|
 
 |
| REVIEW ARTICLE |
|
| Year : 2018 | Volume
: 1
| Issue : 1 | Page : 1-8 |
|
A closer look at the bone marrow microenvironment in multiple myeloma
Julie Stakiw, Mark Bosch, Hadi Goubran
Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, Canada
| Date of Web Publication | 30-Jan-2018 |
Correspondence Address:
Dr. Hadi Goubran
Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, SK, 20 Campus Road, Saskatoon, SK S7N 4H4
Canada
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2395-7182.203049
Multiple myeloma, a plasma cell (PC) neoplasm accounting for nearly 10% of hematologic malignancies, remains an incurable disease of the bone marrow (BM) with a fascinating pathophysiology. The maladaptive nature of myeloma PCs and the BM microenvironment niche has been recognized to play a crucial role in the pathogenesis and progression of the disease which behaves in a manner similar to solid tumors in their growth and dissemination. A complex interaction between osteoclasts, endothelial cells, BM matrix, myeloid as well as the lymphoid elements and the malignant PCs occurs at the level of the microenvironment favoring the expansion of latter cells and their spread. A better understanding of the diseased PC and their milieu will enable the development of novel therapeutic tools capable of improving the outcome of this incurable blood cancer.
Keywords: Bone marrow, microenvironment, multiple myeloma
How to cite this article:
Stakiw J, Bosch M, Goubran H. A closer look at the bone marrow microenvironment in multiple myeloma. Tumor Microenviron 2018;1:1-8 |
| Introduction | |  |
Multiple myeloma (MM) is a plasma cell (PC) malignancy that accounts for <1% of all cancers and for around 10% of hematological malignancies with an estimated incidence of 5.7 per 100,000 in Europe and 5.5 per 100,000 in the US. Worldwide, more than 115,000 new cases are diagnosed each year.[1]
MM is a primary malignancy of the bone marrow (BM) PCs initiated by the transformation of memory B cells (CD19+, CD 27+, CD 38+, the CD45−, and CD 138−)[2] often acquiring a chromosomal translocation into the IgG loci. However, unlike other hematologic malignancies diffusely infiltrating the marrow, it behaves like a tumor metastasis with the involvement of the bone. Osteolytic bone lesions and compression fractures are the hallmark of the disease resulting in its significant morbidity.[3]
MM progresses in the BM under the influence of signals from its microenvironment.
| Normal Bone Marrow Microenvironment | | |
The BM contains two types of cells; hematopoietic stem cells (HSCs) and nonhematopoietic cells.
HSCs bears the CD markers: CD34+, CD59+, Thy1/CD90+, CD38lo/−, C-kit/CD117+, and give rise to both the myeloid or lymphoid lineages of blood cells and a third category consisting of balanced HSC. Only the myeloid-biased and -balanced HSCs have durable self-renewal properties. Long-term HSC (LT-HSC) is quiescent and low cycling capable of maintaining hematopoiesis for moths whereas short-term HSC is capable of self-renewal. Both coexist in the BM milieu.
The nonhematopoietic component includes osteoblasts/osteoclasts (OBs/OCs), endothelial cells (ECs), endothelial progenitor cells and mesenchymal stem cells (MSCs)[4] and for classification purposes OCs/OBs, although these cells are derived from hematopoietic progenitors.[5] Together these cells form specialized “niches.” Niches are local tissue microenvironments that maintain and regulate HSCs.[4] Niches with proximity to the vasculature are called vascular niche. Those close to the endosteum are known as OB niche. OB and vascular niches are found adjacent to each other the three dimensional BM microenvironment and interact in very complex and intimate ways.[3],[6],[7] Defining niche components and how they work in concert to regulate hematopoiesis will improve our understanding of how a disordered niche function could contribute to disease.
In addition, the BM microenvironment may also be divided into the cellular compartment, comprised of hematopoietic cells and nonhematopoietic cells and the noncellular compartment where the extracellular matrix (ECM), cytokines and growth factors are present.[8]
Osteoblastic niche
Dating back to early 1970s, it was known that undifferentiated HSC would localize close to the endosteal bone surface forming a “niche.”[9],[10] The main task of the osteoblastic niche is to maintain the LT-HSCs, which are capable of supporting hematopoiesis for months or even a lifetime as quiescent or low-cycling cells.[11],[12],[13],[14] An increase in the number of osteoblastic lining cells in the trabecular bone area is associated and correlates with an increased number of LT-HSCs in vivo.[12],[15]
The osteoblastic niche is also composed of reticular cells, fibroblasts, and adipocytes. These cells create a supportive environmental matrix for stem cells.[16] Data indicate that the endosteal region is important for hematopoiesis.
