RESUMEN
Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.
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Tejido Adiposo/metabolismo , Adiposidad , Hormona Folículo Estimulante de Subunidad beta/antagonistas & inhibidores , Termogénesis , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo Beige/efectos de los fármacos , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Adiposidad/efectos de los fármacos , Animales , Anticuerpos/inmunología , Anticuerpos/farmacología , Dieta Alta en Grasa/efectos adversos , Femenino , Hormona Folículo Estimulante de Subunidad beta/inmunología , Haploinsuficiencia , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/prevención & control , Osteoporosis/tratamiento farmacológico , Ovariectomía , Consumo de Oxígeno/efectos de los fármacos , Receptores de HFE/antagonistas & inhibidores , Receptores de HFE/genética , Receptores de HFE/metabolismo , Termogénesis/efectos de los fármacos , Proteína Desacopladora 1/biosíntesisRESUMEN
Multiple myeloma is an incurable cancer of the bone marrow that is dependent on its microenvironment, including bone marrow adipocytes (BMAds). Here, we discuss our findings that the reciprocal interaction of myeloma cells and BMAds, leads to myeloma cell survival and induces metabolic dysfunction and senescence-associated secretory phenotype in BMAds.
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Adipocitos/patología , Mieloma Múltiple/patología , Adipocitos/metabolismo , Médula Ósea/metabolismo , Médula Ósea/patología , Supervivencia Celular , Humanos , Redes y Vías Metabólicas , Mieloma Múltiple/metabolismo , Microambiente TumoralRESUMEN
Multiple myeloma (MM) is a clonal plasma cell malignancy typically associated with the high and uniform expression of the CD38 transmembrane glycoprotein. Daratumumab is a humanized IgG1κ CD38 monoclonal antibody (MoAb) which has demonstrated impressive single agent activity even in relapsed refractory MM patients as well as strong synergy with other anti-MM drugs. Natural Killer (NK) cells are cytotoxic immune effector cells that mediate in vivo tumour immunosurveillance. NK cells also play an important role during MoAb therapy by inducing antibody dependent cellular cytotoxicity (ADCC) via their FcγRIII (CD16) receptor. Furthermore, 15% of the population express a naturally occurring variant of CD16 harbouring a single-point polymorphism (F158V). However, the contribution of NK cells to the efficacy of daratumumab remains debatable as clinical data clearly indicate the rapid depletion of CD38high peripheral blood NK cells in patients upon daratumumab administration. In contrast, CD38low peripheral blood NK cells have been shown to survive daratumumab mediated fratricide in vivo, while still retaining their potent anti-MM cytolytic effector functions ex vivo. Therefore, we hypothesize that transiently expressing the CD16F158V receptor using a "safe" mRNA electroporation-based approach on CD38low NK cells in combination with daratumumab could represent a novel therapeutic option for treatment of MM. In the present study, we investigate a NK cell line (KHYG-1), derived from a patient with aggressive NK cell leukemia, as a platform for generating CD38low NK cells expressing CD16F158V which can be administered as an "off-the-shelf" therapy to target both CD38high and CD38low tumour clones in patients receiving daratumumab.
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ADP-Ribosil Ciclasa 1/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Células Asesinas Naturales/inmunología , Mieloma Múltiple/tratamiento farmacológico , Receptores de IgG/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Línea Celular Tumoral , Humanos , Ratones , Mieloma Múltiple/genética , Mieloma Múltiple/patologíaRESUMEN
Aberrant glycosylation resulting from altered expression of sialyltransferases, such as ST3 ß-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the in vitro and in vivo effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3Fax-Neu5Ac delivered as a per-acetylated methyl ester pro-drug. Specifically, we show in vivo that 3Fax-Neu5Ac improves survival by enhancing bortezomib sensitivity in an aggressive mouse model of MM. However, 3Fax-Neu5Ac treatment of MM cells in vitro did not reverse bortezomib resistance conferred by bone marrow (BM) stromal cells. Instead, 3Fax-Neu5Ac significantly reduced interactions of myeloma cells with E-selectin, MADCAM1 and VCAM1, suggesting that reduced sialylation impairs extravasation and retention of myeloma cells in the BM. Finally, we showed that 3Fax-Neu5Ac alters the post-translational modification of the α4 integrin, which may explain the reduced affinity of α4ß1/α4ß7 integrins for their counter-receptors. We propose that inhibiting sialylation may represent a valuable strategy to restrict myeloma cells from entering the protective BM microenvironment, a niche in which they are normally protected from chemotherapeutic agents such as bortezomib. Thus, our work demonstrates that targeting sialylation to increase the ratio of circulating to BM-resident MM cells represents a new avenue that could increase the efficacy of other anti-myeloma therapies and holds great promise for future clinical applications.
