Bone Marrow Microenvironment - A Critical Factor In Multiple Myeloma Development
The close interaction between malignant plasma cells and the bone marrow microenvironment should determine appropriate therapeutic management for a real improvement in prognosis.
Author:Suleman ShahReviewer:Han JuOct 10, 202447.6K Shares744K Views
The aim of this review was to discuss the functional significance of the bone marrow microenvironmentin multiple myeloma development and progression.
Multiple myeloma is one of the most common hematological malignancies, occurring mainly in men over 60 years of age.
Despite significant therapeutic progress and a twofold increase in overall survival, multiple myeloma is still an incurable disease.
The reason for the relatively poor prognosis for multiple myeloma patients lies in the biology of this tumor, the progressive development of which is closely dependent on the bone marrow microenvironment.
The conditions in the bone marrow, in particular, the presence of growth factors for multiple myeloma cells secreted by different cells, promote their survival and proliferation in the bone marrow niches.
These growth factors include:
- interleukin 6 (IL-6)
- insulin-like growth factor-1 (IGF-1)
- vascular endothelial growth factor (VEGF)
Migration and expansion of malignant plasma cells and their mobilization to/from the peripheral blood, characteristic of myeloma progression, are mainly due to disruption of the stromal cell-derived factor-1/CXCR4 (C-X-C chemokine receptor type 4) axis caused by numerous molecular extracellular factors.
It has been shown that the formation of premetastatic niches in the bone marrow, which are indicative of progression, occurs even before the first metastatic cells, home to the bone marrow, and is affected by cellular and extracellular components of the bone marrow.
Discussion
The bone marrow microenvironment plays an essential role in multiple myeloma development and progression, and in the development of cytostatic drug resistance.
Conditions of the bone marrow determine both maturation and maintenance of stem cells and blood precursor cells under physiological conditions and in malignancies such as multiple myeloma.
Studies on the biology of multiple myeloma clearly indicate that its induction probably results from engraftment of long-lived normal plasma cells, produced in the germinal centers of peripheral lymphoid tissues in the bone marrow.
It has been shown that the bone marrow environment per se may promote carcinogenesis, inducing malignant transformation of normal plasma cells.
In addition, conditions in the bone marrow, in particular, the presence of a number of myeloma cell growth factors, promote their survival and proliferation in the bone marrow niches.
The Role Of Stromal Cells
In the process of carcinogenesis within bone marrow stromal elements, structural and functional changes occur, and they cause an imbalance between factors that stimulate and inhibit the growth and differentiation of progenitor blood cells.
In multiple myeloma patients, there are changes in interactions between malignant plasma cells derived from multiple myeloma stem cells and the microenvironment.
These interactions play a significant role in the proliferation, migration, and survival time of myeloma cells and the development of cytostatic drug resistance.
Interactions between myeloma cells, stromal cells, and elements of the extracellular matrix (ECM) occur directly via cell receptors and adhesion molecules, such as:
- integrins
- proteoglycans
- immunoglobulins
- cadherins
- selectins
- syndecans
They are all present on the surface of myeloma cells.
Plasma cell adhesion to extracellular matrix (ECM)proteins activates signaling pathways in plasma cells. These ECM proteins include:
- collagen (mainly type I and VI)
- fibronectin
- laminin
- vitronectin
When the signaling pathways in plasma cells gets activated, it affects their:
- proliferation and survival
- development of drug resistance
- synthesis and secretion of urokinase-type plasminogen activator and metalloproteinases
Some of the adhesion molecules, such as cadherins, facilitate intercellular binding and participate in the formation of functional multicellular structures in the bone marrow by anchoring to the actin cytoskeleton of the cell through catenins.
Free catenins, which accumulate in plasma cells in high concentrations, are involved in Wnt (wingless-related integration site) signal transduction pathways, activating certain oncogenes (e.g., c-Myc) or cyclin D1, and thereby contributing to the development of cancer.
In the process of adhesion of myeloma cells to stromal cells, an important role is also played by extracellular factors, such as:
- cytokines
- chemokines
- growth factors
They have the ability to:
- activate multiple signaling pathways, such as NF-kB (nuclear factor kappa Band) and Notch
- increase the expression of cell cycle regulatory proteins (D-type cyclins) and Bcl-2 (B-cell lymphoma 2) family anti-apoptotic proteins in both stromal and myeloma cells
The activation of these cells leads to secretion of factors that are of particular importance for the proliferation and survival of myeloma cells, especially IL-6, VEGF, and IGF-1, to the environment and intensification of chemotherapy resistance.
