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Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma
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Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 93739

Special Issue Editor

Prof. Dr. Hideto Tamura

E-Mail Website
Guest Editor
1. Division of Diabetes, Endocrinology and Hematology, Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Minamikoshigaya, Koshigaya-shi, Saitama 343-8555, Japan
2. Division of Hematology, Department of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-0086, Japan
Interests: multiple myeloma; tumor microenvironment; tumor immunity; immunotherapy; immune checkpoint

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells with M-protein production. Novel agents have prolonged survival in MM patients, although the disease remains incurable in the majority. Thus, new strategies are needed for the treatment of refractory MM patients and to seek a cure. To develop new treatments, it is crucial to elucidate the precise mechanisms of tumor growth and exacerbation in the myeloma microenvironment. The focus of this Special Issue is therefore on the tumor microenvironment and exacerbation mechanisms, i.e., drug resistance, proliferative signaling, immune evasion, etc., involved in aggressive disease behavior in refractory MM, leading to better management of those patients with the development of new treatment strategies.

Prof. Dr. Hideto Tamura
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Multiple myeloma
  • Tumor microenvironment
  • Drug resistance
  • Proliferative signaling
  • Immune evasion
  • Aggressive disease behavior
  • Refractory myeloma
  • New treatment strategies

Published Papers (21 papers)