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Mieloma Múltiple , Animales , Bortezomib , Moléculas de Adhesión Celular , Comunicación Celular , Selectina E/genética , Humanos , Ratones , Mucoproteínas , Mieloma Múltiple/tratamiento farmacológico , Sialiltransferasas/genética , Microambiente TumoralRESUMEN
PURPOSE OF THE REVIEW: The purpose of this review is to describe the in vitro and in vivo methods that researchers use to model and investigate bone marrow adipocytes (BMAds). RECENT FINDINGS: The bone marrow (BM) niche is one of the most interesting and dynamic tissues of the human body. Relatively little is understood about BMAds, perhaps in part because these cells do not easily survive flow cytometry and histology processing and hence have been overlooked. Recently, researchers have developed in vitro and in vivo models to study normal function and dysfunction in the BM niche. Using these models, scientists and clinicians have noticed that BMAds, which form bone marrow adipose tissue (BMAT), are able to respond to numerous signals and stimuli, and communicate with local cells and distant tissues in the body. This review provides an overview of how BMAds are modeled and studied in vitro and in vivo.
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Adipocitos , Tejido Adiposo , Células de la Médula Ósea , Médula Ósea , Animales , Técnicas de Cocultivo , Técnicas de Cultivo , Citometría de Flujo , Humanos , Técnicas In Vitro , Ratones , Modelos Biológicos , Conejos , RatasRESUMEN
Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.
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Densidad Ósea/efectos de los fármacos , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Fracturas Óseas/prevención & control , Osteocitos/química , Osteogénesis/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Animales , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Proteínas Morfogenéticas Óseas/inmunología , Línea Celular Tumoral , Difosfonatos/uso terapéutico , Marcadores Genéticos/inmunología , Humanos , Imidazoles/uso terapéutico , Ratones , Mieloma Múltiple/complicaciones , Células Tumorales Cultivadas , Ácido ZoledrónicoRESUMEN
Carbon nanotubes (CNTs) hold great potential as drug delivery transporters given their large drug-binding surface area. Herein, we designed novel, multi-walled, discrete CNTs (dMWCNTs), PEGylated dMWCNTs (PEG-dMWCNTs), and bone-targeting (BT), alendronate-conjugated PEG-dMWCNTs (BT-PEG-dMWCNTs). Using zeta potential, thermogravimetric analysis, TEM, SEM, and FTIR, dMWCNTs were characterized as individual, uniform, and stable. Drug binding and release assays validated dMWCNTs as effective doxorubicin (DOX) transporters. The mass ratio of DOX loading onto dMWCNTs was 35% wt/wt with a ~95% wt/wt efficiency. DOX release was ~51% w/w after 48 hours. Neoplastic transformation, chromosomal aberration, and cytotoxicity assays, confirmed biocompatibility for all dMWCNTs. PEG-dMWCNTs were well tolerated and modulated drug pharmacokinetics in mice. In mice with Burkitt's lymphoma, DOX-loaded PEG-dMWCNTs and BT-PEG-dMWCNTs reduced tumor burden and increased survival similarly to free drug. Importantly, DOX toxicity was abrogated when DOX was loaded onto PEG-dMWCNTs or BT-PEG-dMWCNTs. Overall, PEG-dMWCNTs and BT-PEG-dMWCNTs represent a promising new nanocarrier platform.
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Sistemas de Liberación de Medicamentos , Neoplasias Hematológicas/tratamiento farmacológico , Nanotubos de Carbono/química , Células 3T3-L1 , Animales , Huesos/metabolismo , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Humanos , Ratones , Nanotubos de Carbono/ultraestructura , Polietilenglicoles/química , Distribución TisularRESUMEN
The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi-potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic-induced fracture, systemic adiposity, and the presence of bone-homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt-inhibitory molecule secreted from bone matrix-embedded osteocytes, can induce adipogenesis in 3T3-L1 cells, mouse ear- and BM-derived MSCs, and human BM-derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre-adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM-adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti-sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications.
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Adipocitos/metabolismo , Adipogénesis , Tejido Adiposo/metabolismo , Células de la Médula Ósea/metabolismo , Glicoproteínas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteocitos/metabolismo , Células 3T3-L1 , Proteínas Adaptadoras Transductoras de Señales , Tejido Adiposo/citología , Adiposidad , Animales , Medios de Cultivo Condicionados/metabolismo , Glicoproteínas/deficiencia , Glicoproteínas/genética , Péptidos y Proteínas de Señalización Intercelular , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Comunicación Paracrina , Fenotipo , Nicho de Células Madre , Vía de Señalización WntRESUMEN
Malignancies that grow in the bone marrow cause a cascade of devastating consequences and are almost always fatal. For researchers to make significant headway in finding cures and treatments for these tumors and the subsequent devastation of cancer-induced bone disease, novel strategies and creative solutions will have to be considered. Great progress has been made in treating hematologic and sold tumor malignancies that ultimately affect the bone marrow, although it is also obvious that multi-disciplinary teams are required to ultimately win the war on cancers that affect the bone. In this perspective, we review recent advances in the identification of molecular and cellular targets in the bone marrow niche.