It has also been confirmed that the following factors, secreted by stromal cells of patients with multiple myeloma, affect the growth of myeloma cells:
- basic fibroblast growth factor (bFGF)
- angiopoietin-1 (Ang-1)
- transforming growth factor beta (TGF-beta)
- platelet-derived growth factor (PDGF)
- hepatocyte growth factor (HGF)
- interleukin 1 (IL-1)
Recently, it has been reported that there is a novel mechanism of intercellular transfer of genetic information, which involves stromal cell-derived exosomes, which, after entering myeloma cells, modulate their growth mediated by specific microRNAs (miRNAs).
Stromal cells are also a source of chemokines involved in the migration and homing of myeloma cells to the bone marrow due to the presence of chemokine receptor CCR2 on their surface.
Said chemokines include:
- chemokine (C-C motif) ligand 2 (CCL2), aka monocyte chemoattractant protein-1(MCP-1)
- CCL8, aka MCP-2
- CCL7, aka MCP-3
However, a special role in this process is attributed to the SDF-1 (CXCL12)/CXCR4 axis.
Stromal cells also have the ability to secrete CCL3 chemokine (MIP-1α), affecting the severity of adhesion and interaction between the integrins of myeloma plasma cells and vascular cell adhesion protein 1 (VCAM-1) molecules on the surface of endothelial cells, which in turn promotes neovascularization in the bone marrow of multiple myeloma patients.
Further expansion of plasma cells in the bone marrow stroma is promoted by cytokines, growth factors, and metalloproteinases, especially:
| MMP-9 | MIP-1α |
| MMP-2 | IGF-1 |
| IL-6 | IL-1 |
| VEGF | IL-3 |
| TNFα | IL-10 |
| SDF-1 | IL-15 |
These cytokines are secreted by a variety of bone marrow cells.
The Role Of Endothelial Cells And Angiogenesis
Clear intensification of angiogenesis in samples from patients with multiple myeloma, measured by microvessel density (MVD), is observed in patients with active disease as compared to those with inactive multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS).
Bone marrow angiogenesis in multiple myeloma is a determinant of tumor cell growth and disease progression, and a process partially regulated by pro-angiogenic factors released by:
- plasma cells
- stromal cells
- osteoclasts
Among these factors, the most important role is attributed to the following, the secretion of which is a consequence of interaction between stromal cells and myeloma plasma cells:
| VEGF | HGF |
| bFGF | IGF-1 |
| MMP | MIP-1 |
| IL-6 | MCP-1 |
| TNFα | SDF-1 |
Constitutive secretion of VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) by myeloma cells may also result from the activation of oncogenes and/or genetic mutations.
In order to identify the vascular mechanism underlying metastasis and disease progression, expression profiling of genes involved in the regulation of extracellular matrix (ECM) formation or processes which promote disease progression was performed in the endothelial cells of multiple myeloma patients, showing aberrant expression of 22 genes assayed.
Said processes include:
- bone marrow remodeling
- angiogenesis
- cell cycle regulation
- chemotaxis, cell adhesion
- resistance to apoptosis
These studies have highlighted the role of the microenvironment in the induction of bone marrow neovascularization, encouraging development of tumor cells and multiple myeloma progression.
This study clearly shows that the use of anti-angiogenic factors in multiple myeloma therapy can significantly improve the prognosis.
The Role Of Osteoclasts And Osteoblasts
The observed severe bone destruction in the immediate vicinity of myeloma cells indicates their participation in the process of osteoprotegerin (OPG), aka osteoclastogenesis.
In particular, it has been shown that the interaction of myeloma cells with stromal cells in the bone marrow leads to increased expression of RANKL (receptor activator of NF-kB ligand) on myeloma cells; thus, generating a signal for the activation of osteoclast precursors that express the cell-surface receptor RANK.
The RANKL and OPG molecules, which are their competitive receptors, are assigned the most important role in the regulation of bone resorption.
In physiological conditions, a dynamic balance between RANKL and OPG develops, and in the course of multiple myeloma, it shifts towards higher RANKL expression in the bone marrow microenvironment, contributing to increased:
- osteoclast activation
- bone osteolysis
RANK ligand (RANKL) promotes osteoclastogenesis also via inhibition of osteoclast apoptosis, which significantly prolongs their survival.
Blocking RANKL with a soluble form of RANKL:
- modulates bone resorption
- inhibits multiple myeloma progression
The osteoclast activity and bone destruction are also enhanced by:
| MIP-1α | IL-11 |
| IL-1 | TGFα |
| IL-3 | MMP-9 |
| IL-6 | TNFα |
In turn, the process of osteoclastogenesis is inhibited by OPG and TGF-beta.
It has been shown that osteoclasts are also a constant source of osteopontin (OPN), which is a known pro-angiogenic factor, promoting the formation of an environment conducive to the development and progression of the disease.
It has been shown that both disease progression and the resulting increased destruction of bone tissue can result from impaired osteoblast activity, which depends on the activity of the inhibitor dickkopf-1 (DKK1).