Mature osteolineage cells have only an indirect role in modulating HSCs.[4] They elaborate cytokines and ECM proteins that influence a wide range of cell types including some HSC functions. This is exemplified by parathyroid hormone receptor activation which induces expression of multiple regulatory molecules (such as interleukin 6 [IL-6], receptor activator of nuclear factor-kappa B ligand [RANKL], and Jagged1) by OBs influencing other cells in the BM, including the vasculature.[11] The endosteal region and its osteoblastic cells, therefore, provide a unique zone for the maintenance of quiescent HSCs.[4]
Osteoblastic niche is also crucial for the support and proliferation of megakaryocytes.[17]
Physiologically, BM adipogenesis occurs in the osteoblatic niche of all mammals. The MSC is the marrow precursor for adipocytes as well as OBs and peroxisome proliferator-activated receptor gamma is an essential differentiation factor for entrance into the fat lineage. Aging, several chronic conditions including diabetes mellitus and osteoporosis as well as malignancy are associated with accelerated marrow adipogenesis.[18]
Vascular niche
The vascular niche was described later than the osteoblastic one. It has been regarded as an alternative and indispensable compartment for the regulation of HSCs.[19] It is through that the interaction of the HSCs and the vascular ECs initiates HSC self-renewal and differentiation.[20],[21],[22] There the quiescent HSCs residing in the osteoblastic niche penetrates the vascular compartment to enter the circulation.[19]
The structure of the vascular niche is rather complex. Sinusoidal vessels are supplied by arterioles and capillaries which are derived from the bifurcation of arteries spanning the marrow cavity.[21] The sinusoids, interconnected by intersinusoidal capillaries drain into the central sinus. Sinusoidal ECs (SECs) play a role both in providing a differentiation platform for hematopoietic cells and as a conduit for their mobilization and homing into and out of the BM.[21],[23] SECs constitute most of the functional hematopoietic vascular niche and are essential in hematopoietic processes and in the maintenance of HSCs which are mobilized from a dormant LT-HSC state.[21],[24] Under stress, or when the BM is infiltrated, LT-HSCs migrate to bloodstream by penetrating the sinusoidal wall and then differentiate into several kinds of blood cells.[25]
If the BM is under stress, extramedullary hematopoiesis within vascular niche occurs in the spleen or liver to supplement the function in abnormal BM [26] thus reinforcing the concept that the vascular niche supports the maintenance and differentiation of HSCs when the BM works abnormally.
A multitude of molecules and ECs secreting factors mediate HSCs self-renewal and regeneration.[19] Stromal cell-derived factor 1 (SDF-1) mediates transendothelial and stromal migration when binding to its receptor (CXCR-4) and is important in megakaryopoiesis.[27] The role played by G-CSF is also medicated by SDF-1.[28] ECs expressing Notch ligands which are relevant for HSC self-renewal in an undifferentiated state, preventing their exhaustion.[29] Vascular cell adhesion molecule 1 (CD106) induces expression of adhesion molecules needed for HSC maintenance.[30] ECs secreting factor also interplays with HSCs with the Stem Cell Factor maintaining HSCs, Glycoprotein 130 contributing to hematopoiesis and pleiotrophin inducing HSC regeneration.[19]
| the Bone Marrow Microenvironment in Multiple Myeloma | | |
In MM, osteolytic bone lesions and compression fractures are the hallmark of the disease, causing significant morbidity.[2],[3] Hematopoietic alterations are common as anemia, which is an integral element of the symptomatic myeloma (CRAB: High calcium, renal impairment, anemia, and bone lesions) and occurs in more than 70% of the cases at diagnosis and is the primary cause of the decline in performance status noted by patients.[3]
The main cause of the anemia is replacement of the hematopoietic cells by clonal PCs nests in the process of myelophthisis.[31] The erythroid progenitors overexpressing FAS molecules are more prone to apoptosis and are also affected by the reduced erythropoietin level associated with impaired kidney function.[32],[33] Furthermore, the chronic inflammatory state associated with the activity of the disease results in an altered iron metabolism additionally contributing to the anemia.[33]
Multiple pathogenic mechanisms can contribute to kidney injury in myeloma patients ranging from cast nephropathy to amyloidosis or light chain deposition disease. Many patients have chronic glomerular nephropathy and a substantial proportion may progress to end-stage renal disease.[34]
In the presence of a MM clone nesting in the BM, the tumor cells behave like a classic solid tumor in a microenvironment where stromal factors, immunological factors, humoral, and hormonal factors as well as platelets/microparticles and megakaryocytes interact to favor tumor growth, tethering, and dissemination.[35] The role played by the OCs and the myeloid-derived suppressor cells (MDSCs) are primordial in this respect and mediate the osteolytic bone lesions and hypercalcemia.[36]
The introduction of novel agents including immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib), have increased the rates of remission in the newly diagnosed MM patient permitting a better prognosis for transplant-eligible patients, and a more prolonged remission when combined with melphalan or other chemotherapeutic agents in the less fortunate transplant noneligible population.[37] In addition, most patients will benefit from bisphosphonates which reduces bone pain and the risks of pathological fractures.[38]
Encouraging reports from ongoing clinical trials focusing primarily on eradication of the malignant myeloma cells, point to extending progression-free and overall survival for MM patients. An increased probability of drug-resistant clones emerging following these therapeutic interventions however, are likely to occur secondary to MM clones undergoing genetic mutations.[39] Targeting the MM BM microenvironment can, therefore, offer a new avenue to address MM. A better understanding of this milieu is accordingly of great importance.
| Bone Marrow Milieu of Multiple Myeloma | | |
The BM milieu of MM is comprised ECM, hematopoietic and nonhematopoietic cells as well as soluble components including cytokines, growth factors, and adhesion molecules.[8]
The MM mutated PCs grossly destabilize the normal BM niches and interfere with the complex interaction between myeloid-derived cells and lymphoid-derived immunocompetent cells as well as the matrix cells and their by-products. Abnormal marrow milieu reciprocally enhances abnormal PC proliferation.
