INTERACTION OF TUMOR AND HOST CELLS WITH ADHESION AND EXTRACELLULAR MATRIX MOLECULES IN THE DEVELOPMENT OF MULTIPLE MYELOMA
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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Address reprint requests to Kenneth C. Anderson, MD, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 44 Binney Street, Room D289, Boston, MA 02115
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From the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts