Soluble syndecan-1 promotes growth of myeloma tumors in vivo

Yang, Yang; Yaccoby, Shmuel; Liu, Wei; Langford, J. Kevin; Pumphrey, Carla Y.; Theus, Allison; Epstein, Joshua; Sanderson, Ralph D.

doi:10.1182/blood.v100.2.610

Cited by 177 publications

(168 citation statements)

References 28 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…The current study confirmed the transferred expression of syndecan-1 to the endothelial cells. MM is characterized by high expression of syndecan-1 (CD138), which is present on the surface of myeloma cells and can be shed into the tumor microenvironment [4,[38][39][40] . Recently, exosome secretion by myeloma cells and the protein cargo of sydecan-1 were reported to dramatically increase when myeloma cells were exposed to exogenous heparanase or when the expression of heparanase was enhanced [20] .…”

Section: Discussionmentioning

confidence: 99%

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

et al. 2013

View full text Add to dashboard Cite

Aim: To investigate whether human multiple myeloma (MM) cells secrete microvesicles (MVs) and whether the MVs secreted from MM cells (MM-MVs) promote angiogenesis. Methods: RPMI8226 human MM cells and EA.hy926 human umbilical vein cells were used. MVs isolated from RPMI 8226 cells were characterized under laser confocal microscopy, electron microscopy and with flow cytometry. The fusion of MM-MVs and EA.hy926 cells was studied under confocal microscopy, and the transfer of CD138 to EA.hy926 cells was demonstrated with flow cytometry. The proliferation, invasion and tube formation of EA.hy926 cells in vitro were evaluated using MTT, transwell migration and tube formation assays, respectively. The vasculization of EA.hy926 cells in vivo was studied using Matrigel plug assay. The expression of IL-6 and VEGF was analyzed with PCR and ELISA. Results: MM-MVs from the RPMI 8226 cells had the characteristic cup-shape with diameter of 100-1000 nm. Most of the MM-MVs expressed phosphatidylserine and the myeloma cell marker CD138, confirming that they were derived from myeloma cells. After added to EA.hy926 cells, the MM-MVs transferred CD138 to the endothelial cells and significantly stimulated the endothelial cells to proliferate, invade, secrete IL-6 and VEGF, two key angiogenic factors of myeloma, and form tubes in vitro and in vivo. Conclusion: Our results confirm the presence of MVs in MM cells and support the idea that MM-MVs are newfound mediators for myeloma angiogenesis and may serve as a therapeutic target to treat MM.

show abstract

Section: Discussionmentioning

confidence: 99%

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…30 Syndecans can be cleaved from the cell surface and released into the extracellular microenvironment by the action of secretase: cells expressing soluble syndecan-1 metastasize more extensively than cells bearing surface syndecan-1. 31 Since various forms of proteoglycan heparan sulfate have been identified in neuroblastoma cells, 32 it is reasonable to hypothesize that the neuroblastoma also produces and releases molecules capable of binding and neutralizing OPG. This might explain the scarce amount of OPG protein in the culture medium of the various neuroblastoma cell lines, on the one hand, and the poor efficacy of OPG at blocking paracrine RANKL activity, on the other.…”

