The Role of the Bone Marrow Microenvironment in the Pathophysiology of Myeloma and Its Significance in the Development of More Effective Therapies
Section snippets
The Cellular Constituents and Extracellular Components of the Bone Marrow Microenvironment in Myeloma
The microenvironment of the BM includes a broad spectrum of cellular and extracellular components that can influence the biologic behavior of MM cells. For instance, extracellular matrix (ECM) proteins, including fibronectin, collagen, and laminin, provide an architectural meshwork on which diverse cellular components can reside and exert their biologic functions. These cellular constituents include MM cells themselves, cells from various stages of differentiation of normal hematopoietic
The Interaction of Multiple Myeloma Cells with Bone Marrow Stromal Cells
BMSCs are considered to have a key role in the entire nexus of functional interactions between MM cells and the BM microenvironment. In the MM literature, BMSCs are typically identified descriptively as a heterogeneous population of mesenchymal cells that are morphologically reminiscent of fibroblasts (as reviewed in [7]). In the context of normal BM physiology, BMSCs are believed to function as an accessory cell population that supports the survival, cell division, and differentiation of
Interactions of Multiple Myeloma Cells with Multiple Myeloma–Associated Bone Marrow Endothelial Cells
Neoangiogenesis plays a critical role in the establishment of solid tumors, which typically cannot grow beyond a limited size of a few millimeters [52] without the so-called “angiogenic switch.” This event is critical for solid tumors because it allows them to recruit blood vessels that allow them to overcome the growth restrictions imposed by intratumor hypoxia [52], [53]. In the context of BM-localized hematologic neoplasias, such as MM, the functional relevance of increased tumor-associated
Osteoclast–Multiple Myeloma Cell Interactions
Normal bone is being continuously remodeled to respond to changes in applied pressure. In this process, osteoclasts resorb old bone, which is replaced by deposition of new bone by osteoblasts (reviewed in [69]). A substantial difference of the new versus the old bone is that the newly deposited bone components should be architecturally oriented to optimize stress-bearing capacity. Otherwise, bone remodeling should normally create no major net change in bone mass, because new bone deposition by
Interactions of Multiple Myeloma Cells with Osteoblasts
The focal lytic bone lesions or diffuse osteopenia of MM is related not only to the increased activity of osteoclasts but also to the lack of an appropriate compensatory osteoblastic response. The differentiation of mesenchymal stem cells to osteoblastic cells requires the transcriptional activity of Runx2/Cbfa1 [91], [92]. The direct cell-to-cell contact of osteoprogenitor cells with MM cells inhibits Runx2/Cbfa1 activity in osteoprogenitor cells. This event is mediated by binding of MM cell
The Process of Multiple Myeloma Cell Homing to the Bone Marrow
In the early stages of the natural history of MM, malignant plasma cells are not readily detectable in the peripheral blood with routine hematologic analyses. Investigational studies with highly sensitive (eg, PCR-based) studies (eg, [106], [107], [108], [109], [110]) suggest presence of clonotypic cells in the systemic circulation. It is therefore plausible to hypothesize that the pathophysiology of MM involves, even in the absence of overt plasma cell leukemia, a compartment of circulating
An Integrated View of Functional Networks of Cytokines/Mitogens and Their Receptors Mediating the Interactions Between Tumor and Stroma in Multiple Myeloma Lesions
Mutations of individual genes along with amplifications, deletions, or rearrangements of entire chromosomal regions are key determinants of the biologic behavior of neoplastic cells. The pathophysiology of MM is not influenced exclusively by the genetic composition of MM tumor cells but is also affected by how the MM cells interact with their local microenvironment. Although the MM cells perturb normal bone remodeling and lead to establishment of osteolytic bone disease [72], [125], the BM
Signaling Pathways Stimulated in Multiple Myeloma Cells During Their Interaction with Their Local Microenvironment
The direct contact of MM cells to ECM proteins, BMSCs, and other cells of the BM milieu (including osteoblasts, endothelial cells, and hematopoietic cells) [11], [119], [140] and the resulting induction of autocrine/paracrine release of cytokines/growth factors [9], [16], [50] triggers in MM cells a pleiotropic spectrum of proliferative/antiapoptotic signaling pathways, including PI-3K/Akt/mTOR/p70S6K [16], [141], IKK-α/NF-κB [16], [142], Ras/Raf/MAPK [16], and JAK/STAT3 [143], [144], [145],
The Relative Importance of IL-6, IGFs and Other Cytokines in the Biologic Behavior of Multiple Myeloma Cells in the Bone Marrow Milieu
IL-6 has been historically viewed as a major, if not the major, growth factor in the pathophysiology of MM. Although IL-6 promotes differentiation of normal B-lineage cells to normal plasma cells [152], its effects on the malignant plasma cells of MM involve stimulation of proliferation and increased resistance to dexamethasone and other conventional therapeutics [48], [153], [154], [155], [156], [157] by way of IL-6R–mediated activation of PI-3K/Akt, MAPK, and JAK/STAT3 cascades [48], [141],
The Genetic Substrate of Tumor–Microenvironment Interactions in Multiple Myeloma
The bidirectional interactions of MM cells with their BM milieu have important clinical sequelae, which include increased bone resorption and MM cell resistance to conventional chemotherapeutic agents, even in the absence of genetic lesions that would otherwise confer constitutive resistance [7], [99]. It is currently viewed that the biologic behavior of MM cells is determined by the composite effect of their own constitutive genetic features and of the stimuli that they are exposed to in their
Future Directions in the Therapeutic Targeting of Tumor–Stromal Interactions
The interaction of MM cells with their BM milieu is unfavorable from a pathophysiologic and clinical standpoint because it directly interferes with the process of bone remodeling, leads to skeletal lesions (which in turn can lead to further clinical complications, such as spontaneous fractures), and can attenuate the response of MM cell to therapies [16], [141]. Even in early stages of MM, when its neoplastic cells perhaps do not yet harbor all the genetic defects necessary for constitutive
Summary
The three recently FDA-approved anti-MM agents (bortezomib, thalidomide, and lenalidomide) abrogate, at least in part, the protection that the BM microenvironment can confer to MM cells against cytotoxic chemotherapy and dexamethasone. The clinical success of these three agents suggests that further improvements in the therapeutic management for MM may also come through the identification of other classes of anti-MM drugs that share a common property of overcoming the protective effects of the
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