Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients

Calabro, Anthony; Oken, Martin M.; Hascall, Vincent C.; Masellis, Anna M.

doi:10.1182/blood-2002-01-0030

Cited by 64 publications

(44 citation statements)

References 36 publications

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“…19,20 In particular, MM BMMSCs expressed less CD106 and fibronectin, and 2.8 times more IL1b as compared with normal BMMSCs 21 and showed abnormal synthesis of hyaluronan. 22,23 Taken together, these data suggest that MM BMMSCs differ from their normal counterparts. To address this question, we conducted studies in three complementary directions: gene expression profile (GEP) with microarray analysis, phenotypic and functional studies.…”

Section: Introductionmentioning

confidence: 81%

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

et al. 2007

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Recent literature suggested that cells of the microenvironment of tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression profiling and phenotypic and functional studies in three groups of individuals: patients with MM, patients with monoclonal gamopathy of undefined significance (MGUS) and healthy agematched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in an MM group. MGUS BMMSCs were interspersed between these two groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs, 46% may account for a tumor-microenvironment cross-talk. Known soluble factors implicated in MM pathophysiologic features (i.e. IL (interleukin)-6, DKK1) were revealed and new ones were found which are involved in angiogenesis, osteogenic differentiation or tumor growth. In particular, GDF15 was found to induce dosedependent growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an overgrowth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, MM BMMSCs are abnormal and could create a very efficient niche to support the survival and proliferation of the myeloma cells.

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Section: Introductionmentioning

confidence: 81%

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

et al. 2007

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“…These cells communicate through a complex series of molecular pathways including adhesion molecules, cytokines, chemokines, growth factors and their respective receptors that may be critical for disease progression. Previous studies suggest that bone marrow stromal cells (BMSCs) in myeloma patients differ from those of healthy donors [1][2][3][4]8,19,20]. We reported elsewhere that BMSCs of multiple myeloma patients, in comparison to a control, produced more IL-6, IL-10, TNF-α, HGF, OPN and BAFF in response to RPMI8226 cells [21].…”

Section: Introductionmentioning

confidence: 88%

A comparison of cytokine production in 2-dimensional and 3-dimensional cultures of bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells.

Zdzisińska

Roliński²,

Piersiak³

et al. 2009

Folia Histochem Cytobiol.

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Abstract:We examined cytokine production by bone marrow stromal cells (BMSCs) of patients with multiple myeloma (MM) in response to contact with myeloma RPMI8226 cells in standard 2-dimensional (2D) cultures and in 3-dimensional (3D) cultures on a gelatine sponge scaffold. It was detected that BMSCs in the 3D cultures produced more IL-11 and HGF and less IL-10 than in the 2D cultures. Moreover, RPMI8226 cells after contact with BMSCs in 3D cultures produced more sIL-6R than in the classic 2D cultures. We concluded that 3D cultures of BMSCs with myeloma cells offered a promising model for in vitro examination of interactions between myeloma cells and the bone marrow stroma and for examination of potent antimyeloma agents.

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“…MSCs express HA synthases as well as HA (17,18), which is a principal ligand of CD44. As such, we investigated whether HA could influence the survival of CLL cells.…”

Section: Rg7356 Directly Induces Apoptosis Of Cll Cells That Express mentioning

confidence: 99%

Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44

Zhang

Fecteau

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cell-surface glycoprotein receptor for hyaluronic acid. We found that a humanized mAb specific for CD44 (RG7356) was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. Moreover, RG7356 could induce CLL cells that expressed the zeta-associated protein of 70 kDa (ZAP-70) to undergo caspasedependent apoptosis, independent of complement or cytotoxic effector cells. The cytotoxic effect of this mAb was not mitigated when the CLL cells were cocultured with mesenchymal stromal cells (MSCs) or hyaluronic acid or when they were stimulated via ligation of the B-cell receptor with anti-μ. RG7356 induced rapid internalization of CD44 on CLL cells at 37°C, resulting in reduced expression of ZAP-70, which we found was complexed with CD44. Administration of this mAb at a concentration of 1 mg/kg to immune-deficient mice engrafted with human CLL cells resulted in complete clearance of engrafted leukemia cells. These studies indicate that this mAb might have therapeutic activity, particularly in patients with CLL that express ZAP-70.cell survival | preclinical studies | animal model | antibody therapy B -cell chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of mature, antigen-stimulated CD5+/ CD23+ B cells in blood, secondary lymphoid tissues, and marrow (1). Most of the circulating CLL cells in patients are arrested in the G0/G1 phase of the cell cycle and express high levels of antiapoptotic proteins (2). CLL therefore has been characterized as a process of defective apoptosis, rather than increased proliferation. However, despite their apparent longevity in vivo, CLL cells undergo spontaneous and drug-induced apoptosis in vitro, unless rescued by monocyte-derived Nurse-like cells (NLCs), follicular dendritic cells, or mesenchymal stromal cells (MSCs) (3-6). Thus, it has been postulated that CLL cells receive survival signals from these accessory cells, which constitute part of the CLL B-cell microenvironment in secondary lymphoid tissues and marrow (6). These survival signals can inhibit spontaneous or drug-induced apoptosis, particularly for CLL cells that express unmutated Ig heavy-chain variable genes (IGHVs) and/or the zeta-associated protein of 70 kDa (ZAP-70), which typically is not expressed by normal B cells (7). Patients with leukemia cells that possess such characteristics typically have a relatively short interval from diagnosis to initial therapy compared with patients with CLL cells that express mutated IGHVs or that lack expression of .One of the survival signals received by leukemia cells may be mediated via CD44, a surface glycoprotein receptor for the nonsulfated glycosaminoglycan hyaluronic acid (HA), which typically is found in the microenvironment of lymphoid tissues (13). CLL cells express high levels of CD44, particularly those that express unmutated IGHVs and/or . Upon binding HA in the extracellular matrix, CD44 activates the phosphoinositol 3-kinase (PI3K)/AKT and MAPK/ERK ...

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Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients

Cited by 64 publications

References 36 publications

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

A comparison of cytokine production in 2-dimensional and 3-dimensional cultures of bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells.

Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44

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