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Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.
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Neoplasias Ósseas , Microambiente Tumoral , Humanos , Recidiva Local de Neoplasia , Osso e Ossos/patologia , Neoplasias Ósseas/patologia , MacrófagosRESUMO
Bone is one of the most common sites of tumor metastases. During the last step of bone metastasis, cancer cells colonize and disrupt the bone matrix, which is maintained mainly by osteocytes, the most abundant cells in the bone microenvironment. However, the role of osteocytes in bone metastasis is still unclear. Here, we demonstrated that osteocytes transfer mitochondria to metastatic cancer cells and trigger the cGAS/STING-mediated antitumor response. Blocking the transfer of mitochondria by specifically knocking out mitochondrial Rho GTPase 1 (Rhot1) or mitochondrial mitofusin 2 (Mfn2) in osteocytes impaired tumor immunogenicity and consequently resulted in the progression of metastatic cancer toward the bone matrix. These findings reveal the protective role of osteocytes against cancer metastasis by transferring mitochondria to cancer cells and potentially offer a valuable therapeutic strategy for preventing bone metastasis.
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Neoplasias Ósseas , Osteócitos , Humanos , Osteócitos/metabolismo , Osso e Ossos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Mitocôndrias , Microambiente TumoralRESUMO
Deep tissue infection is a common clinical issue and therapeutic difficulty caused by the disruption of the host antibacterial immune function, resulting in treatment failure and infection relapse. Intracellular pathogens are refractory to elimination and can manipulate host cell biology even after appropriate treatment, resulting in a locoregional immunosuppressive state that leads to an inadequate response to conventional anti-infective therapies. Here, a novel antibacterial strategy involving autogenous immunity using a biomimetic nanoparticle (NP)-based regulating system is reported to induce in situ collaborative innate-adaptive immune responses. It is observed that a macrophage membrane coating facilitates NP enrichment at the infection site, followed by active NP accumulation in macrophages in a mannose-dependent manner. These NP-armed macrophages exhibit considerably improved innate capabilities, including more efficient intracellular ROS generation and pro-inflammatory factor secretion, M1 phenotype promotion, and effective eradication of invasive bacteria. Furthermore, the reprogrammed macrophages direct T cell activation at infectious sites, resulting in a robust adaptive antimicrobial immune response to ultimately achieve bacterial clearance and prevent infection relapse. Overall, these results provide a conceptual framework for a novel macrophage-based strategy for infection treatment via the regulation of autogenous immunity.
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Imunidade Inata , Macrófagos , Humanos , Macrófagos/metabolismo , Antibacterianos/metabolismo , Imunidade Adaptativa , RecidivaRESUMO
Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Espécies Reativas de Oxigênio/metabolismo , Plaquetas/metabolismo , Osteossarcoma/metabolismo , Neoplasias Ósseas/metabolismo , Mitocôndrias/metabolismo , Microambiente TumoralRESUMO
Human Vγ9Vδ2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. However, the utility of γδ T cells as APCs to induce CD8+ T cell-mediated antitumor immune response, as well as the mechanism by which they perform APC functions, remains unexplored. In this study, we found that activated Vγ9Vδ2 T cells were capable of inducing robust CD8+ T cell responses in osteosarcoma cells. Activated γδ T cells also effectively suppressed osteosarcoma growth by priming CD8+ T cells in xenograft animal models. Mechanistically, we further revealed that activated γδ T cells exhibited increased HSP90 production, which fed back to upregulate MyD88, followed by JNK activation and a subsequent improvement in CCL5 secretion, leading to enhanced CD8+ T cell cross-priming. Thus, our study suggests that Vγ9Vδ2 T cells represent a promising alternative APC for the development of γδ T cell-based tumor immunotherapy.