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Research

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22 pages, 1407 KiB  
Article
Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma
by Tatiana Pazina, Alexander W. MacFarlane IV, Luca Bernabei, Essel Dulaimi, Rebecca Kotcher, Clinton Yam, Natalie A. Bezman, Michael D. Robbins, Eric A. Ross, Kerry S. Campbell and Adam D. Cohen
Cancers 2021, 13(2), 226; https://doi.org/10.3390/cancers13020226 - 10 Jan 2021
Cited by 36 | Viewed by 3965
Abstract
Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) [...] Read more.
Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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14 pages, 3540 KiB  
Article
Daratumumab and Nanobody-Based Heavy Chain Antibodies Inhibit the ADPR Cyclase but not the NAD+ Hydrolase Activity of CD38-Expressing Multiple Myeloma Cells
by Natalie Baum, Ralf Fliegert, Andreas Bauche, Julia Hambach, Stephan Menzel, Friedrich Haag, Peter Bannas and Friedrich Koch-Nolte
Cancers 2021, 13(1), 76; https://doi.org/10.3390/cancers13010076 - 30 Dec 2020
Cited by 12 | Viewed by 4806
Abstract
The nucleotides ATP and NAD+ are released from stressed cells as endogenous danger signals. Ecto-enzymes in the tumor microenvironment hydrolyze these inflammatory nucleotides to immunosuppressive adenosine, thereby, hampering anti-tumor immune responses. The NAD+ hydrolase CD38 is expressed at high levels on [...] Read more.
The nucleotides ATP and NAD+ are released from stressed cells as endogenous danger signals. Ecto-enzymes in the tumor microenvironment hydrolyze these inflammatory nucleotides to immunosuppressive adenosine, thereby, hampering anti-tumor immune responses. The NAD+ hydrolase CD38 is expressed at high levels on the cell surface of multiple myeloma (MM) cells. Daratumumab, a CD38-specific monoclonal antibody promotes cytotoxicity against MM cells. With long CDR3 loops, nanobodies and nanobody-based heavy chain antibodies (hcAbs) might bind to cavities on CD38 and thereby inhibit its enzyme activity more potently than conventional antibodies. The goal of our study was to establish assays for monitoring the enzymatic activities of CD38 on the cell surface of tumor cells and to assess the effects of CD38-specific antibodies on these activities. We monitored the enzymatic activity of CD38-expressing MM and other tumor cell lines, using fluorometric and HPLC assays. Our results showed that daratumumab and hcAb MU1067 inhibit the ADPR cyclase but not the NAD+ hydrolase activity of CD38-expressing MM cells. We conclude that neither clinically approved daratumumab nor recently developed nanobody-derived hcAbs provide a second mode of action against MM cells. Thus, there remains a quest for “double action” CD38-inhibitory antibodies. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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19 pages, 2582 KiB  
Article
Preclinical Rationale for Targeting the PD-1/PD-L1 Axis in Combination with a CD38 Antibody in Multiple Myeloma and Other CD38-Positive Malignancies
by Christie P. M. Verkleij, Amy Jhatakia, Marloes E. C. Broekmans, Kristine A. Frerichs, Sonja Zweegman, Tuna Mutis, Natalie A. Bezman and Niels W. C. J. van de Donk
Cancers 2020, 12(12), 3713; https://doi.org/10.3390/cancers12123713 - 10 Dec 2020
Cited by 23 | Viewed by 3106
Abstract
The CD38-targeting antibody daratumumab mediates its anti-myeloma activities not only through Fc-receptor-dependent effector mechanisms, but also by its effects on T-cell immunity through depletion of CD38+ regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells. Therefore, combining daratumumab with modulators of other potent [...] Read more.
The CD38-targeting antibody daratumumab mediates its anti-myeloma activities not only through Fc-receptor-dependent effector mechanisms, but also by its effects on T-cell immunity through depletion of CD38+ regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells. Therefore, combining daratumumab with modulators of other potent immune inhibitory pathways, such as the PD-1/PD-L1 axis, may further improve its efficacy. We show that multiple myeloma (MM) cells from relapsed/refractory patients have increased expression of PD-L1, compared to newly diagnosed patients. Furthermore, PD-1 is upregulated on T-cells from both newly diagnosed and relapsed/refractory MM patients, compared to healthy controls. In short-term experiments with bone marrow samples from MM patients, daratumumab-mediated lysis was mainly associated with the MM cells’ CD38 expression levels and the effector (NK-cells/monocytes/T-cells)-to-target ratio, but not with the PD-L1 expression levels or PD-1+ T-cell frequencies. Although PD-1 blockade with nivolumab did not affect MM cell viability or enhanced daratumumab-mediated lysis in short-term ex vivo experiments, nivolumab resulted in a mild but clear increase in T-cell numbers. Moreover, with a longer treatment duration, PD-1 blockade markedly improved anti-CD38 antibody-mediated cytotoxicity in vivo in murine CD38+ tumor models. In conclusion, dual targeting of CD38 and PD-1 may represent a promising strategy for treating MM and other CD38-positive malignancies. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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20 pages, 2564 KiB  
Article
Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
by Kimberley C. Clark, Duncan R. Hewett, Vasilios Panagopoulos, Natalya Plakhova, Khatora S. Opperman, Alanah L. Bradey, Krzysztof M. Mrozik, Kate Vandyke, Siddhartha Mukherjee, Gareth C.G. Davies, Daniel L. Worthley and Andrew C.W. Zannettino
Cancers 2020, 12(8), 2149; https://doi.org/10.3390/cancers12082149 - 3 Aug 2020
Cited by 6 | Viewed by 3450
Abstract
In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors [...] Read more.
In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann–Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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Review