Osteoclasts
Interaction and balance between OB and OC cells maintain normal physiologic bone environment. Dysregulation of OBs and OCs serves as the key process in the pathogenesis of myeloma bone disease. Increased OCs activity in MM patients promotes bone absorption, while suppression of OBs activity leads to impaired bone formation.[40],[41] The increased OCs activity is under the influence of a myriad of important OC activating factors (OAFs) isolated from myeloma cell culture medium. These include IL-6, IL-1b, tumor necrosis factor (TNF)-α, and parathyroid hormone-related protein.[42] Other OAFs such as macrophage inflammatory protein-1a, RANK and RANKL, osteoprotegerin and annexin II also play important roles in bone absorption.[43] Myeloma cells promote OC formation through the endogenous expression of RANKL, TNF-α, and the downregulation of RANKL decoy receptor and OPG.[44]
Interestingly, RANKL, a member of TNF superfamily is regulated by a variety of cytokines sand hormones, such as parathyroid hormone, 1, 25-dihydroxy-vitamin D (cholecalciferol), and prostaglandin E2. After the specific binding between RANKL and RANK, their downstream by-products such as TNF receptor associated factor initiate OC generating gene transcription. Ultimately, OC precursor cells evolve into mature OCs.[41] Once generated, OCs form a resorptive seal on the mineralized bone matrix surface and degrade the bone. They often induce micro-cracks by secreting hydrochloric acid and acidophilic collagenases such as cathepsin K.[45] The damaged bone matrix as well as the platelets recruited to the site, secrete transforming growth factor beta (TGF-β) and insulin growth factor I (IGF-I) that will promote myeloma cell growth.[35],[46] Myeloma cells may even fuse with OCs and affect their functionality; 30% of OCs recruited in BM microenvironment of MM patients contain transcriptionally active chromosomes of myeloma origin [47] and myeloma cell/OCs interaction is often partly mediated by IL-6.[48]
The destructive role of the OCs is unopposed by OBs as it was also noted that in the MM BM milieu, OBs inhibitory factors are present including TGF-β. The plasma concentration of IL-3 significantly increases in patients with MM and can not only significantly increase OC activity but also inhibit osteogenic protein-2 (bone morphogenetic protein-2), thereby inhibiting OB differentiation.[49],[50] The net result therefore is the bone destructive process that characterizes myeloma and additional proliferation of the myeloma clone.
Endothelial cells
ECs of the MM BM exhibit enhanced expression of angiogenic factors and their receptors such as vascular endothelial growth factor (VEGF) and VEGF receptor-2, fibroblast growth factor-2 (FGF-2) and FGF-2 receptor-2, Ang-2 and Tie-2. By increased in vitro and in vivo angiogenic activity, ECs maintains adequate blood supply to the growing MM clone and help its spread.[51] Moreover, MM ECs express more mRNA and secrete larger amounts of the CXC-chemokines, interferon-inducible T-cell alpha, and monocyte chemoattractant than umbilical vein ECs.[52] Circulating ECs were six-fold higher in peripheral blood of MM patients compared to controls and correlated positively with serum M protein and β2-microglobulin.[53] Furthermore, platelet-derived growth factor (PDGF)-receptor beta (PDGFR-β) is expressed by ECs isolated from MM patients.[52] PDGF-BB/PDGFR-β kinase axis promotes MM vessel sprouting and the transcription of MM ECs-released VEGF and IL-8.[54] Finally, the role played by the platelet-endothelial interaction in the tumor milieu, with the P-selectin acting as a key molecule, is crucial for tumor spread and dissemination.[35]
Myeloid cells
The bone microenvironment where myeloma cell nests are growing is studded by immune competent cells. Immature myeloid cells present in the BM differentiate into macrophages, dendritic cells (DCs), and granulocytes. Under the influence of certain tumor-derived growth factors, differentiation is halted and a rapid expansion of immature myeloid cells (often termed MDSCs) which fail to differentiate, interfere with the immune surveillance and contribute to the tumor growth. Myeloid DCs (MDCs) are potential therapeutic targets in myeloma.[36] Görgün et al., assessed the presence, frequency, and functional characteristics of MDSCs in patients with newly diagnosed, relapsed, and relapsed/refractory MM compared with healthy donors and the immunomodulatory effects of novel therapies on this cellular subset. CD11b1CD14-HLA-DR-/lowCD331CD151 MDSCs were significantly increased in both the peripheral blood and the BM of patients with active MM compared with healthy donors. A bidirectional interaction between MDSCs and MM cells and immune effector cells was noted.[55] Furthermore, Malek et al., demonstrated that MDSCs and T regulatory cells (Tregs) are significantly increased in myeloma patients and their levels correlate with disease stage and clinical outcome. MDSCs can therefore mediate suppression of myeloma-specific T-cell responses through the induction of T-cell anergy and promotion of Tregs in the MM microenvironment.[56]
Monocytes are attracted to the tumor milieu by certain chemokines including the CXCR4/CXCL12 axis.[57] A wide range of growth factors and cytokines VEGF and endothelin-2 are thought to educate the macrophages and determine their role as tumoricidal or tumor promoters.[58] Macrophages of the M1 population producing pro-inflammatory cytokines such as TNF-α, IL-1, and IL-12 are tumoricidal/static. These cells can be polarized to an M2 population, acting as tumor promoters and are capable of producing IL-6 needed for the growth of myeloma cells, and IL-10 which further polarizes more M1–M2.[59] Repolarizing M2–M1 or depletion of the M2 population are interesting therapeutic strategies.[60]