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Neoplasias Ósseas , Osteossarcoma , Animais , Humanos , Apresentação de Antígeno , Células Apresentadoras de Antígenos , Antígenos , Linfócitos T CD8-Positivos , Ativação Linfocitária , Fator 88 de Diferenciação Mieloide , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , MAP Quinase Quinase 4/metabolismoRESUMO
Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy (ACT) against solid tumors. Here, we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors. Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+ T cells, which led to improved antitumor outcomes. Mechanistically, infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation. Overall, we presented a simple, cost-effective, and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.
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Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.
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Sistema y+ de Transporte de Aminoácidos , Neoplasias Ósseas , Antígeno CD47 , Osteossarcoma , Animais , Camundongos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Antígeno CD47/genética , Antígeno CD47/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Glutamina/metabolismo , Interleucina-18 , Leucina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fagocitose/genética , Evasão Tumoral/genética , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismoRESUMO
BACKGROUND: Tumor resection and prosthetic replacement have become the treatments of choice for malignant bone tumors. Infections are the leading cause of failure of limb salvage surgeries. Therefore, treating infections around prostheses after limb salvage is essential and challenging. Our research team designed a "domino" sequential treatment plan to treat postoperative infections around tumor prostheses and evaluated its efficacy. PURPOSE: To introduce the new domino sequential treatment plan for postoperative infections of tumor prostheses, and evaluate the technical points of the plan and prognosis in medium- and long-term follow-ups. METHODS: Between January 2015 and August 2021, 14 patients were treated with prosthesis-preserving domino sequential therapy for peripheral prosthesis infections after bone-tumor limb salvage. The sample included eight cases of distal femur tumor, two of proximal tibia tumor, three of pelvic tumor, and one of middle femur tumor. We evaluated routine blood test results, C-reactive protein level, the erythrocyte sedimentation rate, and other indicators. X-rays and CT scans of the surgical site were obtained and the Musculoskeletal Tumor Society (MSTS) score was calculated. Treatment involved debridement and lavage of the prosthesis, and systemic and local antibiotics. RESULTS: The positivity rate of microbial culture was 78.6%. There were three cases of Staphylococcus aureus, one of Staphylococcus epidermidis, two of methicillin-resistant Staphylococcus epidermidis, one of methicillin-resistant Staphylococcus aureus, two of Acinetobacter baumannii, one of Streptococcus lactis (group C), one of Streptococcus mitis, and three with negative cultures. In three cases, sequential treatment failed to control the infection. The operation success rate was 78.6% (11/14). One case eventually required amputation, and another required long-term wound dressings. To control the infection, a third had to be treated using antibiotic bone cement combined with the "intramedullary nail reverse double insertion" technique. The MSTS scores of patients before infection debridement and at the last follow-up showed statistically significant differences (t = 5.312, p = 0.02). CONCLUSIONS: The prosthesis-preserving domino sequential method has certain advantages for treating bone-tumor limb salvage infections around the prosthesis. LEVEL OF EVIDENCE: Level IV, therapeutic.
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Membros Artificiais , Neoplasias Ósseas , Staphylococcus aureus Resistente à Meticilina , Neoplasias Ósseas/cirurgia , Humanos , Salvamento de Membro , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Excessive osteoclast activation is an important cause of imbalanced bone remodeling that leads to pathological bone destruction. This is a clear feature of many osteolytic diseases such as rheumatoid arthritis, osteoporosis, and osteolysis around prostheses. Because many natural compounds have therapeutic potential for treating these diseases by suppressing osteoclast formation and function, we hypothesized that α-mangostin, a natural compound isolated from mangosteen, might be a promising treatment as it exhibits anti-inflammatory, anticancer, and cardioprotective effects. METHODS: We evaluated the therapeutic effect of α-mangostin on the processes of osteoclast formation and bone resorption. The receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) induces osteoclast formation in vitro, and potential pathways of α-mangostin to inhibit osteoclast differentiation and function were explored. A mouse model of lipopolysaccharide-induced calvarial osteolysis was established. Subsequently, micro-computed tomography and histological assays were used to evaluate the effect of α-mangostin in preventing inflammatory osteolysis. RESULTS: We found that α-mangostin could inhibit RANKL-induced osteoclastogenesis and reduced osteoclast-related gene expression in vitro. F-actin ring immunofluorescence and resorption pit assays indicated that α-mangostin also inhibited osteoclast functions. It achieved these effects by disrupting the activation of NF-κB/mitogen-activated protein kinase signaling pathways. Our in vivo data revealed that α-mangostin could protect mouse calvarial bone from osteolysis. CONCLUSIONS: Our findings demonstrate that α-mangostin can inhibit osteoclastogenesis both in vitro and in vivo and may be a potential option for treating osteoclast-related diseases.