DKK1 is a Wnt antagonist, secreted by myeloma cells, which inhibits differentiation of precursor cells toosteoblasts.
In MM patients with osteolytic foci detected in the bones, significantly increased DKK1 expression on the surface of malignant plasma cells has been found.
The importance of DKK1 for multiple myeloma development and progression has been demonstrated in studies which involved:
- blocking of DKK1
- subsequent inhibition of bone osteolysis
- tumor weight reduction
In contrast, despite the loss of their osteogenic function, osteoblasts maintain their ability to produce and secrete OPG, which binds to the TRAIL [targeting TNF (tumor necrosis factor)-related apoptosis-inducing ligand] receptor on the surface of myeloma cells and is responsible for their prolonged survival by blocking apoptosis signal transduction.
Osteoblasts are also an additional source of IL-6, a recognized multiple myeloma cell growth factor, as confirmed in the culture of multiple myeloma cell lines.
The Impact Of The Extracellular Environment On Multiple Myeloma Development
Complex positive and negative interactions mediated by various adhesion molecules, cytokines, and their receptors occur between individual bone marrow cells and myeloma cells.
Some of the growth and survival factors for myeloma cells, such as interleukin-6 (IL-6), are produced by many types of bone cells (osteoblasts, osteoclasts, stromal cells) and the multiple myeloma cells themselves.
Additional external factors such as hypoxia or internal signals generated by a deregulated c-Myc oncogene in myeloma cells lead to hypoxia-inducible factor 1-α (HIF-1α) activation and VEGF secretion by myeloma cells.
VEGF, in turn, stimulates endothelial cells to secrete IGF-1 (insulin-like growth factor 1), which induces proliferation of myeloma cells.
Thus, IL-6, VEGF, and IGF constitute a network of factors essential for multiple myeloma development and progression.
Interleukin-6
Interleukin-6 (IL-6) is a key growth and survival factor for multiple myeloma cells, and it affects tumor growth by autocrine and paracrine mechanisms.
It’s originally produced by:
- stromal cells
- osteoclasts
- malignant plasma cells
IL-6 secretion by medullary stromal cells is regulated directly by adhesion to myeloma cells, and indirectly by soluble factors secreted by these cells (TNFα, VEGF, IL-1β, TGFβ), which lead to activation of the transcription factor NF-kB in plasma cells.
Thus, a cross-regulation network develops between the tumor cells and the microenvironment, which promotes myeloma progression.
After binding to its receptor on myeloma cells, IL-6 induces a signaling pathway that:
- leads to activation and proliferation of plasma cells
- inhibits the activity of p27 and p21 inhibitors
- activates anti-apoptotic proteins (Mcl-1 and Bcl-x) and c-Myc
It has been observed that a high level of IL-6 in the serum of multiple myeloma patients is correlated with poor prognosis and an increased percentage of proliferating myeloma cells in the peripheral blood.
Insulin-Like Growth Factor 1
Insulin-like growth factor 1 (IGF-1) is a factor promoting the carcinogenesis of many cancers.
IGF-1 is secreted by stromal cells, endothelial cells, and bone marrow osteoblasts, and in the paracrine mechanism, it is conducive to multiple myeloma development by binding to its receptor on tumor cells.
This interaction leads to a shift in the balance of factors associated with apoptosis towards cell death inhibitors in myeloma cells.
Vascular Endothelial Growth Factor
It has been shown that increased bone marrow vascularization is positively correlated with a poor prognosis of cancer patients.
The growth of new blood vessels significantly improves the conditions for nutrient and oxygen transport to cells, facilitating further growth of the tumor.
Vascular endothelial growth factor (VEGF), as a known pro-angiogenic factor in a number of hematological malignancies including multiple myeloma, is clearly associated with disease progression.
Secreted by stromal and myeloma cells under the influence of cytokines and other growth factors (e.g., IL-6, bFGF, TGFβ, and TNFα) present in the bone marrow of multiple myeloma patients, it enhances the development of a favorable microenvironment conducive to gradual progression of the disease.
Multiple Myeloma Progression
In most cases, myeloma cells develop primarily in the bone marrow, although in aggressive forms of the disease, malignant plasma cells can also be home to extramedullary sites, such as:
- spleen
- liver
- body fluids
Symptomatic multiple myeloma progression is associated with further expansion of myeloma cells within the bone marrow and spreads to secondary sites in bone marrow by the bloodstream.
Myeloma cell migration from the blood to the bone marrow (called homing) is a multi-stage process actively managed by several interactions in the bone marrow, primarily initiated by the activation of selectins.
The next stages of homing, such as adhesion and extravasation, when myeloma cells exit the capillaries, occur by the activation of integrins LFA-1 (lymphocyte function-associated antigen 1) and VLA-4 (very late antigen-4) on their surface.