DCs, also known as accessory cells, are the major antigen processing and presenting cells in the tumor milieu. DCs usually act as the link between the innate and the adaptive immune systems, presenting the antigen on their surface to the recruited T-cells.[61] The number of plasmoid DCs is significantly increased in the BM of myeloma patients compared to healthy individuals and patients with MGUS with only a modest increase in peripheral blood.[62],[63] DCs have conflicting opposing actions on myeloma cells; on one side, they activate CD8(+) T cells against tumor PCs and on the other, they protect tumor PCs from CD8(+) T-cell killing.[63] Functionally, DCs overexpress activation of B-cell maturation antigen by its ligand, a proliferation-inducing ligand (APRIL) and inhibit RANKL to promote human MM progression in vivo. They can target MM cells harboring p53 mutation in mice.[64] In the MM BM microenvironment, DCs engulf apoptotic MM cells through CD91, and their antigen is presented in the context of a MHC-class I antigen to activate CD8+ ve cells. Using the CD80/CD86 pathway, DCs interact with MM cells overexpressing CD28 resulting in a proteasome degradation that will impair antigen expression, helping MM cells escape the T cell recognition and killing. Furthermore, checkpoint inhibitors such as programmed cell death 1 (PD-1) partially offset immunosuppressive signals from the marrow microenvironment as The majority of PC and DCs subpopulations express PD-1 and a correlation between the proportion of PD-1+ PC and CD141+ mDC has been demonstrated, suggesting both cell types could down-regulate the anti-tumor T cell response.[65],[66] DCs also significantly contribute to the lytic lesions of MM by differentiating into OCs under the influence of IL-17A.[67],[68]
Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role and are intimately involved in angiogenesis and immune tolerance. Their density in the MM BM correlates with circulating levels of various angiogenic factors crucial for the maintenance of blood supply to the MM cell population, namely VEGF, angiopoietin 2, and angiogenin. In addition, their matrix metalloproteinase 9 (MMP-9) is involved in the degradation of the ECM [69] and IL-6 stimulated MM cells which protect them from spontaneous or drug-induced apoptosis.[70] Interestingly, the density of mast cells in the BM of MM patients correlates with the proliferation index Ki-67.[71]
The role played by the megakaryocytes, platelets, and their derived microparticles in the progression of solid tumors and their metastatic seeding have long been recognized.[35],[72],[73],[74],[75],[76]
BM PC tumors are supported by the external growth factors APRIL and IL-6, among others. Recently, eosinophils and megakaryocytes were shown to be functional components of the microenvironmental niches of benign BM PCs and to be important local sources of these cytokines in addition it supports the growth of tumor PCs in the MOPC315.BM model for MM.[77]
Lymphoid cells
Although MM is derived from PC of B cell origin, other B as well as T lymphocytes and natural killer cells (NK) interplay in the MM BM microenvironment favoring tumor growth and tethering.[36]
T-cells expressing the T-cell receptors have a distinct function in the fight against cancer and myeloma in particular. A regulatory subset of CD8+ T cells has been identified in myeloma microenvironment, suppressing CD4+-cell proliferation by producing interferon gamma contributing to the immunosuppression seen in myeloma.[36] The T-cell activity can also be suppressed by the activation of a number of receptors on their surface including PD-1 receptor with its ligand being overexpressed by myeloma cells.[65]
Tregs are developed from CD4 T-cells under the influence of local cytokine production in the MM milieu and are significantly increased in myeloma patients and their levels correlate with disease stage and clinical outcome.[55] The balance between Th1 and Th2 seems also to be altered in the MM milieu with reduced Th1 cytokines and over-expression of Th2 cytokines namely IL-10 and IL-4.[78]
Th17 produce IL-17 that plays a pivotal role in bone disease and 22. PCs express IL-17 receptor on their surface. Th17 are predictive factors of response to therapy in MM and their expansion suppresses immune responses and protect PCs from the T-cell surveillance.[78]
B-cells, on the other hand, results in the formation of the terminally differentiated, antibody-producing PCs.[2] Symptomatic myeloma patients have less B-cell, particularly memory B-cells, compared to healthy individuals or patients with early disease and contribute to the increased frequency of infection among patients.[36]
The decreased NK activity in the MM microenvironment is also contributing to the progression of the disease and are affected by novel therapeutic agents that enhance their function.[36]
[Figure 1] illustrates the interaction of MM PCs with different myeloid and lymphoid cells and the role played by MDCs. | Figure 1: Myeloid precursors fail to differentiate under the effect of the growing myeloma cells with the accumulation of immature myeloid-derived suppressor cells. Furthermore, Macrophages are polarized to M2 favoring tumor growth and dendritic cells engulfing apoptotic plasma cells have an impaired antigen expression potential. Myeloid-derived suppressor cells also favor the transition of T cells to T-regulatory cells
Click here to view |
In MM, a significant interaction between the different components of the BM niches takes place. The myeloma-PC dysregulate the osteoblatic niche and permeate to the vascular niche where intravasation of the cells through the sinusoidal system takes place. As in solid tumor metastasis, trans-vascular migration occurs and abut into extravasation and the involvement of a new site [35] or into the formation of a plasmacytoma.