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Lung cancer is the leading cause of cancer-related death worldwide. Bone metastasis, which usually accompanies severe skeletal-related events, is the most common site for tumor distant dissemination and detected in more than one-third of patients with advanced lung cancer. Biopsy and imaging play critical roles in the diagnosis of bone metastasis; however, these approaches are characterized by evident limitations. Recently, studies regarding potential biomarkers in the serum, urine, and tumor tissue, were performed to predict the bone metastases and prognosis in patients with lung cancer. In this review, we summarize the findings of recent clinical research studies on biomarkers detected in samples obtained from patients with lung cancer bone metastasis. These markers include the following: (1) bone resorption-associated markers, such as N-terminal telopeptide (NTx)/C-terminal telopeptide (CTx), C-terminal telopeptide of type I collagen (CTx-I), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), pyridinoline (PYD), and parathyroid hormone related peptide (PTHrP); (2) bone formation-associated markers, including total serum alkaline phosphatase (ALP)/bone specific alkaline phosphatase(BAP), osteopontin (OP), osteocalcin (OS), amino-terminal extension propeptide of type I procollagen/carboxy-terminal extension propeptide of type I procollagen (PICP/PINP); (3) signaling markers, including epidermal growth factor receptor/Kirsten rat sarcoma/anaplastic lymphoma kinase (EGFR/KRAS/ALK), receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB/osteoprotegerin (RANKL/RANK/OPG), C-X-C motif chemokine ligand 12/C-X-C motif chemokine receptor 4 (CXCL12/CXCR4), complement component 5a receptor (C5AR); and (4) other potential markers, such as calcium sensing receptor (CASR), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2), cytokeratin 19 fragment/carcinoembryonic antigen (CYFRA/CEA), tissue factor, cell-free DNA, long non-coding RNA, and microRNA. The prognostic value of these markers is also investigated. Furthermore, we listed some clinical trials targeting hotspot biomarkers in advanced lung cancer referring for their therapeutic effects.
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BACKGROUND: Osteosarcoma is a malignant tumor of bone and soft tissue in adolescents. Due to its tumor biological behavior pattern, osteosarcoma usually generates poor prognosis. Autophagy is an important self-defense mechanism in osteosarcoma. METHODS: Cell viability in IC50 testing and reverse assays was examined by the MTT assay. Cell apoptosis conditions were examined by flow cytometry, Hoechst 33,342 staining and apoptosis-related protein immunoblotting. Autophagy conditions were tested by autophagy-related protein immunoblotting, transmission electron microscopic observation and dual fluorescence autophagy flux detection. The possible targets of aloin were screened out by network pharmacology and bioinformatic methods. Osteosarcoma xenografts in nude BALB/c mice were the model for in vivo research on tumor suppression, autophagy induction, pathway signaling and toxicity tests. In vivo bioluminescence imaging systems, immunohistochemical assays, and gross tumor volume comparisons were applied as the main research methods in vivo. RESULTS: Aloin induced osteosarcoma apoptosis in a dose-dependent manner. Its possible effects on the PI3K/AKT pathway were screened out by network pharmacology methods. Aloin increased autophagic flux in osteosarcoma by downregulating the PI3K/AKT pathway. Aloin promoted autophagic flux in the osteosarcoma cell lines HOS and MG63 in a dose-dependent manner by promoting autophagosome formation. Chloroquine reversed the apoptosis-promoting and autophagy-enhancing effects of aloin. Autophagy induced by starvation and rapamycin significantly enhanced the autophagic flux and apoptosis induced by aloin, which verified the role of the PI3K/AKT axis in the pharmacological action of aloin. Therapeutic effects, autophagy enhancement and regulatory effects on the PI3K/AKT/mTOR pathway were demonstrated in a nude mouse xenogeneic osteosarcoma transplantation model. CONCLUSIONS: Aloin inhibited the proliferation of osteosarcoma by inhibiting the PI3K/AKT/mTOR pathway, increasing autophagic flux and promoting the apoptosis of osteosarcoma cells.
