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Mirca Lazzaretti

Publications and source records attributed to Mirca Lazzaretti.

9 recordsLinked to original sources
PubMed2006

CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival.

BACKGROUND AND OBJECTIVES: The chemokine receptor CXCR3, involved in chemotaxis, is expressed on normal and malignant B cells and plasma cells. Recent data suggest that CXCR3-binding chemokines may also regulate proliferation and survival in endothelial cells through the interaction with two distinct isoforms of CXCR3 (CXCR3-A and CXCR3-B). DESIGN AND METHODS: We evaluated the potential expression of CXCR3 isoforms in myeloma cells, also investigating whether CXCR3 expression is affected by cell cycle and apoptosis. Furthermore, we assessed the effect of CXCR3 activation on myeloma cell proliferation and survival. RESULTS: We found that CXCR3 is widely expressed on human myeloma cell lines and freshly purified myeloma cells. The presence of both CXCR3 isoforms, CXCR3-A and CXCR3-B, was observed in myeloma cells with different ratios of expression. Interestingly, we found that CXCR3 expression in myeloma cell was cell cycle dependent and that myeloma growth factors inhibited CXCR3 expression in myeloma cells. On the other hand, we found that FAS (CD95)-mediated apoptosis up-regulated CXCR3 expression. A similar behavior was observed for the CXCR3-binding chemokines. Finally we found that the activation of CXCR3 on myeloma cells by CXCL10/IP-10 partially blunted FAS-mediated apoptosis in myeloma cells that express CXCR3-A and that high concentrations of CXCL10/IP-10 inhibit myeloma cell proliferation. INTERPRETATION AND CONCLUSIONS Our data indicate that myeloma cells express the CXCR3 system with patterns correlated to cell cycle and apoptosis and that CXCR3 activation may affect myeloma cell survival and proliferation.

Cell Line, Tumor↗
PubMed2005

Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation.

Decreased bone formation contributes to the development of bone lesions in multiple myeloma (MM) patients. In this study, we have investigated the effects of myeloma cells on osteoblast formation and differentiation and the potential role of the critical osteoblast transcription factor RUNX2/CBFA1 (Runt-related transcription factor 2/core-binding factor Runt domain alpha subunit 1) in the inhibition of osteoblastogenesis in MM. We found that human myeloma cells suppress the formation of human osteoblast progenitors in bone marrow (BM) cultures. Moreover, an inhibitory effect on osteocalcin, alkaline phosphatase, collagen I mRNA, protein expression, and RUNX2/CBFA1 activity by human preosteoblastic cells was observed in cocultures with myeloma cells. The inhibitory effect was more pronounced in the cell-to-cell contact conditions compared with those without the contact and involved the very late antigen 4 (VLA-4) integrin system. Among the soluble osteoblast inhibitors screened, we show the potential contribution of interleukin-7 (IL-7) in the inhibitory effect on osteoblast formation and RUNX2/CBFA1 activity by human myeloma cells in coculture. Finally, our in vitro results were supported in vivo by the finding of a significant reduction in the number of Runx2/Cbfa1-positive cells in the BM biopsies of patients with MM who had osteolytic lesions compared with those who did not have bone lesions, suggesting the critical involvement of RUNX2/CBFA1 in the decreased bone formation in MM.

Alkaline Phosphatase↗
PubMed2005

Effect of the macrolide antibacterial drug, tylosin, on TNBS-induced colitis in the rat.

Bacterial antigens, such as intestinal microflora, are known to play a role in the pathogenesis of human inflammatory bowel disease (IBD). Tylosin, a macrolide antimicrobial agent, has proven to be effective in cat and dog chronic colitis, but the reasons underlying this efficacy are still unclear. In the present study we evaluated the effects of tylosin on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in the rat, in comparison with the antibacterial drug metronidazole and the corticosteroid budesonide. Colitis was induced by a single intrarectal administration of 10 mg TNBS under light ether anesthesia. Tylosin (20 mg/kg twice a day), metronidazole (160 mg/kg twice a day) and budesonide (500 microg/kg once a day) were given orally for up to 6 days to separate groups of rats. The animals were sacrificed after 6 days and colonic lesions evaluated (colon weight, macroscopic and histologic damage, myeloperoxidase activity). Tylosin and metronidazole significantly lowered macroscopic lesion score, reduced colon weight, the severity of histologic lesions and myeloperoxidase activity; budesonide did not significantly change the parameters of colonic inflammation. These data indicate a protective effect of tylosin against intestinal inflammation, suggesting a major role for bacteria, anaerobes in particular, in the development of TNBS-induced mucosal damage.