| Therapeutic Implications | | |
Over the last decade, many novel treatments have been developed. Many of these new treatments target both MM PCs as well as the BM microenvironment. New potential therapeutic targets include histone deacetylation, the catalytic activity of proteasomes, signaling pathways of Akt, mammalian target of rapamycin, MEK, as well as cellular expression of CS-1, CD38, and CD40.[79] Current gold standard treatments for MM include immunomodulators imide drug (IMiDs) namely targeting the tumor microenvironment and protosome inhibitors and melphalan primarily targeting tumor cells.
Historically, it was the investigation of thalidomide anti-angiogenic properties that led to the rapid expansion of novel clinical drugs.[80] Thalidomide is an IMiDs,[81] that not only demonstrates anti-angiogenic activity, but also enhances T cell- and NK cell-mediated immunological responses, apoptosis, and downregulates cytokine production within the BM microenvironment.[82],[83] Lenalidomide, a 4-amino-glutamyl analog of thalidomide that lacks the neurologic side effects of sedation and neuropathy with similar properties to thalidomide exerts an antitumor necrosis factor alpha activity, modulates the immune response stimulating activities of T cells and NK cells, induces apoptosis of tumor cells, and decreases the binding of MM cells to BMSCs.[83],[84],[85] In addition, IMiDs affect bone resorption by inhibiting OC formation.[86],[87] Newer studies demonstrate its effects on signal transduction that can partly explain its selective efficacy in subsets of myelodysplastic syndrome.[88] Lenalidomide, therefore interplay with the MM BM microenvironment.
Bortezomib is a proteasome inhibitor which can also cause ECs apoptosis.[88],[89] It has also been shown to inhibit VEGF, IL-6, Ang-1, Ang-2, and IGF-1 secretion in BMSCs and ECs.[90],[91] Bortezomib may also induce the differentiation of MSCs into osteoblasts and induce apoptosis of OCs.[92]
Interestingly, lenalidomide has been shown to sensitize MM PCs to other agents like bortezomib.[93] This perhaps explains why combination novel agents are more effective than single agent treatments.[94]
Bisphosphonates are a supportive medication commonly administered clinically in a patient with MM. Bisphosphonates have shown promise in reducing the risk of skeletal-related events.[95] Some studies have shown bisphosphonates inhibit OC activity and exert an anti-angiogenic activity. Bisphosphonate effect on the BM microenvironment has been shown to inhibit in vitro proliferation, chemotaxis, and angiogenesis of MM ECs.[96]
In our center, a treatment algorithm stratifies MM patients into transplant-eligible and noneligible patients. Transplant-eligible ones would receive a bortezomib-based induction therapy followed by high-dose chemotherapy and autologous stem cell transplantation, followed by consolidation and maintenance with lenalidomide. Transplant-ineligible patients would receive a bortezomib-based or lenalidomide-based therapy for an extended duration. Bisphosphonates are offered to all patients.
Although these novel agents target the PCs, stromal cells, and the microenvironment, they cannot completely eradicate the malignant clone, and their use aims at inducing long-lasting remissions rather that a complete cure. A better understanding of the pathophysiology of the disease may result in the discovery of novel targets and individualizing therapy with a potential for cure.
| Conclusions | | |
MM remains an incurable disease with a fascinating pathophysiology. The interactions between tumor cells and their microenvironment have allowed for many novel approaches to treatment that induce long-term tumor quiescence with little cross-resistance. The maladaptive nature of MM PCs and the BM niche has been recognized to play a crucial role in the pathogenesis and progression of MM. The current standard of care and most active anti-MM agents, bortezomib, thalidomide, and lenalidomide, work against both the diseased cell and it microenvironment. Only by inhibiting the ever expanding targets of the disease PC and the microenvironment will we be able to eradicate this currently incurable blood cancer.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hematological malignancies. Ann Oncol 2007;18 Suppl 1:i3-8.  [ PUBMED] |
| 2. | Mayani H. Hematopoietic and microenvironment alterations in bone marrow from patients with multiple myeloma. Leuk Res 2013;37:228-9. [ PUBMED] |
| 3. | Kyle RA, Rajkumar SV. Multiple myeloma. Blood 2008;111:2962-72. [ PUBMED] |
| 4. | Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature 2014;505:327-34. [ PUBMED] |
| 5. | Bar-Shavit Z. The osteoclast: A multinucleated, hematopoietic-origin, bone-resorbing osteoimmune cell. J Cell Biochem 2007;102:1130-9. [ PUBMED] |