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BACKGROUND: Surgical therapy of breast cancer and bone metastasis can effectively improve the prognosis of breast cancer. However, after the first operation, the relationship between preoperative indicators and outcomes in patients who underwent metastatic bone surgery remained to be studied. Purpose 1. Recognize clinical and laboratory prognosis factors available to clinical doctors before the operation for bone metastatic breast cancer patients. 2. Develop a risk prediction model for 3-year postoperative survival in patients with breast cancer bone metastasis. METHODS: From 2014 to 2020, patients who suffered from breast cancer bone metastasis and received therapeutic procedures in our institution were included for analyses (n=145). For patients who underwent both breast cancer radical surgery and bone metastasis surgery, comprehensive datasets of the parameters of interest (clinical features, laboratory factors, and patient prognoses) were collected (n=69). We performed Multivariate Cox regression to identify factors that were associated with postoperative outcome. 3-year survival prediction model and nomograms were established by 100 bootstrapping. Its benefit was evaluated by calibration plot, C-index, and decision curve analysis. The Surveillance, Epidemiology, and End Results database was also used for external validation. RESULTS: Radiotherapy for primary cancer, pathological type of metastatic breast cancer, lymph node metastasis, elevated serum alkaline phosphatase, lactate dehydrogenase were associated with postoperative prognosis. Pathological types of metastatic breast cancer, multiple bone metastasis, organ metastases, and elevated serum lactate dehydrogenase were associated with 3-year survival. Then those significant variables and serum alkaline phosphatase counts were integrated to construct nomograms for 3-year survival. The C-statistic of the established predictive model was 0.83. The calibration plot presents a graphical representation of calibration. In the decision curve analysis, the benefits are higher than those of the extreme curve. The receiver operating characteristic of the external validation of the model was 0.82, indicating a favored fitting degree of the two models. CONCLUSION: Our study suggests that several clinical features and serological markers can predict the overall survival among the patients who are about to receive bone metastasis surgery after breast cancer surgery. The model can guide the preoperative evaluation and clinical decision-making for patients. Level of evidence Level III, prognostic study.
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Accumulating evidence suggests that extracellular signal-regulated kinase (ERK) is a valuable target molecule for cancer. However, antitumor drugs targeting ERK are still in their clinical phase and no FDA-approved medications exist. In this study, we identified an ERK inhibitor (ERKi; Vx-11e) with potential antitumor activities, which was reflected by the inhibition in the survival and proliferation of Osteosarcoma (OS) cells. Mechanistically, the ERKi regulated autophagic flux by promoting the translocation of transcription factor EB (TFEB) in OS cells, thereby increasing the dependence of OS cells on autophagy and sensitivity to treatment with autophagy inhibitors in OS. Besides, we also found that the ERKi could regulate mitochondrial apoptosis through the ROS/mitochondria pathway and aerobic glycolysis in OS, which also increases the dependence of OS cells on autophagy to clear metabolites to a certain extent. These results may provide a reference for the clinically improved efficacy of ERKis in combination with autophagy inhibitors in the treatment of OS and indicate its potential as a therapeutic agent.
