RESUMO
Invasive fungal infections (IFIs), mainly due to pulmonary aspergillosis, are considered a serious complication in acute leukaemia, with an unfavourable impact on patient. In this well-conducted retrospective study, Reynolds et al. suggest that the use of posaconazole prophylaxis in association with venetoclax plus hypomethylating agents or chemotherapy leads to a reduction of IFI incidence. Therapeutic drug monitoring of posaconazole levels is suggested, even if no correlation with IFI risk has been demonstrated. Commentary on: Reynolds et al. Invasive fungal infection following venetoclax and posaconazole co-administration. Br J Haematol 2023;203:593-598.
Assuntos
Infecções Fúngicas Invasivas , Leucemia Mieloide Aguda , Humanos , Antifúngicos/uso terapêutico , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/complicações , Infecções Fúngicas Invasivas/tratamento farmacológicoRESUMO
Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.
Assuntos
Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Rituximab/uso terapêutico , Consenso , Ciclofosfamida/uso terapêutico , Cloridrato de Bendamustina/uso terapêuticoRESUMO
Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche.
Assuntos
Medula Óssea/imunologia , Citocinas/imunologia , Modelos Imunológicos , Mieloma Múltiplo/imunologia , Animais , HumanosRESUMO
Spontaneously arising tumor cells are not usually angiogenic at first. The phenotypic switch to angiogenesis is usually accomplished by a substet that induces new capillaries that then converge toward the tumor. The switch clearly involves more than simple upregulation of angiogenic activity and is thought to be the result of a net balance of positive and negative regulators. Tumor growth is although to require disruption of this balance and hence this switch must turned on for cancer progression. Progenitor endothelial cells, the crosstalk between angiogenic factors and their receptors and the interaction between vasculogenesis and lymphangiogenesis are all factors that may contribute to the switch. Its promotion is also the outcome of genetic instability resulting in the emergence of tumor cell lines. This review describes the history of the angiogenic switch illustrated in the literature and with particular reference to the three transgenic mouse models, namely RIP1-TAG2, keratin-14 (K14) (human papilloma virus) HPV16 and papilloma virus, used for stage-specific assessment of the effects of antiangiogenic and antitumorigenic agents.
Assuntos
Neoplasias/irrigação sanguínea , Neovascularização Patológica , Animais , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Células da Medula Óssea/patologia , Transformação Celular Neoplásica , Modelos Animais de Doenças , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Queratina-14/genética , Queratina-14/metabolismo , Camundongos , Camundongos Transgênicos , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transdução de Sinais , Células-Tronco/patologia , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/genética , Interferência de RNA , Proteínas de Ligação a RNA/genética , Animais , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Genes myc , Xenoenxertos , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Proteínas de Ligação a RNA/metabolismoRESUMO
The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.
Assuntos
Medula Óssea/metabolismo , Matriz Extracelular/metabolismo , Mieloma Múltiplo/metabolismo , Proteoma , Anexina A2/metabolismo , Estudos de Casos e Controles , Galectina 1/metabolismo , Perfilação da Expressão Gênica , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Análise de Sobrevida , Microambiente TumoralRESUMO
Brain edema and severe alterations of the glial and endothelial cells have recently been demonstrated in the dystrophin-deficient mdx mouse, an experimental model of Duchenne muscular dystrophy, and an increase in microvessel density in patients affected by Duchenne muscular dystrophy has also been shown. In order to further elucidate the mechanisms underlying the angiogenetic processes occurring in Duchenne muscular dystrophy, in this study we analyzed matrix-metalloproteinase-2 and -9 expression in the brain of 20-month-old mdx and control mice by means of immunohistochemistry, in situ hybridization, immunoblotting and gelatin zymography. Moreover, we studied vascular endothelial growth factor expression by means of Western blot and immunohistochemistry, and by dual immunofluorescence using anti-vascular endothelial growth factor and anti matrix-metalloproteinase-2 and-9 antibodies. Ultrastructural features of the brain choroidal plexuses were evaluated by electron microscopy. Spatial relationships between endothelium and astrocyte processes were studied by confocal laser microscopy, using an anti-CD31 antibody as a marker of endothelial cells, and anti-glial fibrillary acidic protein (GFAP) as a marker of glial cells. The results demonstrate that high expression of matrix-metalloproteinase-2 and matrix-metalloproteinase-9 protein content occurs in mdx brain and in choroidal plexuses where, by in situ hybridization, matrix-metalloproteinase-2 and matrix-metalloproteinase-9 mRNA was localized in the epithelial cells. Moreover, matrix-metalloproteinase-2 mRNA was found in both mdx perivascular astrocytes and blood vessels, while matrix-metalloproteinase-9 mRNA was localized in mdx vessels. Through zymography, increased expression of matrix-metalloproteinase-2 and matrix-metalloproteinase-9 was found in mdx brain compared with the controls. These enhanced matrix-metalloproteinase levels in mdx mice were found to be associated with increased vascular endothelial growth factor