Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression

Solimando, Antonio Giovanni; Viá, Matteo Da; Leone, Patrizia; Borrelli, Paola; Croci, Giorgio Alberto; Tabares, Paula; Brandl, Andreas; Lernia, Giuseppe Di; Bianchi, Francesco Paolo; Tafuri, Silvio; Steinbrunn, Torsten; Balduini, Alessandra; Melaccio, Assunta; Summa, Simona De; Argentiero, Antonella; Rauert-Wunderlich, Hilka; Frassanito, Maria Antonia; Ditonno, Paolo; Henke, Erik; Klapper, Wolfram; Ria, Roberto; Terragna, Carolina; Rasche, Leo; Rosenwald, Andreas; Kortüm, K. Martin; Cavo, Michèle; Ribatti, Doménico; Racanelli, Vito; Einsele, Hermann; Beilhack, Andreas

doi:10.3324/haematol.2019.239913

Cited by 50 publications

(41 citation statements)

References 48 publications

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“…It has been uncovered that some integrins were detected in high levels in MM, while in non-detectable levels in non-active MM and MGUS patients, suggesting the adhesion molecules support the interactions between MM and the microvasculature and facilitate disease progression 70 . Furthermore, junctional adhesion molecule A has been identified as a key mediator of MM progression by promoting MM-associated angiogenesis and an independent prognostic factor for both newly diagnosed MM and relapsed/refractory MM 71 , 72 . Similarly, our enrichment analysis of up-regulated DEGs had identified positive regulation of angiogenesis and cell adhesion, demonstrating that myeloma SP cells may be relevant to angiogenesis and cell adhesion to propagate MM progression.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in Myeloma side population cells by Bioinformatics Analysis

Qin

et al. 2020

Int. J. Med. Sci.

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Background: Multiple myeloma (MM) is the second most common hematological malignancy, which is still incurable and relapses inevitably, highlighting further understanding of the possible mechanisms. Side population (SP) cells are a group of enriched progenitor cells showing stem-like phenotypes with a distinct low-staining pattern with Hoechst 33342. Compared to main population (MP) cells, the underlying molecular characteristics of SP cells remain largely unclear. This bioinformatics analysis aimed to identify key genes and pathways in myeloma SP cells to provide novel biomarkers, predict MM prognosis and advance potential therapeutic targets. Methods: The gene expression profile GSE109651 was obtained from Gene Expression Omnibus database, and then differentially expressed genes (DEGs) with P-value <0.05 and |log2 fold-change (FC)| > 2 were selected by the comparison of myeloma light-chain (LC) restricted SP (LC/SP) cells and MP CD138 + cells. Subsequently, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, protein-protein interaction (PPI) network analysis were performed to identify the functional enrichment analysis of the DEGs and screen hub genes. Cox proportional hazards regression was used to select the potential prognostic DEGs in training dataset (GSE2658). The prognostic value of the potential prognostic genes was evaluated by Kaplan-Meier curve and validated in another external dataset (MMRF-CoMMpass cohort from TCGA). Results: Altogether, 403 up-regulated and 393 down-regulated DEGs were identified. GO analysis showed that the up-regulated DEGs were significantly enriched in innate immune response, inflammatory response, plasma membrane and integral component of membrane, while the down-regulated DEGs were mainly involved in protoporphyrinogen IX and heme biosynthetic process, hemoglobin complex and erythrocyte differentiation. KEGG pathway analysis suggested that the DEGs were significantly enriched in osteoclast differentiation, porphyrin and chlorophyll metabolism and cytokine-cytokine receptor interaction. The top 10 hub genes, identified by the plug-in cytoHubba of the Cytoscape software using maximal clique centrality (MCC) algorithm, were ITGAM, MMP9, ITGB2, FPR2, C3AR1, CXCL1, CYBB, LILRB2, HP and FCER1G. Modules and corresponding GO enrichment analysis indicated that myeloma LC/SP cells were significantly associated with immune system, immune response and cell cycle. The predictive value of the prognostic model including TFF3, EPDR1, MACROD1, ARHGEF12, AMMECR1, NFATC2, HES6, PLEK2 and SNCA was identified, and validated in another external dataset (MMRF-CoMMpass cohort from TCGA). Conclusions: In conclusion, this study provides reliable molecular biomarkers for screening, prognosis, as well as novel therapeutic targets for myeloma LC/SP cells.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in Myeloma side population cells by Bioinformatics Analysis

Qin

et al. 2020

Int. J. Med. Sci.