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Osteosarcoma is a malignant bone tumor that is easy to metastasize in the early stage and has a very poor prognosis. Fraxinellone (FRA) is one of the main components isolated from the D. dasycarpus plant. Its anti-inflammatory and neuroprotective effects have been confirmed, but the research on the anti-cancer effect of FRA and its potential mechanism is relatively scarce. In this study, we found that FRA inhibited the proliferation and migration of osteosarcoma cells HOS and MG63 in a dose-dependent manner. Immunofluorescence, fluorescence staining and western blotting analysis showed that FRA could simultaneously induce osteosarcoma cell apoptosis and increase autophagy flux. Subsequent turnaround experiments suggested that the pro-apoptotic effect of FRA was achieved through excessive autophagy flux. The results of the xenograft orthotopic model further supported the anti-cancer effects of FRA, indicating that FRA treatment inhibited the growth of osteosarcoma, and the pro-apoptotic and autophagy effects of FRA were also proved in vivo. These studies provide new ideas for the future treatment of osteosarcoma and offer theoretical support for the anti-cancer mechanism of FRA.
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Bone-related malignancies, such as osteosarcoma, Ewing's sarcoma, multiple myeloma, and cancer bone metastases have similar histological context, but they are distinct in origin and biological behavior. We hypothesize that a distinct immune infiltrative microenvironment exists in these four most common malignant bone-associated tumors and can be used for tumor diagnosis and patient prognosis. After sample cleaning, data integration, and batch effect removal, we used 22 publicly available datasets to draw out the tumor immune microenvironment using the ssGSEA algorithm. The diagnostic model was developed using the random forest. Further statistical analysis of the immune microenvironment and clinical data of patients with osteosarcoma and Ewing's sarcoma was carried out. The results suggested significant differences in the microenvironment of bone-related tumors, and the diagnostic accuracy of the model was higher than 97%. Also, high infiltration of multiple immune cells in Ewing's sarcoma was suggestive of poor patient prognosis. Meanwhile, increased infiltration of macrophages and B cells suggested a better prognosis for patients with osteosarcoma, and effector memory CD8 T cells and type 2 T helper cells correlated with patients' chemotherapy responsiveness and tumor metastasis. Our study revealed that the random forest diagnostic model based on immune infiltration can accurately perform the differential diagnosis of bone-related malignancies. The immune microenvironment of osteosarcoma and Ewing's sarcoma has an important impact on patient prognosis. Suppressing the highly inflammatory environment of Ewing's sarcoma and promoting macrophage and B cell infiltration may have good potential to be a novel adjuvant treatment option for osteosarcoma and Ewing's sarcoma.
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PURPOSE: Osteosarcoma is a malignant musculoskeletal tumor with early metastasis and a poor prognosis, especially in adolescents. Ganoderma lucidum (Leyss. Ex Fr.) Karst (G. lucidum), a traditional East Asian medicine, has been reported to play a critical role in antitumor and immunomodulatory activity. The aim of this study was to investigate the effects and molecular mechanisms of water extract of sporoderm-broken spores of G. lucidum (BSGWE) on osteosarcoma PD-L1 (programmed cell death-ligand 1) transcriptional regulation, efficacy enhancement, and side effect remission. METHODS: The antitumor effects on cell proliferation of BSGWE in osteosarcoma cells were detected by apoptosis flow cytometry, and the migration ability of HOS and K7M2 cells were evaluated by cell scratch assay. Potential signaling regulation of PD-L1 was detected by western blotting. To confirm the signaling pathway of BSGWE-related PD-L1 downregulation, a pho-STAT3 turnover experiment was carried out. Colivelin was administered as a pho-STAT3 activator to rescue the BSGWE-induced PD-L1 inhibition. To further study in vivo signaling, in a Balb/c osteosarcoma allograft model, tumor volume was measured using an in vivo bioluminescence imaging system. The body weight curve and tumor volume curve were analyzed to reveal the remission effects of BSGWE on PD-L1 