Wen Ling's scientific contributionswhile working at University of Arkansas at Little Rock (Little Rock, United States) and other institutions
- Abstract: Word Count: 196
- Abstract: Multiple myeloma (MM) growth in the bone marrow is associated with increased osteoclast activity and a reduced number of osteoblasts. Experimental studies suggest that bone disease drives the progression of MM. Whereas those studies focused on the critical role of myeloma-induced osteoclastogenesis in disease progression, little is known about the impact of osteoblasts and increased bone formation on MM. We investigated the effect of isolated osteoblasts and osteoclasts on survival and... Show More
- Abstract: Dickkopf-1 (DKK1), a soluble inhibitor of Wnt signaling secreted by multiple myeloma (MM) cells contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. In this study, we tested the effect of anti-DKK1 therapy on bone metabolism and tumor growth in a SCID-rab system. SCID-rab mice were engrafted with primary MM cells expressing varying levels of DKK1 from 11 patients and treated with control and DKK1-neutralizing antibodies for 4 to 6 weeks. Whereas bone... Show More
- Abstract: Multiple myeloma (MM), a hematologic malignancy of terminally differentiated plasma cells is closely associated with induction of osteolytic bone disease, induced by stimulation of osteoclastogenesis and suppression of osteoblastogenesis. The ubiquitin-proteasome pathway regulates differentiation of bone cells and MM cell growth. The proteasome inhibitor, bortezomib, is a clinical potent antimyeloma agent. The main goal of this study was to investigate the effect of bortezomib on... Show More
- Abstract: Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast-induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured alone or cocultured with myeloma cells, and tested the effects of DASH inhibitor, PT-100, on myeloma cell growth, bone disease, osteoclast... Show More
- Abstract: Fenretinide (4HPR), a nontoxic analog of ATRA, has been investigated in various malignancies but not in multiple myeloma (MM), a plasma cell malignancy associated with induction of osteolytic bone disease. Here we show that 4HPR induces apoptosis through increased level of ROS and activation of caspase-8, 9 and 3, and inhibits growth of several MM cell lines in a dose-dependent manner. Serum or co-culture with the supportive osteoclasts partially protects MM cells from 4HPR-induced growth... Show More
- Abstract: Myeloma bone disease is caused by uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Bidirectional signaling between the cell-surface ligand ephrinB2 and its receptor, EphB4, is involved in the coupling of osteoblastogenesis and osteoclastogenesis and in angiogenesis. EphrinB2 and EphB4 expression in mesenchymal stem cells (MSCs) from myeloma patients and in bone cells in myelomatous bones was lower than in healthy counterparts. Wnt3a induced up-regulation of EphB4... Show More
- Abstract: Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates. We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary... Show More
Data: Table S1Abstract: Genes whose expression was significantly upregulated or downregulated by PTH treatment in whole human bone from SCID-hu mice. SCID-hu mice engrafted with Hg myeloma cells were treated with saline or PTH for 4 weeks. Mice were sacrificed 2 hours after the last injection. RNA extracted from the whole myelomatous human bone (five bones/group) was subjected to global gene expression profiling. Positive (POS) or negative (NEG) expression of those genes in Hg myeloma cells is indicated to assess... Show More
- Abstract: Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not... Show More
- Abstract: Iron overload is a significant clinical feature in multiple myeloma (MM) and has been implicated in osteoporosis. MM patients also frequently suffer from anemia presumably due to elevated hepcidin secretion and dysfunctional erythropoiesis. The aims of the study were to shed light on molecular mechanisms associated with iron overload in MM cells and study the effect of the novel iron chelator, Dp44mT, on MM cell growth, osteoclastogenesis and MM bone disease in vitro and in vivo. In our... Show More
- Abstract: The cytotherapeutic potential of mesenchymal stem cells (MSCs) has been evaluated in various disorders including those involving inflammation, autoimmunity, bone regeneration, and cancer. Multiple myeloma (MM) is a systemic malignancy associated with induction of osteolytic lesions that often are not repaired even after prolonged remission. The aims of this study were to evaluate the effects of intrabone and systemic injections of MSCs on MM bone disease, tumor growth, and tumor regrowth in... Show More
Conference Paper: HMOX1 Is a Targeted Therapy for Myeloma-Induced Bone Disease.