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20 pages, 520 KiB  
Review
Myeloma–Bone Interaction: A Vicious Cycle via TAK1–PIM2 Signaling
by Takeshi Harada, Masahiro Hiasa, Jumpei Teramachi and Masahiro Abe
Cancers 2021, 13(17), 4441; https://doi.org/10.3390/cancers13174441 - 3 Sep 2021
Cited by 5 | Viewed by 3435
Abstract
Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by [...] Read more.
Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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28 pages, 873 KiB  
Review
Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression
by Patricia Maiso, Pedro Mogollón, Enrique M. Ocio and Mercedes Garayoa
Cancers 2021, 13(11), 2542; https://doi.org/10.3390/cancers13112542 - 22 May 2021
Cited by 19 | Viewed by 4222
Abstract
Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to [...] Read more.
Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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14 pages, 1902 KiB  
Review
Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma
by Fatih M. Uckun
Cancers 2021, 13(9), 2018; https://doi.org/10.3390/cancers13092018 - 22 Apr 2021
Cited by 27 | Viewed by 5973
Abstract
SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells [...] Read more.
SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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14 pages, 583 KiB  
Review
Role and Therapeutic Targeting of SDF-1α/CXCR4 Axis in Multiple Myeloma
by Shigeki Ito, Tsuyoshi Sato and Takahiro Maeta
Cancers 2021, 13(8), 1793; https://doi.org/10.3390/cancers13081793 - 9 Apr 2021
Cited by 12 | Viewed by 2689
Abstract
The C-X-C chemokine receptor type 4 (CXCR4) is a pleiotropic chemokine receptor that is expressed in not only normal hematopoietic cells but also multiple myeloma cells. Its ligand, stromal cell-derived factor 1α (SDF-1α) is produced in the bone marrow microenvironment. The SDF-1α/CXCR4 axis [...] Read more.
The C-X-C chemokine receptor type 4 (CXCR4) is a pleiotropic chemokine receptor that is expressed in not only normal hematopoietic cells but also multiple myeloma cells. Its ligand, stromal cell-derived factor 1α (SDF-1α) is produced in the bone marrow microenvironment. The SDF-1α/CXCR4 axis plays a pivotal role in the major physiological processes associated with tumor proliferation, survival, invasion, dissemination, and drug resistance in myeloma cells. This review summarizes the pleiotropic role of the SDF-1α/CXCR4 axis in multiple myeloma and discusses the future perspective in the SDF-1α/CXCR4 axis-targeted therapies in multiple myeloma. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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26 pages, 2105 KiB  
Review
Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression
by Andrea Díaz-Tejedor, Mauro Lorenzo-Mohamed, Noemí Puig, Ramón García-Sanz, María-Victoria Mateos, Mercedes Garayoa and Teresa Paíno
Cancers 2021, 13(6), 1353; https://doi.org/10.3390/cancers13061353 - 17 Mar 2021
Cited by 21 | Viewed by 5225
Abstract
Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and [...] Read more.
Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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21 pages, 1372 KiB  
Review
Boosting Immunity against Multiple Myeloma
by Raquel Lopes, Bruna Velosa Ferreira, Joana Caetano, Filipa Barahona, Emilie Arnault Carneiro and Cristina João
Cancers 2021, 13(6), 1221; https://doi.org/10.3390/cancers13061221 - 11 Mar 2021
Cited by 8 | Viewed by 3408
Abstract
Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug [...] Read more.
Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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16 pages, 995 KiB  
Review
The Immune Microenvironment in Multiple Myeloma: Friend or Foe?
by Raquel Lopes, Joana Caetano, Bruna Ferreira, Filipa Barahona, Emilie Arnault Carneiro and Cristina João
Cancers 2021, 13(4), 625; https://doi.org/10.3390/cancers13040625 - 5 Feb 2021
Cited by 25 | Viewed by 4762
Abstract
Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests [...] Read more.
Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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23 pages, 1043 KiB  
Review
DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment
by Takayuki Saitoh and Tsukasa Oda
Cancers 2021, 13(3), 504; https://doi.org/10.3390/cancers13030504 - 28 Jan 2021
Cited by 14 | Viewed by 4076
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA [...] Read more.
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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15 pages, 2752 KiB  
Review
Immune Functions of Signaling Lymphocytic Activation Molecule Family Molecules in Multiple Myeloma
by Mariko Ishibashi, Rimpei Morita and Hideto Tamura
Cancers 2021, 13(2), 279; https://doi.org/10.3390/cancers13020279 - 13 Jan 2021
