P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment

Azab, Abdel Kareem; Quang, Phong; Azab, Feda; Pitsillides, Costas; Thompson, B.; Chonghaile, Tríona Ní; Patton, John T.; Maiso, Patricia; Monrose, Val; Sacco, Antonio; Ngo, Hai T.; Flores, Ludmila M.; Lin, Charles P.; Magnani, John L.; Kung, Andrew L.; Letaï, Anthony; Carrasco, Ruben D.; Roccaro, Aldo M.; Ghobrial, Irène M.

doi:10.1182/blood-2011-07-368050

Cited by 101 publications

(133 citation statements)

References 36 publications

(43 reference statements)

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“…81 Similarly, P-selectin glycoprotein ligand-1 knockdown or inhibition by a small pan-selectin inhibitor (GMI-1070; Glycomimetics) showed significant inhibition of rolling and homing in vitro and in vivo. 82 Similarly, we showed another interaction of the SDF-1/CXCR4 with downstream GTPases, including RhoA and Rac1. 59 Other regulators of homing in MM include integrin-␤7, VEGF, and IGF-1.…”

Section: The Process Of Extravasation or Homingmentioning

confidence: 95%

Myeloma as a model for the process of metastasis: implications for therapy

Ghobrial

2012

Blood

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170

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Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed. IntroductionMultiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple lytic lesions at the time of diagnosis. 1,2 The presence of multiple myelomatous "omas" throughout the axial skeleton detected at the time of diagnosis in most patients indicates that there is continuous spread or dissemination of tumor cells from the original site of tumor development to multiple sites in the BM niches, leading to the final development of symptomatic disease. Therefore, MM may represent a good model disease to study cell trafficking or cell metastasis. Although the term "metastasis" is not commonly used to describe dissemination of hematologic malignancies, this review attempts to examine how MM can use a process of cell dissemination that is similar to cell trafficking of hematopoietic stem cell (HSCs) and cell metastasis in solid epithelial carcinomas. These studies can guide our understanding of the biologic changes that occur during progression in MM. Cell metastasis and cell traffickingThe process of cell metastasis is usually described as a multistep process, often termed as the invasion-metastasis cascade. [3][4][5][6] This involves several steps of changes that include: (1) cell invasion, (2) intravasation (egress) into nearby blood vessels, (3) passage of the tumor cells into the circulation, followed by (4) homing or extravasation of tumor cells from these vessels into the specific predetermined distant tissues, (5) the formation of new foci of tumor micrometastases, and (6) finally the growth of micrometastatic lesions into macroscopic tumors, a step called "colonization."A similar process occurs with cell trafficking ...

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Section: The Process Of Extravasation or Homingmentioning

confidence: 95%

Myeloma as a model for the process of metastasis: implications for therapy

Ghobrial

2012

Blood

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170

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“…Stessman and colleagues showed that the reduced CXCR4 expression in MM patients was associated with better survival (22). Furthermore, migration and invasion of MM cells to BM may require the E/P-selectins and their common receptor P-selectin glycoprotein ligand-1 (23). Other factors, such as the integrin ITGAL, the sialyltransferase ST3GAL6, and SDC1, may also contribute to MM BM homing (11,24,25).…”

Section: Discussionmentioning

confidence: 99%

Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response

Zheng

Wang

et al. 2016

JNCI J Natl Cancer Inst

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Background: Multiple myeloma (MM) remains an incurable cancer characterized by accumulation of malignant plasma cells in the bone marrow (BM). The mechanism underlying MM homing to BM is poorly elucidated. Methods: The clinical significance of migration inhibitory factor (MIF) expression was examined by analyzing six independent gene expression profile databases of primary MM cells using the Student's t test and Kaplan-Meier test. Enzymelinked immunosorbent assay was used to examine MIF expression. In vivo bioluminescent imaging was used to determine MM cell localization and treatment efficacy in human MM xenograft mouse models, with three to four mice per group. MM cell attachment to BM stromal cells (BMSCs) was monitored by cell adhesion assay. MIF regulation of the expression of adhesion molecules was determined by chromatin immunoprecipitation (ChIP) assay. Statistical tests were two-sided. Results: High levels of MIF were detected in MM BM (MIF level in BM plasma: healthy ¼ 10.72 6 5.788 ng/mL, n ¼ 5; MM ¼ 1811 6 248.7 ng/mL, n ¼ 10; P < .001) and associated with poor survival of patients (Kaplan-Meier test for MM OS: 87 MIF high patients, 86 MIF low patients, P ¼ .02). Knocking down MIF impaired MM cell adhesion to BMSCs in vitro and led to formation of extramedullary tumors in SCID mice. MIF acted through surface receptor CXCR4 and adaptor COPS5 to regulate the expression of adhesion molecules ALCAM, ITGAV, and ITGB5 on MM cells. More importantly, MIF-deficient MM cells were sensitive to chemotherapy in vitro when cocultured with BMSCs and in vivo. MIF inhibitor 4-IPP sensitized MM cells to chemotherapy. Conclusions: MIF is an important player and a novel therapeutic target in MM. Inhibiting MIF activity will sensitize MM cells to chemotherapy.

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“…All human MM cell lines and BMSCs were cultured as in previous studies. 4,9 Green-fluorescent-protein and luciferase-positive (GFP-Luc 1 ) MM1S cells were generated using lentivirus infection, as previously described. 11 Calcein-AM cells were obtained from Invitrogen (Carlsbad, CA).…”

Section: Cell Lines and Primary Cellsmentioning

confidence: 99%

“…P-selectin glycoprotein ligand 1 (PSGL-1) is highly expressed in MM and can bind to both E-and P-selectin, and the potential therapeutic benefit of selectin inhibition in MM has been demonstrated. 4 Functional selectin ligands require posttranslational modification of scaffold proteins by glycosyltransferases and sulfotransferases ( Figure 1A). The minimal recognition motif for all selectins is sialyl-Lewis x (sLe x ) and its isomer sialyl-Lewis a (sLe a ), which are tetrasaccharides that are synthesized by the combined action of a-1, 3-fucosyltransferases, a-2,3-sialyltransferases, 1,4-galactosyltranferases, and N-acetyl-glucosaminyltransferases.…”

Section: Introductionmentioning

confidence: 99%

The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma

Glavey

Manier

Natoni

et al. 2014

Blood

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100

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Key Points• Knockdown of the sialyltransferase, ST3GAL6, in MM inhibits in vivo homing and prolongs survival in xenograft mice.• In MM patients, high expression of ST3GAL6 is associated with inferior overall survival.Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated.In the present study we identified high expression of b-galactoside a-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of a-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration. (Blood. 2014;124(11):1765-1776

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P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment

Cited by 101 publications

References 36 publications

Myeloma as a model for the process of metastasis: implications for therapy

Myeloma as a model for the process of metastasis: implications for therapy

Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response

The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma

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