- Abstract: Multiple myeloma (MM) cells typically grow in focal lesions, stimulating osteoclasts that destroy bone and support MM. Osteoclasts and MM cells are hypermetabolic. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) not only is essential for cellular metabolism but also affects activity of NAD-dependent enzymes, such as PARP-1 and SIRT-1. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin, encoded by PBEF1) is a rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide.... Show More
- Abstract: Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)-6- or stroma-dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and... Show More
- Abstract: Anthropogenic soil contamination has become a worldwide environmental problem in the past decades. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants in soil contaminated with crude oil, creosote, and coal tar. They are generated and dispersed into the environment by fossil fuel combustion, wood treatment processes, automobile exhaust, and waste incineration. The effect and fate of PAHs in soil is of great environmental and human health concern because of the... Show More
- Abstract: Bruton's tyrosine kinase (BTK) and the chemokine receptor CXCR4 are linked in various hematologic malignancies. The aim of the study was to understand the role of BTK in myeloma cell growth and metastasis using the stably BTK knockdown luciferase-expressing INA6 myeloma line. BTK knockdown had reduced adhesion to stroma and migration of myeloma cells toward stromal cell-derived factor-1. BTK knockdown had no effect on short-term in vitro growth of myeloma cells, although clonogenicity was... Show More
Publications citing this author (722)
[Show abstract] [Hide abstract] ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. Copyright © 2015. Published by Elsevier Inc.
- As a therapy for multiple myeloma , this strategy has yielded conflicting conclusions, with in vivo efficacy depending on the model system and treatments used. Some mouse models, such as the patient xenograft SCID-hu model, demonstrated that osteoanabolic treatments hold promise for inhibiting multiple myeloma , although results were highly variable and patient-specific . There is mounting evidence that the anti-myeloma proteasome inhibitors carfilzomib  and bortezomib  have bone anabolic effects on bone and induce osteogenic differentiation of MSCs, which may contribute to their anti-myeloma effects , but concrete evidence remains elusive to demonstrate that these agents can produce anti-myeloma effects via changes in the bone microenvironment.
[Show abstract] [Hide abstract] ABSTRACT: Multiple myeloma (MM) bone disease is a major cause of morbidity and mortality in MM patients and persists even in patients in remission. This bone disease is caused by an uncoupling of bone remodeling, with increased osteoclast and decreased osteoblast activity and formation, culminating in lytic bone destruction. Bisphosphonates are the current standard of care but new therapies are needed. As the molecular mechanisms controlling MM bone disease are increasingly well understood, new therapeutic targets are extensively explored in the preclinical setting and initial clinical trials with novel compounds now show promising results. In this review, we will provide a comprehensive overview of the biology of MM bone disease, summarize its current clinical management and discuss preclinical and clinical data on next generation therapies.
- Other dual effect factors for which further exploration as therapeutic targets is warranted include 2DDR, MIP-1a, TNF-a, HGF, IL-3 and GDF15. Finally, many of the previously described factors involved in the biology of MM bone disease have been targeted via different means in different murine MM models, including ephrinB2/ ephB4, adiponectin, MIP-1aand its receptor C–C motif chemokine receptor 1 (CCR1), BAFF, notch, insulin-like growth factor 1 (IGF-1)and TGF-b. In all these studies, an inhibition of MM bone disease was observed warranting further exploration of these strategies in clinical trials.