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Neoplasias de la Médula Ósea , Humanos , Nicho de Células Madre , Ingeniería de TejidosRESUMEN
Cover: The cover image, by Michaela R. Reagan et al., is based on the Perspective A Perspective on Malignancy in the Marrow, DOI 10.1002/jcp.25860.
RESUMEN
Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK-STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies.
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Médula Ósea/metabolismo , Médula Ósea/patología , Comunicación Celular , Mucina-1/biosíntesis , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Células del Estroma/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Técnicas de Cocultivo , Citocinas/metabolismo , Resistencia a Antineoplásicos/genética , Expresión Génica , Silenciador del Gen/efectos de los fármacos , Humanos , Janus Quinasa 2/metabolismo , Mucina-1/genética , Mieloma Múltiple/genética , Inhibidores de Proteasoma/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.
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Adipocitos/patología , Médula Ósea/patología , Huesos/patología , Mieloma Múltiple/patología , Microambiente Tumoral , HumanosRESUMEN
PURPOSE OF REVIEW: Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. RECENT FINDINGS: MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics.
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Tejido Adiposo/metabolismo , Médula Ósea/metabolismo , MicroARNs/metabolismo , Mieloma Múltiple/genética , Exosomas/metabolismo , HumanosRESUMEN
PURPOSE OF THE REVIEW: Herein we dissect mechanisms behind the dissemination of cancer cells from primary tumor site to the bone marrow, which are necessary for metastasis development, with a specific focus on multiple myeloma. RECENT FINDINGS: The ability of tumor cells to invade vessels and reach the systemic circulation is a fundamental process for metastasis development; however, the interaction between clonal cells and the surrounding microenvironment is equally important for supporting colonization, survival, and growth in the secondary sites of dissemination. The intrinsic propensity of tumor cells to recognize a favorable milieu where to establish secondary growth is the basis of the "seed and soil" theory. This theory assumes that certain tumor cells (the "seeds") have a specific affinity for the milieu of certain organs (the "soil"). Recent literature has highlighted the important contributions of the vascular niche to the hospitable "soil" within the bone marrow. In this review, we discuss the crucial role of stromal cells and endothelial cells in supporting primary growth, homing, and metastasis to the bone marrow, in the context of multiple myeloma, a plasma cell malignancy with the unique propensity to primarily grow and metastasize to the bone marrow.
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Médula Ósea/irrigación sanguínea , Neoplasias Óseas/secundario , Tejido Conectivo/irrigación sanguínea , Células Endoteliales/metabolismo , Células Madre Mesenquimatosas/metabolismo , Mieloma Múltiple/patología , Médula Ósea/metabolismo , Tejido Conectivo/metabolismo , Células Endoteliales/citología , Humanos , Células Madre Mesenquimatosas/citología , Mieloma Múltiple/metabolismo , Metástasis de la Neoplasia , Microambiente TumoralRESUMEN
Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(D,L-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.
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Antineoplásicos , Neoplasias Óseas/tratamiento farmacológico , Ácidos Borónicos , Sistemas de Liberación de Medicamentos , Ácido Láctico , Mieloma Múltiple/tratamiento farmacológico , Nanopartículas , Polietilenglicoles , Ácido Poliglicólico , Pirazinas , Microambiente Tumoral/efectos de los fármacos , Alendronato/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Xenoinjertos , Humanos , Ácido Láctico/síntesis química , Ácido Láctico/química , Ácido Láctico/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Nanopartículas/química , Nanopartículas/ultraestructura , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ácido Poliglicólico/síntesis química , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Pirazinas/química , Pirazinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required. Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillary-like assembly of endothelial cells and cell adhesion-mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)- and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone-useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation.
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Células de la Médula Ósea/patología , Mieloma Múltiple/patología , Osteogénesis/fisiología , Cultivo Primario de Células/métodos , Nicho de Células Madre , Diferenciación Celular , Células Cultivadas , Técnicas de Cocultivo , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Modelos Biológicos , Osteoblastos/citología , Osteoblastos/fisiología , Nicho de Células Madre/fisiología , Andamios del TejidoRESUMEN
Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated. In the present study we identified high expression of ß-galactoside α-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of α-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.
