can trigger cytokine secretion, which in turn affects adhesion molecule expression. For example, adhesion of MM cells to bone marrow SCs triggers IL-6 secretion from bone marrow SCs60; adherent MM cells secrete transforming growth factor (TGF)-β1, which further augments IL-6 secretion from bone marrow SCs.63 In addition to its effects

Expression of Adhesion Molecules in Multiple Myeloma

A broad spectrum of adhesion molecules is expressed on MM and PCL cells; Table 2 compares their expression with normal plasmacytic counterparts. Acquisition of CD56, CD58, and RHAMM, as well as loss of CD11a expression heralds transition to malignancy in bone marrow MM cells. The malignant cells are also identified by lack of CD19 and CD45RA/RO molecules (Table 3). In addition, CD56 positivity is also associated with malignant rather than benign paraproteinemia.37 Acquisition of CD11b and

CONCLUSION

Adhesion molecules mediate interactions between host and tumor cells in vitro and are likely to play an important role at several stages in the growth regulation and migration of MM cells in vivo. After class switching in the LN, adhesion molecules (for example, CD44, VLA-4, VLA-5, LFA-1, CD-56, syndecan-1, and MPC-1) mediate homing of MM cells back to the bone marrow. Subsequently, binding of MM cells to bone marrow SCs mediates signal transduction events. Such juxtacrine signaling stimulates

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