[Show abstract] [Hide abstract] ABSTRACT: Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal, neoplastic disorder of the hematopoietic stem cells, in which inflammation and immune dysregulation play an important role. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), also known as visfatin, is a cytokine implicated in a number of inflammatory and neoplastic diseases. Here we examined plasma levels of eNAMPT in patients with MPN-associated myelofibrosis and their effects on disease phenotype and outcomes. We also studied the concordance of eNAMPT levels with the marker of general inflammation high-sensitivity C-reactive protein (hs-CRP). A total of 333 MPN-associated myelofibrosis patients (187 males and 146 females) and 31 age- and gender-matched normal-weight healthy subjects were enrolled in the study main body. Levels of eNAMPT and hs-CRP were simultaneously assayed in 209 MPN-associated myelofibrosis patients. Twenty-four polycythemia vera or essential thrombocythemia patients were used as controls. eNAMPT was over expressed in MPN-associated myelofibrosis, and eNAMPT expression was correlated with higher white blood cell count, higher hemoglobin and higher platelet count, suggesting that eNAMPT is an indispensable permissive agent for myeloproliferation of MPN-associated myelofibrosis. The lack of correlation between eNAMPT and hs-CRP revealed that eNAMPT in MPN-associated myelofibrosis does not behave as a canonical inflammatory cytokine. In addition, higher levels of eNAMPT predicted longer time to blast transformation, and protected against progression towards thrombocytopenia and large splenomegaly. In conclusion, in MPN-associated myelofibrosis high levels of eNAMPT mark the myeloproliferative potential and, at variance with a high number of cancers, are protective against disease progression. This article is protected by copyright. All rights reserved.
- Accordingly, anemia, leucopenia, and thrombocytopenia in MPN-associated myelofibrosis did not imply a defective NAMPT production: as a matter of fact, the concentration of eNAMPT dropped in cases with a myelodepletive phenotype, but was still in the range of the control normal group. This interpretation is in line with the results in primary myeloma cell culture that documented NAMPT being indispensable for cell growth . In this study we documented that, at variance from healthy controls, higher eNAMPT levels in MPN-associated myelofibrosis patients had also strong relationship with younger age.
[Show abstract] [Hide abstract] ABSTRACT: Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease.
- In myeloma, up-regulation of BTK leads to increased bone resorption and homing of MM cell to the BM . Recent findings from our group have strongly implicated BTK in MMSC maintenance and drug resistance pathways [62, 64]. Thus, we found that BTK levels in putative MMSCs are significantly higher than in bulk myeloma cells.
- Therapeutics), described as culture expanded mesenchymal-like cells, which are CD34-negative and CD10, CD200, and CD105-positive (Li et al. 2011; He et al. 2013). @BULLET HPDSC (human placenta–derived stem cells produced by Celgene Cellular Therapeutics).
- En igual sendo, la administración de sitaglipn a ratas con tumor de queranocitos reduce el crecimiento tumo‐ ral en individuos afectados y, en conjunción a IL‐2α, disminuye la incidencia o retarda la aparición del tu‐ mor en individuos sanos (Arwert et al. 2012). El inhibi‐ dor PT100 (Val‐boro‐Pro) (Fig. 2), no selecvo para los miembros de la familia de DPP‐IV, reduce el creci‐ miento de líneas tumorales humanas derivadas de fibrosarcoma, linfoma, melanoma, mastocitoma (Adams et al. 2004) y mieloma (Pennisi et al. 2009). En estudios más recientes, PT‐100 y ARI‐4175 se ha demostrado que estos compuestos sobrerregulan la expresión de citoquinas y/o quimiocinas, modulan el tráfico de células dendrícas y células inmunorregula‐ torias y acvan o aceleran respuestas inmunitarias dependientes de células T contra tumores sólidos (Walsh et al. 2013, Duncan et al. 2013).
[Show abstract] [Hide abstract] ABSTRACT: Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas. Recently the regulatory role of the bone marrow microenvironment or niche has also become increasingly recognised. The interface between the bone and bone marrow (endosteum) and the region surrounding the blood vessels (perivascular) provide distinct niches harbouring quiescent HSC or proliferative HSC respectively. Current chemotherapeutic regimes can often successfully target the proliferative HSC but disease relapse occurs due to residual quiescent HSC. Understanding these developmental and regulatory processes and the associated cell communication mechanisms are thus crucial to the development of new treatment strategies. The CCN family of proteins have been recognised to play a key role in all aspects of haematopoiesis.
- This study suggests that increasing CCN1 levels in the BM microenvironment may offer an approach to delay the progression of MGUS/SMM to active MM, as well as enhancing survival of patients with active myeloma. In support of this theory, Li (Li et al. 2012) reported that intrabone injection of mesenchymal stem cells, expressing high levels of bone remodelling proteins such as CCN1, prevented MM-induced bone disease, promoted osteoblast maturation, suppressed osteoclast formation and inhibited MM cell growth in a preclinical model of MM. While the role of CCN1 in MM is not yet fully unravelled, overall the evidence to date suggests that CCN1 could provide a therapeutic strategy for treating MM bone disease.