Section: Discussionmentioning

confidence: 99%

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

Granchi

Amato

Battistelli

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

Proliferation and differentiation of osteoclasts are regulated by a cytokine system that includes RANKL, which binds 2 receptors: RANK, which activates osteoclast differentiation, and osteoprotegerin (OPG), a decoy receptor that limits RANKL action. We investigated the role of the OPG/ RANKL/RANK network in the pathogenesis of skeletal metastasis in neuroblastoma. Four different neuroblastoma cell lines (NB100, CHP212, SH-SY5Y, SJ-NK-P) showed a large amount of OPG and RANKL transcripts. Soluble RANKL was detectable in all cell lines, but poor release of OPG was observed. SH-SY5Y showed the lowest OPG-to-RANKL ratio and promoted osteoclastic differentiation of FLG29.1 and peripheral mononuclear cells, inducing expression of the osteoclast markers RANK, c-src, c-fos, cathepsin-K and TRAP. SJ-N-KP, which released both OPG and RANKL, did not show the same capability. OPG, neutralizing anti-RANKL antibody and antisense oligonucleotides were evaluated for their ability to inhibit RANKL activity. The neutralizing antibody hampered osteoclastic differentiation by blocking both the juxtacrine and the paracrine activity of RANKL. Our findings confirm that neuroblastoma cells induce osteoclastogenesis via RANKL and suggest that the RANKL expression associated with lack of the decoy receptor OPG could be a peculiarity of some tumors that makes them able to induce metastatic osteolysis. Moreover, our results suggest that RANKL could be a relevant target in the adjuvant therapy of bone metastatic neuroblastoma as proper neutralization revokes completely osteoclastic differentiation. © 2004 Wiley-Liss, Inc. Key words: neuroblastoma; bone metastasis; osteoclast; RANKL; osteoprotegerinMetastasis is the most relevant prognostic factor for survival in neuroblastoma patients, and bone is one of the target organs of metastasis in advanced neuroblastoma. Patients with bone metastasis are classified as stage IV, regardless of other clinical manifestations, since the presence of bone/bone marrow metastasis is responsible for poor prognosis despite high-dose chemotherapy and autologous hematopoietic stem cell transplantation. 1 One possible reason for this ominous prognosis is the difficulty in reaching cancer cells that have colonized the bone/bone marrow microenvironment. This suggests the need for effective therapeutic modalities for patients with skeletal metastases based on a precise understanding of the pathophysiology of bone colonization in neuroblastoma. Two classical theories are generally advocated to explain the invasion of tumor cells in bone, i.e., the soil hypothesis 2 and the circulation theory. 3 The first suggests that proper factors favor the implantation of metastatic cells, including nutrients, oxygen tension, hormonal environment and hydrogen ion concentrations. The second assumes that development of cancer metastases is dependent on the blood volume inside a target organ. This hemodynamic theory alone cannot explain the high frequency of skeletal metastasis from some neoplasms because blood flow in bone is very p...

show abstract

“…34,35 Syndecan-1 is produced and shed from myeloma plasma cells and is involved in myeloma cell metastasis and growth. [36][37][38] A recent study also demonstrated that syndecans, including syndecan-1, directly bind to tumor cells and activate TACI signaling. 39 These studies may suggest that in contrast to BAFF, APRIL plays a nonredundant role in the survival of myeloma due to its interaction with syndecan-1 and possibly other HSPGs.…”

Section: Antimyeloma Response Of Atacicept and Baffr-ig In Scid-hu Micementioning

confidence: 97%

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

Yaccoby

Pennisi

et al. 2007

Leukemia

View full text Add to dashboard Cite

APRIL (a proliferation-inducing Ligand) and BLyS/BAFF (B-lymphocyte stimulator/B-cell-activating factor of the TNF (tumor necrosis factor) family have been shown to be the survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BAFFR, whereas APRIL binds to TACI and BCMA and to heparan sulfate proteoglycans (HSPG) such as syndecan-1. TACI gene expression in myeloma reportedly can distinguish tumors with a signature of microenvironment dependence (TACI high ) versus a plasmablastic signature (TACI low ). We tested the effect of atacicept (formerly TACI-Ig, which blocks APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on primary myeloma growth in the SCID-hu model and in coculture with osteoclasts. With only few exceptions, atacicept and to a lesser extent BAFFR-Ig, inhibited growth of TACI high but not TACI low myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACI high myeloma cells were molecularly classified as being low risk with our recently described 70-gene model. APRIL and BAFF were highly expressed by osteoclasts and were upregulated in myeloma cells after coculture with osteoclasts. Our findings suggest that APRIL plays an essential role in the survival of TACI high bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.

show abstract

Soluble syndecan-1 promotes growth of myeloma tumors in vivo

Cited by 177 publications

References 28 publications

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

Atacicept (TACI-Ig) inhibits growth of TACIhigh primary myeloma cells in SCID-hu mice and in coculture with osteoclasts

Contact Info

Product

Resources

About