expression, as determined by immunoblotting and immunocytochemistry and with ultrastructural alterations of the mdx choroidal epithelial cells and brain vessels, as previously reported [Nico B, Frigeri A, Nicchia GP, Corsi P, Ribatti D, Quondamatteo F, Herken R, Girolamo F, Marzullo A, Svelto M, Roncali L (2003) Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. Glia 42:235-251]. Indeed, in the mdx epithelial cells of the plexuses, the apical microvilli were located on the lateral membranes, whereas in the controls they were uniformly distributed over the free ventricular surface. Moreover, by dual immunofluorescence, a colocalization of vascular endothelial growth factor and matrix-metalloproteinase-2 and matrix-metalloproteinase-9 was found in the ependymal and epithelial cells of plexuses in mdx mice and, under confocal laser microscopy, mdx CD-31 positive vessels were enveloped by less GFAP-positive astrocyte processes than the controls. Overall, these data point to a specific pathogenetic role of matrix-metalloproteinase-2 and matrix-metalloproteinase-9 in neurological dysfunctions associated with Duchenne muscular dystrophy.
Assuntos
Barreira Hematoencefálica/enzimologia , Encéfalo/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Microcirculação/enzimologia , Distrofia Muscular de Duchenne/enzimologia , Animais , Astrócitos/enzimologia , Astrócitos/patologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Plexo Corióideo/enzimologia , Plexo Corióideo/patologia , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Epêndima/enzimologia , Epêndima/patologia , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Microcirculação/patologia , Microcirculação/fisiopatologia , Microscopia Eletrônica de Transmissão , Microvilosidades/enzimologia , Microvilosidades/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Neovascularização Patológica/enzimologia , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , RNA Mensageiro/metabolismo , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.
Assuntos
Mieloma Múltiplo/patologia , Neovascularização Patológica/tratamento farmacológico , Animais , Anticorpos/uso terapêutico , Medula Óssea , Movimento Celular , Células Clonais/patologia , Progressão da Doença , Células Endoteliais/patologia , Camundongos , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Prevenção Secundária , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologiaRESUMO
Multiple myeloma (MM) progresses from an avascular to a vascular phase (active MM) accompanied by a significant increase in microvessel density in the bone marrow. This article summarizes the literature concerning the specific role played by vascular endothelial growth factor (VEGF) in this process. Recent applications of antiangiogenic agents that interfere with VEGF signaling and block MM progression are also described.
Assuntos
Fatores de Crescimento Endotelial/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Linfocinas/fisiologia , Mieloma Múltiplo/fisiopatologia , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Inibidores da Angiogênese/uso terapêutico , Progressão da Doença , Fatores de Crescimento Endotelial/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfocinas/genética , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Neovascularização Patológica , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.
Assuntos
Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Quimioterapia Combinada , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Receptores CXCR4/genética , Recidiva , Rituximab/administração & dosagem , Rituximab/efeitos adversosRESUMO
Factor VIII-related antigen (FVIII-RA)-positive microvessel areas were measured by both immunohistochemistry and computerized image analysis in patients with active multiple myeloma (MM), nonactive MM, and monoclonal gammopathies of undetermined significance (MGUS). A five-to sixfold larger area was found in patients with active MM compared to the other two groups. Aquaporin 1 (AQP1)-positive microvessel areas, measured with the same techniques on adjacent tissue sections, were also increased in active MM, and tended to be larger than and closely correlated with the FVIII-RA areas. Numerous mast cells were found in the bone marrow of active MM patients, and counts were strictly correlated with the microvessel density. The conditioned medium (CM) of bone marrow plasma cells from active MM patients stimulated endothelial cell proliferation and chemotaxis, monocyte chemotaxis, and angiogenesis in vivo (assessed by the chick embryo chorioallantoic membrane [CAM] system) more strongly and frequently than the CM of patients with nonactive MM and MGUS. Immunoassay of plasma cell lysates gave significantly higher levels of fibroblast growth factor-2 (FGF-2) in patients with active MM than in the other two groups, and a neutralizing anti-FGF-2 antibody inhibited by 46% to 68% the biological activity exerted by the CM in vitro and in the CAM. In situ hybridization of bone marrow plasma cells and zymography of CM showed that patients with active MM express higher levels of matrix metalloproteinase-2 (MMP-2) mRNA and protein than those with nonactive MM and MGUS, whereas MMP-9 expression and secretion overlapped in all groups. Overall data indicate that patients with active MM represent the vascular phase of plasma cell tumors that is induced, at least partly, through FGF-2 and MMP-2. Mast cells possibly contribute to the vascular phase via angiogenic factors in their secretory granules. Both angiogenesis and MMP-2 secretion can account for intramedullary and extramedullary spreading of plasma cells in patients with active MM.