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Mieloma Múltiple/enzimología , Proteínas de Neoplasias/metabolismo , Sialiltransferasas/metabolismo , Migración Transendotelial y Transepitelial , Animales , Células de la Médula Ósea/enzimología , Células de la Médula Ósea/patología , Adhesión Celular/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Femenino , Técnicas de Silenciamiento del Gen , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones SCID , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Ácido N-Acetilneuramínico/biosíntesis , Ácido N-Acetilneuramínico/genética , Proteínas de Neoplasias/genética , Sialiltransferasas/genética , Células del Estroma/enzimología , Células del Estroma/patología , beta-Galactosida alfa-2,3-SialiltransferasaAsunto(s)
Pandemias , Investigadores , Mujeres , Carga de Trabajo , Investigación Biomédica , COVID-19 , Cuidadores , Femenino , Humanos , Madres , Grupo Paritario , SARS-CoV-2 , Apoyo SocialRESUMEN
OBJECTIVE: To determine abdominal adipose tissue parameters on PET/CT in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) that may serve as predictors of progression of MGUS to MM. We hypothesized that patients with MM had higher abdominal adiposity and higher fat metabolic activity compared to patients with MGUS. MATERIALS AND METHODS: Our retrospective study was IRB approved and HIPAA compliant. The study group comprised 40 patients (mean age 64 ± 13 years) with MGUS and 32 patients (mean age 62 ± 10 years) with recently diagnosed MM (mean time since diagnosis of MM 3.0 ± 3.9 months) who had not undergone MM treatment. All patients underwent whole body FDG-PET/CT. Total abdominal adipose tissue (TAT), abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) cross sectional areas (CSA) (cm(2)) and metabolic activity (SUV) were assessed. Groups were compared using ANOVA. ROC curve analysis was performed to determine cutoff values for abdominal adipose tissue parameters to detect MM. RESULTS: Patients with recently diagnosed MM had higher TAT and SAT CSA (p ≤ 0.03) and higher fat metabolic activity (p < 0.01). VAT metabolic activity showed the highest sensitivity and specificity for identifying patients with MM (area under the curve 0.95 with cutoff value of >0.34, sensitivity 90.6 %, specificity 92.5 %, p < 0.0001). CONCLUSIONS: Patients who were recently diagnosed with MM had higher abdominal fat CSA and higher fat metabolic activity compared to patients with MGUS. These parameters may serve as novel biomarkers of progression of MGUS to MM.
Asunto(s)
Grasa Abdominal/diagnóstico por imagen , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico por imagen , Mieloma Múltiple/diagnóstico por imagen , Adiposidad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios RetrospectivosRESUMEN
Obesity contributes to many cancers, including breast cancer and multiple myeloma, two cancers that often colonize the bone marrow (BM). Obesity often causes metabolic disease, but at the cellular level, there is uncertainty regarding how these shifts affect cellular phenotypes. Evidence is building that different types of fuel affect tumor cell metabolism, mitochondrial function, and signaling pathways differently, but tumor cells are also flexible and adapt to less-than ideal metabolic conditions, suggesting that single-pronged attacks on tumor metabolism may not be efficacious enough to be effective clinically. In this review, we describe the newest research at the pre-clinical level on how tumor metabolic pathways and energy sources affect cancer cells, with a special focus on multiple myeloma (MM). We also describe the known forward-feedback loops between bone marrow adipocytes (BMAds) and local tumor cells that support tumor growth. We describe how metabolic targets and transcription factors related to fatty acid (FA) oxidation, FA biosynthesis, glycolysis, oxidative phosphorylation (OXPHOS), and other pathways hold great promise as new vulnerabilities in myeloma cells. Specifically, we describe the importance of the acetyl-CoA synthetase (ACSS) and the acyl-CoA synthetase long chain (ACSL) families, which are both involved in FA metabolism. We also describe new data on the importance of lactate metabolism and lactate transporters in supporting the growth of tumor cells in a hypoxic BM microenvironment. We highlight new data showing the dependency of myeloma cells on the mitochondrial pyruvate carrier (MPC), which transports pyruvate to the mitochondria to fuel the tricarboxylic acid (TCA) cycle and electron transport chain (ETC), boosting OXPHOS. Inhibiting the MPC affects myeloma cell mitochondrial metabolism and growth, and synergizes with proteosome inhibitors in killing myeloma cells. We also describe how metabolic signaling pathways intersect established survival and proliferation pathways; for example, the fatty acid binding proteins (FABPs) affect MYC signaling and support growth, survival, and metabolism of myeloma cells. Our goal is to review the current the field so that novel, metabolic-focused therapeutic interventions and treatments can be imagined, developed and tested to decrease the burden of MM and related cancers.