However, substantial mobilization of malignant plasma cells from the peripheral blood to the bone marrow occurs due to activity of the SDF-1(stromal cell-derived factor 1)/CXCR4 (C-X-C chemokine receptor type 4) axis.
SDF-1 chemokine, which induces homing of myeloma cells into the bone marrow, is secreted by stromal cells (e.g., endothelial cells, mesenchymal stem cells), and binds specifically to the cell-surface receptor CXCR4 expressed on plasma cells.
Worth mentioning is the large diversity of CXCR4 expression on myeloma cells, confirmed on the surface of 10% to 100% of the cells.
It has been found that blocking CXCR4 inhibits migration of myeloma cells to SDF-1 chemokines in the bone marrow.
In turn, migration and expansion of myeloma cells in the bone marrow and their mobilization or egress into the peripheral blood occur due to disruption of the SDF-1/CXCR4 axis, which involves:
- weakening of SDF-1 expression under the influence of bone marrow environment proteases
- intensification of CXCR4 expression following hypoxic myeloid niches (1% to 2% oxygen)
Nevertheless, the bone marrow microenvironment is not sufficiently prepared for metastatic myeloma cell engraftment.
The requirement for multiple myeloma dissemination within the bone marrow is the adaptation of myeloid niches to conditions that enable further development of multiple myeloma, which is mediated by:
- extracellular matrix (ECM) components
- stroma
- endothelial cells
- cytokines
- chemokines
- growth factors, in particular, IL-6, IGF-1, and APRIL (a proliferation-inducing ligand)
It has been demonstrated that myeloma cells can invade large areas of the bone marrow with particular ease by entering into abnormal interactions with both ECM proteins and bone marrow stromal cells, on which they are closely dependent.
The formation of pre-metastatic niches in the bone marrow, which are an expression of a pathological response of the bone marrow environment to the presence of myeloma cells, occurs even before the first arrival of metastatic cells and substantially facilitates their distribution; thus, promoting the creation of new malignant foci.
This results in characteristic premetastatic disorders in the said components of the bone marrow microenvironment, which together facilitate the growth and survival of the metastasizing myeloma cells.
This specific bone marrow microenvironment remodeling is also affected by increased osteoclast activity mediated by RANKL/RANK and MIP-1alpha, osteoblastogenesis attenuated by DKK1 and IL-3, as well as the previously mentioned intensive neoangiogenesis.
It is believed that myeloma cells circulating in the peripheral blood and molecular factors secreted by them, including metalloproteinases, are also of particular importance in the phenomenon of multiple myeloma bone marrow metastases.
Metalloproteinases (MMPs) have the ability to degrade ECM, and at the same time, they stimulate angiogenesis, which promotes the spread of malignant cells.
Among the various MMPs, considerable importance in multiple myeloma progression is attributed mainly to gelatinases MMP-2 and MMP-9, which degrade type IV collagen, the major component of the basal membrane of cells, and thus, affect their ability to spread myeloma.
Among other factors involved in pre-metastatic bone marrow remodeling, there are also adhesion molecules, characterized by increased VLA-4 expression on the surface of myeloma cells, and exosomes which induce neoangiogenesis in metastatic lesion locations.
Additionally, cells of hematopoietic origin that exhibit the expression of fibronectin (VLA-4) and VEGF (VEGFR1) receptors on their surface allow implantation of new myeloma cells into the bone marrow.
Conclusion
The recent studies clearly emphasize a strong interaction between myeloma cells and elements of the bone marrow microenvironment both in multiple myeloma development and progression.
It even seems that the role of each component of the tumor-host interactions is equivalent in multiple myeloma pathogenesis.
Novel therapeutic approaches should target not only the malignant plasma cell, but also its interaction with the bone marrow microenvironment, to sufficiently prevent disease progression.
Despite administration of several immunomodulators and proteasome inhibitors, other therapies are still under active investigation.
Therefore, more studies involving bone marrow microenvironment should be conducted.
Jump to
Discussion
The Role Of Stromal Cells
The Role Of Endothelial Cells And Angiogenesis
The Role Of Osteoclasts And Osteoblasts
The Impact Of The Extracellular Environment On Multiple Myeloma Development
Interleukin-6
Insulin-Like Growth Factor 1
Vascular Endothelial Growth Factor
Multiple Myeloma Progression
Conclusion
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
Each article at World Wide Journals is a piece of this ongoing quest, blending analysis with personal reflection. Whether exploring quantum frontiers or strumming chords under the stars, my aim is to inspire and provoke thought, inviting you into a world where every discovery is a note in the grand symphony of existence.
Welcome aboard this journey of insight and exploration, where curiosity leads and music guides.
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