1,721,024 research outputs found
Cancer associated fibroblasts in hematological malignancies
No full textTumor microenvironment plays an important role in cancer initiation and progression. In hematological malignancies, the bone marrow represents the paradigmatic anatomical site in which tumor microenvironment expresses its morphofunctional features. Among the cells participating in the composition of this microenvironment, cancer associated fibrobasts (CAFs) have received less attention in hematopoietic tumors compared to solid cancers. In this review article, we discuss the involvement of CAFs in progression of hematological malignancies and the potential targeting of CAFs in a therapeutic perspective
In vitro and in vivo antitumor activity of the novel derivatized polyvinyl alcohol-based polymer P10(4).
No full textLaboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
PURPOSE: The major limitation to successful chemotherapy of neuroblastoma is the
toxicity of traditional antitumor drugs. Hence, less toxic and more effective
drugs are to be found, and novel formulations of conventional compounds allowing
a more favorable biodistribution should be sought for. In an attempt to pursue
this task, we recently synthesized an amphiphilic polymer based on a polyvinyl
alcohol backbone [P10(4)]. EXPERIMENTAL DESIGN: The cytotoxic activity of P10(4)
was evaluated both in vitro on neuroblastoma and melanoma cell lines and in vivo
in pseudometastatic neuroblastoma models. Apoptosis was assessed by morphology,
cytofluorimetric analysis of DNA content, and DNA fragmentation assay. Caspases
activation was investigated by kits specific for caspase-1, caspase-2,
caspase-3, caspase-4, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10,
and caspase-13. Colony formation was evaluated by soft agar assay. RESULTS:
P10(4) exerted a potent cytotoxic activity on different neuroblastoma and
melanoma cell lines through induction of both extrinsic and intrinsic caspase
cascades and subsequent apoptosis. Moreover, the clonogenic potential of cells
that survived P10(4) treatment was strongly reduced. Next, we tested the effects
of P10(4) in nude mice injected with both a human and a murine neuroblastoma
cell lines i.v. P10(4) significantly increased the life span and the long-term
survival of treated mice over controls. No side effects were observed, even at
doses higher than those used for therapeutic purposes. CONCLUSIONS: Our data
suggest that P10(4) holds promise as an anticancer compound and, because of its
lack of interaction with DNA, is unlikely to give rise to drug resistance
Immunosuppressive cells and tumour microenvironment: Focus on mesenchymal stem cells and myeloid derived suppressor cells
No full textTumours have been compared to unhealed wounds that produce large amounts of inflammatory mediators, including cytokines, chemokines, and growth factors. These molecules participate in the formation of a rich and heterogeneous microenvironment by attracting non malignant cells that promote tumour progression and dissemination. Tumour infiltrating cells include macrophages, myeloid-derived suppressor cells (MDSCs), mesenchymal stromal cells (MSCs) and TIE2-expressing monocytes. Most of them are bone marrow-derived, although MSC are present in virtually every tissue. This review focuses on MDSCs and MSCs, both of which can exert pro-tumorigenic effects through egative regulation of immune responses. MDSCs represent a heterogeneous population of cells of myeloid origin that are expanded and activated in response to growth factors and cytokines released by tumours. Once MDSCs are activated, they accumulate in lymphoid organs and tumours where they exert T cell immunosuppression. Like MDSCs, MSCs can be mobilized from the bone marrow into the bloodstream and home in the tumour stroma, where they either help or hinder tumour growth. Here, we will discuss the origin, the functions and the mechanisms of action of MSCs and MDSCs, as well as the strategies to target these cells for the therapeutic benefit of cancer patients
Cytokines in neuroblastoma: From pathogenesis to treatment
No full textCytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment. These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis. IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-? can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis. On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies. These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy. © 2011 Future Medicine Ltd
Delivery of c-myb antisense oligodeoxynucleotides to human neuroblastoma cells via disialoganglioside GD(2)-targeted immunoliposomes: antitumor effects
Full text linkBACKGROUND:Advanced-stage neuroblastoma resists conventional treatment; hence, novel therapeutic approaches are required. We evaluated the use of c-myb antisense oligodeoxynucleotides (asODNs) delivered to cells via targeted immunoliposomes to inhibit c-Myb protein expression and neuroblastoma cell proliferation in vitro.METHODS:Phosphorothioate asODNs and control sequences were encapsulated in cationic lipid, and the resulting particles were coated with neutral lipids to produce coated cationic liposomes (CCLs). Monoclonal antibodies directed against the disialoganglioside GD(2) were covalently coupled to the CCLs. (3)H-labeled liposomes were used to measure cellular binding, and cellular uptake of asODNs was evaluated by dot-blot analysis. Growth inhibition was quantified by counting trypan blue dye-stained cells. Expression of c-Myb protein was examined by western blot analysis.RESULTS:Our methods produced GD(2)-targeted liposomes that stably entrapped 80%-90% of added c-myb asODNs. These liposomes showed concentration-dependent binding to GD(2)-positive neuroblastoma cells that could be blocked by soluble anti-GD(2) monoclonal antibodies. GD(2)-targeted liposomes increased the uptake of asODNs by neuroblastoma cells by a factor of fourfold to 10-fold over that obtained with free asODNs. Neuroblastoma cell proliferation was inhibited to a greater extent by GD(2)-targeted liposomes containing c-myb asODNs than by nontargeted liposomes or free asODNs. GD(2)-targeted liposomes containing c-myb asODNs specifically reduced expression of c-Myb protein by neuroblastoma cells. Enhanced liposome binding and asODN uptake, as well as the antiproliferative effect, were not evident in GD(2)-negative cells.CONCLUSIONS:Encapsulation of asODNs into immunoliposomes appears to enhance their toxicity toward targeted cells while shielding nontargeted cells from antisense effects and may be efficacious for the delivery of drugs with broad therapeutic applications to tumor cells
CXCL12 does not attract CXCR4(+) human metastatic neuroblastoma cells: Clinical implications
No full textPURPOSE: The role of CXCR4 in bone marrow localization of neuroblastoma cells has been recently proposed. The aim of this study was to investigate the expression and chemotactic functionality of CXCR4 in human metastatic neuroblastoma cells isolated from the bone marrow and, for comparison, in a panel of neuroblastoma cell lines.
EXPERIMENTAL DESIGN: CXCR4 expression and chemotactic functionality were investigated in metastatic neuroblastoma cells isolated from patient bone marrow and in neuroblastoma cell lines. The former cells were isolated as CD45- or GD2+ cells by immunomagnetic bead manipulation. Chemotactic assays were done in a transwell system. Regulator of G protein signaling expression was investigated by reverse transcription-PCR.
RESULTS: Metastatic neuroblastoma cells consistently expressed CXCR4, which was also detected in 5 of 10 neuroblastoma cell lines. CXCL12 did not stimulate the chemotaxis of primary tumor cells or cell lines in either normoxia or hypoxia, irrespective of CXCR4 up-regulation detected under the latter condition. Accordingly, neuroblastoma cells failed to modulate filamentous actin and to activate mitogen-activated protein kinase upon treatment with CXCL12. RGS16 mRNA was consistently expressed in primary tumor cells and cell lines, but its down-regulation by RNA interference did not restore CXCR4 chemotactic functionality.
CONCLUSIONS: These results show unambiguously that CXCR4 expressed in human metastatic neuroblastoma cells is not functional and do not support the clinical use of CXCR4 antagonists to prevent neuroblastoma metastasis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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