| 6. | Li L, Neaves WB. Normal stem cells and cancer stem cells: The niche matters. Cancer Res 2006;66:4553-7. [ PUBMED] |
| 7. | Moore KA, Lemischka IR. Stem cells and their niches. Science 2006;311:1880-5. [ PUBMED] |
| 8. | Manier S, Sacco A, Leleu X, Ghobrial IM, Roccaro AM. Bone marrow microenvironment in multiple myeloma progression. J Biomed Biotechnol. 2012;2012:157496. [ PUBMED] |
| 9. | Lord BI, Wright EG. Spatial organisation of CFU-S proliferation regulators in the mouse femur. Leuk Res 1984;8:1073-83. [ PUBMED] |
| 10. | Gong JK. Endosteal marrow: A rich source of hematopoietic stem cells. Science 1978;199:1443-5. [ PUBMED] |
| 11. | Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841-6. [ PUBMED] |
| 12. | Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003;425:836-41. [ PUBMED] |
| 13. | Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004;118:149-61. [ PUBMED] |
| 14. | Passegué E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med 2005;202:1599-611. |
| 15. | Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol 2007;25:238-43. [ PUBMED] |
| 16. | Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol 2006;7:333-7. [ PUBMED] |
| 17. | Pallotta I, Lovett M, Rice W, Kaplan DL, Balduini A. Bone marrow osteoblastic niche: A new model to study physiological regulation of megakaryopoiesis. PLoS One 2009;4:e8359. [ PUBMED] |
| 18. | Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM. Marrow fat and the bone microenvironment: Developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr 2009;19:109-24. [ PUBMED] |
| 19. | He N, Zhang L, Cui J, Li Z. Bone marrow vascular niche: Home for hematopoietic stem cells. Bone Marrow Res 2014;2014:128436. [ PUBMED] |
| 20. | Chute JP, Muramoto GG, Salter AB, Meadows SK, Rickman DW, Chen B, et al. Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice. Blood 2007;109:2365-72. [ PUBMED] |
| 21. | Kopp HG, Avecilla ST, Hooper AT, Rafii S. The bone marrow vascular niche: Home of HSC differentiation and mobilization. Physiology (Bethesda) 2005;20:349-56. [ PUBMED] |
| 22. | Li B, Bailey AS, Jiang S, Liu B, Goldman DC, Fleming WH. Endothelial cells mediate the regeneration of hematopoietic stem cells. Stem Cell Res 2010;4:17-24. [ PUBMED] |
| 23. | Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, Shido K, et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 2004;10:64-71. [ PUBMED] |
| 24. | Abkowitz JL, Robinson AE, Kale S, Long MW, Chen J. Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood 2003;102:1249-53. [ PUBMED] |
| 25. | Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. Physiological migration of hematopoietic stem and progenitor cells. Science 2001;294:1933-6. [ PUBMED] |
| 26. | Schepers K, Hsiao EC, Garg T, Scott MJ, Passegué E. Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice. Blood 2012;120:3425-35. |
| 27. | Hamada T, Möhle R, Hesselgesser J, Hoxie J, Nachman RL, Moore MA, et al. Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med 1998;188:539-48. |
| 28. | Lapidot T, Petit I. Current understanding of stem cell mobilization. Exp Hematol 2002;30:973-81. [ PUBMED] |
| 29. | Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005;6:314-22. [ PUBMED] |
| 30. | Avraham H, Cowley S, Chi SY, Jiang S, Groopman JE. Characterization of adhesive interactions between human endothelial cells and megakaryocytes. J Clin Invest 1993;91:2378-84. [ PUBMED] |
| 31. | Makoni SN, Laber DA. Clinical spectrum of myelophthisis in cancer patients. Am J Hematol 2004;76:92-3. [ PUBMED] |
| 32. | Silvestris F, Tucci M, Cafforio P, Dammacco F. Fas-L up-regulation by highly malignant myeloma plasma cells: Role in the pathogenesis of anemia and disease progression. Blood 2001;97:1155-64. [ PUBMED] |
| 33. | Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 2010;116:3635-44. [ PUBMED] |
| 34. | Gorsane I, Barbouch S, Mayara M, Abdelghani KB, Goucha R, Hamida FB, et al. Renal impairment in multiple myeloma: A single center experience. Saudi J Kidney Dis Transpl 2016;27:480-5. [ PUBMED] [Full text] |
| 35. | Goubran HA, Kotb RR, Stakiw J, Emara ME, Burnouf T. Regulation of tumor growth and metastasis: The role of tumor microenvironment. Cancer Growth Metastasis 2014;7:9-18. [ PUBMED] |
| 36. | Shay G, Hazlehurst L, Lynch CC. Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities. J Mol Med (Berl) 2016;94:21-35. [ PUBMED] |
| 37. | Wang X, Li Y, Yan X. Efficacy and safety of novel agent-based therapies for multiple myeloma: A meta-analysis. Biomed Res Int 2016;2016:6848902. [ PUBMED] |
| 38. | Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996;334:488-93. [ PUBMED] |
| 39. | Abdi J, Chen G, Chang H. Drug resistance in multiple myeloma: Latest findings and new concepts on molecular mechanisms. Oncotarget 2013;4:2186-207. [ PUBMED] |