Cited by 9 | Viewed by 3857
Abstract
The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated [...] Read more.
The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated protein (SAP) or Ewing’s sarcoma-associated transcript 2 (EAT-2), which target immunoreceptor tyrosine-based switch motifs in the cytoplasmic regions of the receptors. Notably, SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly and constitutively expressed on MM cells that do not express the adaptor proteins SAP and EAT-2. This review summarizes recent studies on the expression and biological functions of SLAM family receptors during the malignant progression of MM and the resulting preclinical and clinical research involving four SLAM family receptors. A better understanding of the relationship between SLAM family receptors and MM disease progression may lead to the development of novel immunotherapies for relapse prevention. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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16 pages, 1084 KiB  
Review
Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma
by Ichiro Hanamura
Cancers 2021, 13(2), 256; https://doi.org/10.3390/cancers13020256 - 12 Jan 2021
Cited by 44 | Viewed by 7693
Abstract
Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. [...] Read more.
Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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22 pages, 8957 KiB  
Review
The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression
by Almudena García-Ortiz, Yaiza Rodríguez-García, Jessica Encinas, Elena Maroto-Martín, Eva Castellano, Joaquín Teixidó and Joaquín Martínez-López
Cancers 2021, 13(2), 217; https://doi.org/10.3390/cancers13020217 - 9 Jan 2021
Cited by 94 | Viewed by 9123
Abstract
Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and [...] Read more.
Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell–cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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17 pages, 1098 KiB  
Review
Signaling Pathway Mediating Myeloma Cell Growth and Survival
by Teru Hideshima and Kenneth C. Anderson
Cancers 2021, 13(2), 216; https://doi.org/10.3390/cancers13020216 - 8 Jan 2021
Cited by 38 | Viewed by 3945
Abstract
The multiple myeloma (MM) bone marrow (BM) microenvironment consists of different types of accessory cells. Both soluble factors (i.e., cytokines) secreted from these cells and adhesion of MM cells to these cells play crucial roles in activation of intracellular signaling pathways mediating MM [...] Read more.
The multiple myeloma (MM) bone marrow (BM) microenvironment consists of different types of accessory cells. Both soluble factors (i.e., cytokines) secreted from these cells and adhesion of MM cells to these cells play crucial roles in activation of intracellular signaling pathways mediating MM cell growth, survival, migration, and drug resistance. Importantly, there is crosstalk between the signaling pathways, increasing the complexity of signal transduction networks in MM cells in the BM microenvironment, highlighting the requirement for combination treatment strategies to blocking multiple signaling pathways. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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24 pages, 5230 KiB  
Review
Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma
by Kazuhito Suzuki, Kaichi Nishiwaki and Shingo Yano
Cancers 2021, 13(2), 215; https://doi.org/10.3390/cancers13020215 - 8 Jan 2021
Cited by 22 | Viewed by 4633
Abstract
Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow [...] Read more.
Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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17 pages, 1140 KiB  
Review
PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression
by Federica Costa, Valentina Marchica, Paola Storti, Fabio Malavasi and Nicola Giuliani
Cancers 2021, 13(2), 164; https://doi.org/10.3390/cancers13020164 - 6 Jan 2021
Cited by 17 | Viewed by 5005
Abstract
The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade [...] Read more.
The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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18 pages, 785 KiB  
Review
Current Understanding of Myelomatous Mesenchymal Stromal Cells Extended through Advances in Experimental Methods
by Michiko Ichii and Naoki Hosen
Cancers 2021, 13(1), 25; https://doi.org/10.3390/cancers13010025 - 23 Dec 2020
Cited by 2 | Viewed by 2178
Abstract
Multiple myeloma is an incurable cancer formed by malignant plasma cells. For the proliferation and survival of myeloma cells, as well as the occurrence of the complications, numerous intra- and extra-cellular mechanisms are involved. The interaction of myeloma cells with the microenvironment is [...] Read more.