Assuntos
Medula Óssea/irrigação sanguínea , Mieloma Múltiplo/patologia , Indutores da Angiogênese/metabolismo , Aquaporina 1 , Aquaporinas/metabolismo , Antígenos de Grupos Sanguíneos , Medula Óssea/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Técnicas Imunoenzimáticas , Mastócitos/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/metabolismo , Neovascularização Patológica , Paraproteinemias/metabolismo , Paraproteinemias/patologia , Prognóstico , Tromboplastina/metabolismoRESUMO
The bursa of Fabricius is a lymphoid organ of the chick which plays an important role in the development of the immune system. The role of angiogenic factors in the development of the vascular system of this organ has been poorly investigated. Vascular endothelial growth factor (VEGF) is a major regulator of endothelial cell proliferation, angiogenesis and vascular permeability, and its activities are mediated by two receptors, VEGFR-1 and VEGFR-2. In this study we have investigated by immunohistochemistry the VEGF and VEGFR-2 immunoreactivity in developing bursa of Fabricius. Starting from day 10 of incubation, the endodermal epithelium reacts with VEGF and gives rise to the lymphoid follicles, while the vascular endothelium reacts with VEGFR-2. These data support the view that VEGF acts as a paracrine stimulator of angiogenesis in the avian embryo and confirm the requirement of the endodermal layer for the normal formation of blood vessels by mesodermal cells.
Assuntos
Bolsa de Fabricius/irrigação sanguínea , Bolsa de Fabricius/crescimento & desenvolvimento , Fatores de Crescimento Endotelial/metabolismo , Linfocinas/metabolismo , Comunicação Parácrina/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/imunologia , Receptores de Fatores de Crescimento/metabolismo , Animais , Bolsa de Fabricius/imunologia , Embrião de Galinha , Ligantes , Neovascularização Fisiológica/imunologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Bone marrow microenvironment has been shown to play a crucial role in supporting the pathogenesis and the progression of several B-cell malignancies, including Waldenstrom's Macroglobulinemia (WM). Among the different cell types within the bone marrow milieu, endothelial cells have been proven to support WM cells growth. Based on the understanding of bone marrow neo-angiogenesis in plasma cell dyscrasias, a number of anti-angiogenic molecules are now available for the treatment of these diseases. Indeed, anti-angiogenic drugs, such as proteasome-, proteins kinase-C (PKC)-, phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR)-, and histone deacetylase (HDAC)- inhibitors are now available, playing a key role in the treatment of WM both in the preclinical settings and as part of clinical trials.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologia , Inibidores da Angiogênese/farmacologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Ácidos Borônicos/uso terapêutico , Bortezomib , Células Endoteliais/patologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Panobinostat , Inibidores de Proteases , Inibidores de Proteassoma , Proteína Quinase C/antagonistas & inibidores , Pirazinas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Microambiente TumoralRESUMO
The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ß-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
Assuntos
Antineoplásicos/uso terapêutico , Lactonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Inibidores de Proteassoma , Pirróis/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoAssuntos
Leucemia Linfocítica Crônica de Células B/etiologia , Mastócitos/enzimologia , Neovascularização Patológica/enzimologia , Serina Endopeptidases/análise , Medula Óssea/irrigação sanguínea , Estudos de Casos e Controles , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , TriptasesAssuntos
Mieloma Múltiplo/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Sobrevivência Celular , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Isoenzimas , Camundongos , Camundongos SCID , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
The ubiquitin-proteasome pathway (UPP) is the major non-lysosomal proteolytic system in the cytosol and nucleus of all eukaryotic cells. Bortezomib (also known as PS-341 and Velcade) is a proteasome inhibitor, a novel class of cancer therapies. Bortezomib blocks multi-ubiquitinated protein degradation by inhibiting 26S proteasome activity, including regulating cell cycle, anti-apoptosis, and inflammation, as well as immune surveillance. In multiple myeloma (MM) cells, bortezomib directly induces cell stress response followed by activation of c-Jun NH(2) terminal kinase (JNK)/stress-activated protein kinase (SAPK), and triggers caspase-dependent apoptosis of tumor cells. Recent clinical studies demonstrated that bortezomib had remarkable anti-tumor activity in refractory and relapsed MM, providing the basis to approval by FDA. Its anti-tumor activities earlier in the course, in combination therapies, and in other malignancies is ongoing.