| 40. | Hameed A, Brady JJ, Dowling P, Clynes M, O'Gorman P. Bone disease in multiple myeloma: Pathophysiology and management. Cancer Growth Metastasis 2014;7:33-42. |
| 41. | Xi H, An R, Li L, Wang G, Tao Y, Gao L. Myeloma bone disease: Progress in pathogenesis. Prog Biophys Mol Biol 2016;122:149-55. [ PUBMED] |
| 42. | Nakashima T, Hayashi M, Takayanagi H. New insights into osteoclastogenic signaling mechanisms. Trends Endocrinol Metab 2012;23:582-90. [ PUBMED] |
| 43. | Terpos E, Dimopoulos MA. Myeloma bone disease: Pathophysiology and management. Ann Oncol 2005;16:1223-31. [ PUBMED] |
| 44. | Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barillé S. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood 2001;98:3527-33. |
| 45. | Crockett JC, Rogers MJ, Coxon FP, Hocking LJ, Helfrich MH. Bone remodelling at a glance. J Cell Sci 2011;124(Pt 7):991-8. |
| 46. | Lentzsch S, Ehrlich LA, Roodman GD. Pathophysiology of multiple myeloma bone disease. Hematol Oncol Clin North Am 2007;21:1035-49, viii. [ PUBMED] |
| 47. | Andersen TL, Boissy P, Sondergaard TE, Kupisiewicz K, Plesner T, Rasmussen T, et al. Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: A new type of cancer-host partnership? J Pathol 2007;211:10-7. [ PUBMED] |
| 48. | Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, et al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: A vicious cycle between bone destruction and myeloma expansion. Blood 2004;104:2484-91. [ PUBMED] |
| 49. | Ehrlich LA, Chung HY, Ghobrial I, Choi SJ, Morandi F, Colla S, et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood 2005;106:1407-14. [ PUBMED] |
| 50. | Lee JW, Chung HY, Ehrlich LA, Jelinek DF, Callander NS, Roodman GD, et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood 2004;103:2308-15. [ PUBMED] |
| 51. | Vacca A, Ria R, Semeraro F, Merchionne F, Coluccia M, Boccarelli A, et al. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood 2003;102:3340-8. [ PUBMED] |
| 52. | Pellegrino A, Ria R, Di Pietro G, Cirulli T, Surico G, Pennisi A, et al. Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells. Br J Haematol 2005;129:248-56. [ PUBMED] |
| 53. | Ribatti D, Moschetta M, Vacca A. Microenvironment and multiple myeloma spread. Thromb Res 2014;133 Suppl 2:S102-6. [ PUBMED] |
| 54. | Coluccia AM, Cirulli T, Neri P, Mangieri D, Colanardi MC, Gnoni A, et al. Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: Preclinical efficacy of the novel, orally available inhibitor dasatinib. Blood 2008;112:1346-56. [ PUBMED] |
| 55. | Görgün GT, Whitehill G, Anderson JL, Hideshima T, Maguire C, Laubach J, et al. Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 2013;121:2975-87. |
| 56. | Malek E, de Lima M, Letterio JJ, Kim BG, Finke JH, Driscoll JJ, et al. Myeloid-derived suppressor cells: The green light for myeloma immune escape. Blood Rev 2016;30:341-8. [ PUBMED] |
| 57. | Beider K, Bitner H, Leiba M, Gutwein O, Koren-Michowitz M, Ostrovsky O, et al. Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype. Oncotarget 2014;5:11283-96. [ PUBMED] |
| 58. | Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006;66:605-12. [ PUBMED] |
| 59. | Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat Immunol 2010;11:889-96. [ PUBMED] |
| 60. | Ries CH, Hoves S, Cannarile MA, Rüttinger D. CSF-1/CSF-1R targeting agents in clinical development for cancer therapy. Curr Opin Pharmacol 2015;23:45-51. |
| 61. | Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-52. [ PUBMED] |
| 62. | Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: A therapeutic target. Cancer Cell 2009;16:309-23. [ PUBMED] |
| 63. | Leone P, Berardi S, Frassanito MA, Ria R, De Re V, Cicco S, et al. Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+T-cell killing. Blood 2015;126:1443-51. [ PUBMED] |
| 64. | Tai YT, Acharya C, An G, Moschetta M, Zhong MY, Feng X, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 2016;127:3225-36. [ PUBMED] |
| 65. | Rapoport AP. Myeloma escape from immunity: An “inside” job. Blood 2015;126:1401-3. [ PUBMED] |
| 66. | Sponaas AM, Moharrami NN, Feyzi E, Standal T, Holth Rustad E, Waage A, et al. PDL1 Expression on plasma and dendritic cells in myeloma bone marrow suggests benefit of targeted anti PD1-PDL1 therapy. PLoS One 2015;10:e0139867. [ PUBMED] |
| 67. | Tucci M, Ciavarella S, Strippoli S, Brunetti O, Dammacco F, Silvestris F. Immature dendritic cells from patients with multiple myeloma are prone to osteoclast differentiation in vitro. Exp Hematol 2011;39:773-83.e1. |
| 68. | Tucci M, Stucci S, Savonarola A, Ciavarella S, Cafforio P, Dammacco F, et al. Immature dendritic cells in multiple myeloma are prone to osteoclast-like differentiation through interleukin-17A stimulation. Br J Haematol 2013;161:821-31. [ PUBMED] |