[Show abstract] [Hide abstract] ABSTRACT: The growth of myeloma cells depends on bone marrow (BM) stroma consisting of stromal cells, secreted cytokines and the extracellular matrix (ECM). Decorin, a small leucine-rich proteoglycan in the ECM, is a signaling ligand and native anti-tumor agent. However, the role of decorin in patients with myeloma is not clear. We evaluated the correlation between the decorin levels measured by enzyme-linked immunosorbent assay in BM plasma from 121 patients with newly diagnosed myeloma based on their clinical features and treatment response. The median decorin levels in the patients and the normal control group were 12.31 ng/mL [standard deviation (SD), 7.50 ng/mL; range, 2.45 to 44.46 ng/mL] and 10.31 ng/mL (SD, 2.42 ng/mL; range, 4.85-15.14 ng/mL), respectively (P < 0.001). Using 15.15 ng/mL as a cut-off, 46 patients (38%) exhibited higher decorin levels (H-DCN), whereas the other patients exhibited normal to lower decorin levels (NL-DCN). Except for the median age, which was significantly younger in the H-DCN than in the NL-DCN group (60.6±14.0 vs. 65.8±12.2 years, respectively; P = 0.034), there were no differences between the two groups. However, in 79 patients who had received novel agent-based induction, the overall response rate was significantly better in the H-DCN than in the NL-DCN (97 vs. 63%, respectively; P < 0.001), as was the depth of responses (P = 0.008), which were not observed in those who had received chemotherapeutic agents alone. Progression-free survival (PFS) was significantly longer in H-DCN than NL-DCN (not reached vs. 19.5 mo, respectively; P = 0.0003). Multivariate analyses indicated that H-DCN, as a significantly independent factor, was associated with better treatment response (odds ratio, 20.014; 95% CI, 2.187-183.150; P = 0.008) and longer PFS (hazard ratio, 0.135; 95% CI, 0.051-0.361; P < 0.001). These findings disclose the potential role of decorin in myeloma and provide a basis for further study on possible synergistic anti-myeloma effects between decorin and the novel agents that target BM stroma.
- Although decorin may sequester TGF-β in the ECM, it was recently reported that TGF-β might induce decorin downregulation through micro RNA-181b . By contrast, decorin has been reported to be upregulated by the parathyroid hormone and certain demethylating agents  . Intriguingly , the PIs (e.g., BTZ, CFZ) have been demonstrated to increase decorin expression in OBs .
[Show abstract] [Hide abstract] ABSTRACT: Successful management of metastatic breast cancer still needs better chemotherapeutic approaches. The combination of fenretinide (4-HPR), a synthetic retinoid inducing apoptosis by ROS generation, and TRAIL, a cell death ligand inducing caspase-dependent apoptosis, might result in more powerful cytotoxic activity. We therefore investigated the cytotoxic activity and resulting cell death mode of this combination in MDA-MB-231 cell line as a representative of metastatic state. Cytotoxicity was assessed by the ATP viability assay while the mode of cell death was determined both morphologically using fluorescence microscopy and biochemically using Western blotting and ELISA. The combination resulted in an additive cytotoxic effect at the doses used. Fragmented and/or pyknotic nuclei, which is a feature of apoptosis, were observed after treatment with fenretinide or TRAIL. However, the combinatorial treatment further increased apoptotic figures. Confirming apoptosis, active caspase-3 and cleaved PARP were increased by fenretinide or TRAIL in both western blotting and ELISA. Again, apoptosis was further increased by the combination. The combination warrants further studies due to its superior cytotoxic activity in the metastatic setting of breast cancer.
- The synthetic retinoid, fenretinide (N-(4-hydro- xyphenyl) retinamide, 4-HPR) is one the most studied retinoids due to its low toxicity . Because of this low toxicity profile fenretinide has been studied for its activity on distinct types of cancer cell lines including skin , breast , lung , ovarian  and pancreatic  cancer cell lines, multiple myeloma  and neuroblastoma  cell lines. Fenretinide is also widely used in chemoprevention studies in vitro and in vivo and it is an advantageous compound in breast cancer chemoprevention because of its selective uptake in the mammary gland .