Animals↗
PubMed2005

P53, bcl-2 and Ki-67 expression in adenoid cystic carcinoma of the palate. A clinico-pathologic study of 21 cases with long-term follow-up.

Adenoid cystic carcinoma (ACC) is an indolent tumor that pursues a protracted clinical course with recurrences and late metastases. The aim of this study was to investigate immunohistochemically the expression of p53, bcl-2 protein, and Ki-67 in 21 cases of ACC of the palate, all with a minimum of 10 years and a maximum of 22 years of clinical follow-up. These results were also analyzed with regard to different clinical prognoses of the histologic subtypes of ACC. High expression of p53 and bcl-2 was noted in 19 out of 21 ACC cases (90%), in which most tumor cells (from 66% to 99%) proved to be immunopositive. A relation to the histologic types, clinical staging, and survival was not found. Therefore, the high immunoreactivity against these oncoproteins in the same tumor cells suggests that these two oncogenes may be involved since the early stage of carcinogenesis. Loss of function of the p53 protein combined with bcl-2 upregulation might give the tumor cells a double growth advantage, because uncontrolled proliferation is combined with a reduced cell death rate. The interaction with other oncogenes may then trigger a multistep process able to promote tumor progression. The low labeling index Ki-67 was detected in nine out of 21 cases (42%), with a low percentage of tumor cells (from 3% to 15%) being positive, whereas the remaining 12 cases were negative. We found no relation to the histologic types, clinical staging, and survival; however, the low proliferation rate could explain the natural course of tumor.

Adult↗
PubMed2004

OPG/RANKL system imbalance in a case of hepatitis C-associated osteosclerosis: the pathogenetic key?

Hepatitis C-associated osteosclerosis (HCAO) is an impressive example of acquired diffuse osteosclerosis in adults, recently described in ten patients infected with hepatitis C virus (HCV). Its hallmark is a painful and generalized increase of bone mass. Bone biopsies show enhanced accretion rate, usually without histological abnormalities. The HCAO pathogenesis is hitherto unknown. HCV might induce a slow bone cell infection and the production of bone growth factors, such as insulin-like growth factors. Recently, receptor activator of nuclear factor-kappaB (RANK), its ligand (RANKL), and soluble decoy receptor osteoprotegerin (OPG) have been identified as a pivotal cytokine system in the bone remodeling control. We describe the 11th case of HCAO. Notably, the patient's bone biopsy showed the presence of a high number of OPG-positive osteoblasts, a slight increase of RANKL-positive stromal cells, and a dramatic reduction of the osteoclasts. Moreover, OPG serum levels were increased. These findings reported here for the first time are consistent with a pathogenetic role of the OPG/RANKL system imbalance in HCAO.

Absorptiometry, Photon↗
PubMed2003

Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis.

Patients with multiple myeloma (MM) have increased bone marrow (BM) angiogenesis; however, the proangiogenic properties of myeloma cells and the mechanisms of MM-induced angiogenesis are not completely clarified. The angiopoietin system has been identified as critical in the regulation of vessel formation. In this study we have demonstrated that myeloma cells express several proangiogenic factors, and, in particular, we found that angiopoietin-1 (Ang-1), but not its antagonist Ang-2, was expressed by several human myeloma cell lines (HMCLs) at the mRNA and the protein levels. In a transwell coculture system, we observed that myeloma cells up-regulated the Ang-1 receptor Tie2 in human BM endothelial cells. Moreover, in an experimental model of angiogenesis, the conditioned medium of HMCLs significantly stimulated vessel formation compared with control or vascular endothelial growth factor (VEGF) treatment. The presence of anti-Tie2 blocking antibody completely blunted the proangiogenic effect of XG-6. Finally, our in vitro results were supported by the in vivo finding of Ang-1, but not Ang-2, mRNA and protein expression in purified MM cells obtained from approximately 47% of patients and by high BM angiogenesis in patients with MM positive for Ang-1, suggesting that the angiopoietin system could be involved, at least in part, in MM-induced angiogenesis.

Adult↗
PubMed2002

Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease.

The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-kappaB ligand (RANKL), and interferon gamma (IFN-gamma) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti-interleukin 6 (anti-IL-6) or anti-IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-gamma by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell-free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 microg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.

Aged↗