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“…Monocytic myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) play a crucial role in the “stromal 2” signature [ 19 , 20 ]. Overall, as in other hematological niche addicted malignancies [ 21 , 22 , 23 , 24 ], the current evidence pinpoints that DLBCL disease progression is a multistep transformation process characterized by a complex vicious cycle between lymphoma cells and the tumor milieu.…”

Section: Introductionmentioning

confidence: 65%

“…Lymphoproliferative disorders [ 89 , 90 ] and DLBCL [ 91 ] are no exception. Accordingly, strategies combining anti-angiogenic therapy and immunotherapy seem to have the potential to tip the balance of the tumor microenvironment and improve the treatment response of lymphoid malignancies [ 21 , 22 , 92 , 93 ]. These pieces of evidence prompted an intense translational investigation aimed at targeting angiogenesis and the immune system in a coordinated fashion, based on the preclinical insights available [ 94 , 95 ].…”

Section: Bridging the Gaps Between Disease Biology And Clinical Trmentioning

confidence: 99%

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

Solimando

Annese

Tamma

et al. 2020

Cancers

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Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we analyzed the role of different cellular components of the tumor microenvironment, including mast cells, macrophages, and lymphocytes, in the tumor progression of DLBCL. We examined several approaches to confront the available pieces of evidence, whereby three key points emerged. DLBCL is a disease of malignant B cells spreading and accumulating both at nodal and at extranodal sites. In patients with both nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. The DLBCL cell interaction with mature stromal cells and vessels confers tumor protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL–milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.

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“…Disruption of JAM-A pathways increased cell apoptosis and decreased proliferation, however, no differences in angiogenesis or infiltration of DCs or macrophages were found. In addition, treatment with anti-JAM-A mAb suppressed progression of malignant tumors by impairing cell proliferation and angiogenesis in malignant myeloma xenograft murine models (73). Altogether, these studies suggest that although JAM-A expressed by tumor cells may have a protective role on progression of cancer, JAM-A antagonism could enhance immune response against these abnormal cells by possibly facilitating leukocyte infiltration into tumors and DC egress to LNs (see Figure 2).…”

Section: Jam-a Manipulation In Cancer Modelsmentioning

confidence: 90%

Targeting Opposing Immunological Roles of the Junctional Adhesion Molecule-A in Autoimmunity and Cancer

et al. 2020

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The junctional adhesion molecule-A (JAM-A) is a cell surface adhesion molecule expressed on platelets, epithelial cells, endothelial cells and leukocytes (e. g. monocytes and dendritic cells). JAM-A plays a relevant role in leukocyte trafficking and its therapeutic potential has been studied in several pathological conditions due to its capacity to induce leukocyte migration out of inflamed sites or infiltration into tumor sites. However, disruption of JAM-A pathways may worsen clinical pathology in some cases. As such, the effects of JAM-A manipulation on modulating immune responses in the context of different diseases must be better understood. In this mini-review, we discuss the potential of JAM-A as a therapeutic target, summarizing findings from studies manipulating JAM-A in the context of inflammatory diseases (e.g. autoimmune diseases) and cancer and highlighting described mechanisms.

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Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression

Abstract: Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression.

Cited by 50 publications

References 48 publications

Identification of Key Genes and Pathways in Myeloma side population cells by Bioinformatics Analysis

Identification of Key Genes and Pathways in Myeloma side population cells by Bioinformatics Analysis

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

Targeting Opposing Immunological Roles of the Junctional Adhesion Molecule-A in Autoimmunity and Cancer

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