| 69. | Vyzoukaki R, Tsirakis G, Pappa CA, Devetzoglou M, Tzardi M, Alexandrakis MG. The impact of mast cell density on the progression of bone disease in multiple myeloma patients. Int Arch Allergy Immunol 2015;168:263-8. [ PUBMED] |
| 70. | Kim J, Denu RA, Dollar BA, Escalante LE, Kuether JP, Callander NS, et al. Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells. Br J Haematol 2012;158:336-46. [ PUBMED] |
| 71. | Pappa CA, Tsirakis G, Stavroulaki E, Kokonozaki M, Xekalou A, Konsolas I, et al. Mast cells influence the proliferation rate of myeloma plasma cells. Cancer Invest 2015;33:137-41. [ PUBMED] |
| 72. | Goubran HA, Elemary M, Radosevich M, Seghatchian J, El-Ekiaby M, Burnouf T. Impact of transfusion on cancer growth and outcome. Cancer Growth Metastasis 2016;9:1-8. [ PUBMED] |
| 73. | Goubran H, Sabry W, Kotb R, Seghatchian J, Burnouf T. Platelet microparticles and cancer: An intimate cross-talk. Transfus Apher Sci 2015;53:168-72. [ PUBMED] |
| 74. | Goubran HA, Burnouf T, Radosevic M, El-Ekiaby M. The platelet-cancer loop. Eur J Intern Med 2013;24:393-400. [ PUBMED] |
| 75. | Goubran HA, Stakiw J, Radosevic M, Burnouf T. Platelets effects on tumor growth. Semin Oncol 2014;41:359-69. [ PUBMED] |
| 76. | Goubran HA, Stakiw J, Radosevic M, Burnouf T. Platelet-cancer interactions. Semin Thromb Hemost 2014;40:296-305. [ PUBMED] |
| 77. | Wong D, Winter O, Hartig C, Siebels S, Szyska M, Tiburzy B, et al. Eosinophils and megakaryocytes support the early growth of murine MOPC315 myeloma cells in their bone marrow niches. PLoS One 2014;9:e109018. [ PUBMED] |
| 78. | Romano A, Conticello C, Cavalli M, Vetro C, La Fauci A, Parrinello NL, et al. Immunological dysregulation in multiple myeloma microenvironment. Biomed Res Int 2014;2014:198539. [ PUBMED] |
| 79. | Ocio EM, Richardson PG, Rajkumar SV, Palumbo A, Mateos MV, Orlowski R, et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: A report from the International Myeloma Working Group (IMWG). Leukemia 2014;28:525-42. [ PUBMED] |
| 80. | Ribatti D, Vacca A. Novel therapeutic approaches targeting vascular endothelial growth factor and its receptors in haematological malignancies. Curr Cancer Drug Targets 2005;5:573-8. [ PUBMED] |
| 81. | Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004;4:314-22. [ PUBMED] |
| 82. | Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210-6. [ PUBMED] |
| 83. | Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: Therapeutic implications. Blood 2002;99:4525-30. [ PUBMED] |
| 84. | Görgün G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010;116:3227-37. |
| 85. | Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007;7:585-98. [ PUBMED] |
| 86. | Anderson G, Gries M, Kurihara N, Honjo T, Anderson J, Donnenberg V, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood 2006;107:3098-105. [ PUBMED] |
| 87. | Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008;22:1925-32. [ PUBMED] |
| 88. | Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol 2009;2:36. [ PUBMED] |
| 89. | Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol Cancer Ther 2003;2:835-43. [ PUBMED] |
| 90. | Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003;101:1530-4. [ PUBMED] |
| 91. | Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 2006;66:184-91. [ PUBMED] |
| 92. | Chauhan D, Singh A, Brahmandam M, Podar K, Hideshima T, Richardson P, et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008;111:1654-64. [ PUBMED] |
| 93. | Kastritis E, Palumbo A, Dimopoulos MA. Treatment of relapsed/refractory multiple myeloma. Semin Hematol 2009;46:143-57. [ PUBMED] |
| 94. | Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, et al. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: Prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia 2010;24:1769-78. [ PUBMED] |
| 95. | Mhaskar R, Redzepovic J, Wheatley K, Clark OA, Miladinovic B, Glasmacher A, et al. Bisphosphonates in multiple myeloma: A network meta-analysis. Cochrane Database Syst Rev 2012;(5):CD003188. |
| 96. | Scavelli C, Di Pietro G, Cirulli T, Coluccia M, Boccarelli A, Giannini T, et al. Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. Mol Cancer Ther 2007;6 (12 Pt 1):3256-62. |
[Figure 1]
| This article has been cited by | | 1 |
The evolution of immune dysfunction in multiple myeloma |
|
| Cinnie Yentia Soekojo, Wee Joo Chng | | European Journal of Haematology. 2022; | | [Pubmed] | [DOI] | | | 2 |
Bone Marrow Microenvironment Interplay and Current Clinical Practice in Multiple Myeloma: A Review of the Balkan Myeloma Study Group |
|
| Jelena Bila,Eirini Katodritou,Margarita Guenova,Sandra Basic-Kinda,Daniel Coriu,Milena Dapcevic,Lejla Ibricevic-Balic,Arben Ivanaj,Oliver Karanfilski,Samo Zver,Meral Beksac,Evangelos Terpos,Meletios Athanassios Dimopoulos | | Journal of Clinical Medicine. 2021; 10(17): 3940 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
Search Pubmed for