Assuntos
Ácidos Borônicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Ubiquitina/metabolismo , Animais , Antineoplásicos/administração & dosagem , Bortezomib , Ensaios Clínicos como Assunto , HumanosRESUMO
Erythropoietin (Epo) is produced by the fetal liver and adult kidney and is an essential stimulator of erythropoiesis. It has, however, been shown to modulate host cellular signal transduction pathway to perform many other functions. New sites of Epo production have been found, such as the female reproductive organs and central nervous system. This review summarizes the involvement of Epo in the regulation of angiogenesis in both normal and pathological conditions.
Assuntos
Indutores da Angiogênese/farmacologia , Eritropoetina/fisiologia , Neovascularização Patológica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Encéfalo/irrigação sanguínea , Feminino , Genitália Feminina/irrigação sanguínea , Humanos , Neoplasias/irrigação sanguíneaRESUMO
Factor VIII-related antigen-positive microvessel areas were measured by both immunohistochemistry and computerized image analysis in patients with active multiple myeloma (MM), nonactive MM and monoclonal gammopathies of undetermined significance (MGUS). A 5- to 6-fold larger area was found in patients with active MM compared to the other two groups. The conditioned medium (CM) of their bone marrow plasma cells stimulated endothelial cell proliferation and chemotaxis, monocyte chemotaxis and angiogenesis in vivo [chick embryo chorioallantoic membrane (CAM) system] more strongly and frequently than the CM of patients with nonactive MM and MGUS. An immunoassay of plasma cell lysates gave significantly higher levels of fibroblast growth factor-2 (FGF-2) in patients with active MM than in the other two groups, and a neutralizing anti-FGF-2 antibody inhibited by 54-68% the biological activity exerted by the CM in vitro and in the CAM. In situ hybridization of bone marrow plasma cells and gelatin zymography of CM showed that patients with active MM express higher levels of matrix metalloproteinase-2 (MMP-2) mRNA and protein than those with nonactive MM and MGUS, whereas MMP-9 expression and secretion overlapped in all groups. Overall data suggest that patients with active MM represent the vascular phase of plasma cell tumors that is triggered by bone marrow plasma cells, at least partly, through FGF-2 and MMP-2. Both angiogenesis and MMP-2 secretion can account for intramedullary and extramedullary spreading of plasma cells during the active MM.
Assuntos
Medula Óssea/irrigação sanguínea , Mieloma Múltiplo/patologia , Neovascularização Patológica/patologia , Plasmócitos/patologia , Medula Óssea/patologia , Movimento Celular , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Mieloma Múltiplo/enzimologia , Invasividade Neoplásica , Plasmócitos/enzimologiaRESUMO
The current wisdom is that tumours are endowed with an angiogenic capability and that their growth, invasion and metastasis are angiogenesis dependent. It is now well documented that neoplastic cells are influenced by their microenvironment and vice versa. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion and survival. Tumour cells are surrounded by an infiltrate of inflammatory cells, namely lymphocytes, neutrophils, macrophages and mast cells (MCs), which communicate via a complex network of intercellular signalling pathways, mediated by surface adhesion molecules, cytokines and their receptors. This review article summarizes: (i) the MC mediators involved in angiogenesis; (ii) the experimental evidence concerning the role played by MCs in angiogenesis; (iii) the list of solid and haematological tumours in which a close relationship between angiogenesis, tumour progression and MCs has been demonstrated; (iv) the circumstances in which MCs are a critical source of angiogenic factors in vivo, and in such cases, the signals that regulate their production and secretion that need to be determined as a prelude to the elaboration of new therapeutic strategies associated with MC presence and activation.