The Role of the Bone Marrow Microenvironment in the Pathophysiology of Myeloma and Its Significance in the Development of More Effective Therapies

https://doi.org/10.1016/j.hoc.2007.08.007Get rights and content

Multiple myeloma (MM) is viewed as a prototypic disease state for the study of how neoplastic cells interact with their local bone marrow (BM) microenvironment. This interaction reflects not only the osteotropic clinical behavior of MM and the clinical impact of the lytic bone lesions caused by its tumor cells but also underlines the broadly accepted notion that nonneoplastic cells of the BM can attenuate the activity of cytotoxic chemotherapy and glucocorticoids. This article summarizes the recent progress in characterization, at the molecular and cellular levels, of how the BM milieu interacts with MM cells and modifies their biologic behavior.

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

References (227)

  • K. Podar et al.

    Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration

    Blood

    (2001)
  • K. Podar et al.

    Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation

    J Biol Chem

    (2002)
  • D. Chauhan et al.

    A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib

    Cancer Cell

    (2005)
  • A.J. Novak et al.

    Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival

    Blood

    (2004)
  • J. Moreaux et al.

    BAFF and APRIL protect myeloma cells from apoptosis induced by IL-6 deprivation and dexamethasone

    Blood

    (2004)
  • T. Hideshima et al.

    Advances in biology of multiple myeloma: clinical applications

    Blood

    (2004)
  • G.D. Roodman

    Pathogenesis of myeloma bone disease

    Blood Cells Mol Dis

    (2004)
  • B.R. Greenberg et al.

    Granulopoietic effects of human bone marrow fibroblastic cells and abnormalities in the “granulopoietic microenvironment”

    Blood

    (1981)
  • M. Kawano et al.

    Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma

    Blood

    (1989)
  • B.A. Barut et al.

    Role of interleukin 6 in the growth of myeloma-derived cell lines

    Leuk Res

    (1992)
  • M. Urashima et al.

    CD40 ligand triggered interleukin-6 secretion in multiple myeloma

    Blood

    (1995)
  • M. Urashima et al.

    Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein

    Blood

    (1996)
  • D. Chauhan et al.

    Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells

    Blood

    (1997)
  • H. Uchiyama et al.

    Characterization of adhesion molecules on human myeloma cell lines

    Blood

    (1992)
  • H. Uchiyama et al.

    Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion

    Blood

    (1993)
  • J. Folkman

    Role of angiogenesis in tumor growth and metastasis

    Semin Oncol

    (2002)
  • R.A. Nawab et al.

    The laboratory diagnosis of plasma cell myeloma and related disorders

    Orthop Clin North Am

    (1979)
  • S.V. Rajkumar et al.

    Angiogenesis in multiple myeloma

    Semin Oncol

    (2001)
  • A. Vacca et al.

    Endothelial cells in the bone marrow of patients with multiple myeloma

    Blood

    (2003)
  • Y.T. Tai et al.

    CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells

    Blood

    (2002)
  • J.S. Oh et al.

    Insulin-like growth factor-1 inscribes a gene expression profile for angiogenic factors and cancer progression in breast epithelial cells

    Neoplasia

    (2002)
  • A.J. Ashcroft et al.

    Aetiology of bone disease and the role of bisphosphonates in multiple myeloma

    Lancet Oncol

    (2003)
  • O. Sezer et al.

    RANK ligand and osteoprotegerin in myeloma bone disease

    Blood

    (2003)
  • D.L. Lacey et al.

    Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation

    Cell

    (1998)
  • M. Kawano et al.

    Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma

    Blood

    (1989)
  • G.R. Mundy

    Hypercalcemic factors other than parathyroid hormone-related protein

    Endocrinol Metab Clin North Am

    (1989)
  • M. Nakagawa et al.

    Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts

    FEBS Lett

    (2000)
  • J.H. Han et al.

    Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand

    Blood

    (2001)
  • S.J. Choi et al.

    Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma

    Blood

    (2000)
  • N.S. Callander et al.

    Myeloma bone disease

    Semin Hematol

    (2001)
  • Y. Oba et al.

    MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells

    Exp Hematol

    (2005)
  • M. Urashima et al.

    Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells

    Blood

    (1996)
  • N. Franchimont et al.

    Transforming growth factor-beta increases interleukin-6 transcripts in osteoblasts

    Bone

    (2000)
  • P. Ducy et al.

    Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation

    Cell

    (1997)
  • G. Karsenty et al.

    Cbfa1 as a regulator of osteoblast differentiation and function

    Bone

    (1999)
  • N. Giuliani et al.

    Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation

    Blood

    (2005)
  • T. Oshima et al.

    Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2

    Blood

    (2005)
  • J.W. Lee et al.

    IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells

    Blood

    (2004)
  • L.A. Ehrlich et al.

    IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma

    Blood

    (2005)
  • T. Standal et al.

    HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma

    Blood

    (2007)
  • Cited by (114)

    • Anti-cancer effects of Staphylococcal Enterotoxin type B on U266 cells co-cultured with Mesenchymal Stem Cells

      2017, Microbial Pathogenesis
      Citation Excerpt :

      Furthermore, suppressing effects of SEB on metastasis and growth of malignant cells had been documented [27–29]. NF-κB pathway is the most important molecular pathway in MCs which is over-activated by different mutations [30,31]. According to different studies, NF-κB pathway is involved in tumor cells survival, proliferation of cells, gene expression and resistance to anti-cancer drugs [32].

    • The role of free kappa and lambda light chains in the pathogenesis and treatment of inflammatory diseases

      2017, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Bortezomib mainly decreases the FLCs via augmented endoplasmic reticulum stress and apoptosis of myeloma cells with different mechanisms, including activation of NOXA, reactive oxygen species, a proapoptotic protein belonging to the Bcl-2 family, and decreasing of HIF-1α protein synthesis and MAPK pathways [149]. Furthermore, it interrupts myeloma-stromal cell interactions and tumoral angiogenesis [150]. Bortezomib prevents renal damage by NF-κB [151].

    • Myeloma bone disease: Pathophysiology

      2017, Revue du Rhumatisme Monographies
    View all citing articles on Scopus
    View full text