Multiple myeloma is an incurable cancer formed by malignant plasma cells. For the proliferation and survival of myeloma cells, as well as the occurrence of the complications, numerous intra- and extra-cellular mechanisms are involved. The interaction of myeloma cells with the microenvironment is known to be one of the most critical mechanisms. A specific microenvironment could affect the progression and growth of tumor cells, as well as drug resistance. Among various microenvironment components, such as hematological and non-hematological cells, and soluble factors (cytokines, chemokines, and extracellular matrix (ECM) proteins), in this review, we focus on the role of mesenchymal cells. We aimed to summarize the experimental strategies used for conducting studies and current understanding of the biological roles in the pathogenesis of myeloma. Furthermore, we discuss the possible clinical applications targeting mesenchymal cells. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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14 pages, 1016 KiB  
Review
The Acidic Microenvironment: Is It a Phenotype of All Cancers? A Focus on Multiple Myeloma and Some Analogies with Diabetes Mellitus
by Stefano Fais and Yoshinori Marunaka
Cancers 2020, 12(11), 3226; https://doi.org/10.3390/cancers12113226 - 2 Nov 2020
Cited by 16 | Viewed by 2789
Abstract
Multiple myeloma (MM) is a hematological malignancy with a poor prognosis while with a long and progressive outcome. To date, the therapeutic options are restricted to few drugs, including thalidomide or its derivates and autologous transplantation including stem-cell transplantation. More recently, the use [...] Read more.
Multiple myeloma (MM) is a hematological malignancy with a poor prognosis while with a long and progressive outcome. To date, the therapeutic options are restricted to few drugs, including thalidomide or its derivates and autologous transplantation including stem-cell transplantation. More recently, the use of both proteasome inhibitors and monoclonal antibodies have been included in MM therapy, but the clinical results are still under evaluation. Unfortunately, death rates (within the 5-year overall survival rates) are still very high (45%), with no relevant improvement over the past 10 years. Here, we discuss data supporting a new therapeutic approach against MM, based on a common phenotype of tumor malignancies, which is the acidic microenvironment. Extracellular acidity drastically reduces the efficacy of both anti-tumor drugs and the immune reaction against tumors. Pre-clinical data have shown that anti-acidic drugs, such as proton pump inhibitors (PPIs), have a potent cytotoxic effect against human MM cells, thus supporting their use in the treatment of this malignancy. Here, we discuss also similarities between MM and type II diabetes mellitus (DM) with high risk of developing MM, suggesting that both anti-diabetic drugs and a hypocaloric diet may help in curing MM patients. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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17 pages, 4383 KiB  
Review
Ex Vivo Models Simulating the Bone Marrow Environment and Predicting Response to Therapy in Multiple Myeloma
by Konstantinos Papadimitriou, Ioannis V. Kostopoulos, Anastasia Tsopanidou, Nikolaos Orologas-Stavrou, Efstathios Kastritis, Ourania E. Tsitsilonis, Meletios A. Dimopoulos and Evangelos Terpos
Cancers 2020, 12(8), 2006; https://doi.org/10.3390/cancers12082006 - 22 Jul 2020
Cited by 13 | Viewed by 3265
Abstract
Multiple myeloma (MM) remains incurable despite the abundance of novel drugs. As it has been previously shown, preclinical 2D models fail to predict disease progression due to their inability to simulate the microenvironment of the bone marrow. In this review, we focus on [...] Read more.
Multiple myeloma (MM) remains incurable despite the abundance of novel drugs. As it has been previously shown, preclinical 2D models fail to predict disease progression due to their inability to simulate the microenvironment of the bone marrow. In this review, we focus on 3D models and present all currently available ex vivo MM models that fulfil certain criteria, such as development of complex 3D environments using patients’ cells and ability to test different drugs in order to assess personalized MM treatment efficacy of various regimens and combinations. We selected models representing the top-notch ex vivo platforms and evaluated them in terms of cost, time-span, and feasibility of the method. Finally, we propose where such a model can be more informative in a patient’s treatment timeline. Overall, advanced 3D preclinical models are very promising as they may eventually offer the opportunity to precisely select the optimal personalized treatment for each MM patient. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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