antibody-related body weight loss and its immunomodulatory effects on the osteosarcoma and spleen. The PD-L1 expression level and expression of related transcription-factor pho-STAT3 in tumor cells and spleens were assessed by IHC analysis. RESULTS: BSGWE suppressed the proliferation and migration of osteosarcoma cells in vitro via induction of apoptosis. In addition, BSGWE downregulated PD-L1 expression and related STAT3 (signal transducers and activators of transcription) phosphorylation levels in a dose-dependent manner. Western blotting and qRT-PCR assay revealed that BSGWE downregulated PD-L1 expression by inhibiting STAT3 phosphorylation. A turnover experiment showed that colivelin administration could rescue PD-L1 inhibition via pho-STAT3 activation. BSGWE not only downregulated PD-L1 expression via the STAT3 pathway in an allograft Balb/c mouse model, but also relieved complications including weight loss and spleen atrophy in a mouse monoclonal antibody therapy model on the basis of its traditional advantages in immune enhancement. CONCLUSION: BSGWE downregulated PD-L1 expression via pho-STAT3 inhibition of protein and RNA levels. BSGWE enhanced PD-L1 antibody efficacy via phosphorylated STAT3 downregulation in vitro and in vivo. BSGWE also relieved complications of weight loss and spleen atrophy in a murine allograft osteosarcoma immune checkpoint blockade therapy model.
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Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Reishi , Animais , Anticorpos Monoclonais/efeitos adversos , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Osteossarcoma/patologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Esporos Fúngicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Excessive activation of osteoclast activity is responsible for many bone diseases, such as osteoporosis, rheumatoid arthritis, periprosthetic osteolysis, and periodontitis. Natural compounds that inhibit osteoclast formation and/or function have therapeutic potential for treating these diseases. Catalpol, a bioactive iridoid extracted from a traditional herbal medicine Rehmannia glutinosa, exhibits various pharmacological properties, including anti-inflammatory, antioxidant, antidiabetic, and antitumor effects. However, its effects on osteoclast formation and function remain unknown. In the present study, we showed that catalpol inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and bone resorption, as well as the expression of osteoclast-related marker genes. The investigation of molecular mechanisms showed that catalpol upregulated phosphatase and tensin homolog (PTEN) activity by reducing its ubiquitination and degradation, subsequently suppressing RANKL-induced NF-κB and AKT signaling pathways, leading to an inhibition on NFATc1 induction. Furthermore, catalpol protected mice against inflammation- and ovariectomy-induced bone loss by inhibiting osteoclast activity in vivo. These results suggest that catalpol might be developed as a promising candidate for treating osteoclast-related bone diseases.
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Reabsorção Óssea/prevenção & controle , Glucosídeos Iridoides/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Animais , Reabsorção Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Osteogênese/genética , PTEN Fosfo-Hidrolase/genética , Ligante RANK/farmacologia , Células RAW 264.7RESUMO
Osteoclast overactivation-induced imbalance in bone remodelling leads to pathological bone destruction, which is a characteristic of many osteolytic diseases such as rheumatoid arthritis, osteoporosis, periprosthetic osteolysis and periodontitis. Natural compounds that suppress osteoclast formation and function have therapeutic potential for treating these diseases. Stachydrine (STA) is a bioactive alkaloid isolated from Leonurus heterophyllus Sweet and possesses antioxidant, anti-inflammatory, anticancer and cardioprotective properties. However, its effects on osteoclast formation and function have been rarely described. In the present study, we found that STA suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and bone resorption, and reduced osteoclast-related gene expression in vitro. Mechanistically, STA inhibited RANKL-induced activation of NF-κB and Akt signalling, thus suppressing nuclear factor of activated T cells c1 induction and nuclear translocation. In addition, STA alleviated bone loss and reduced osteoclast number in a murine model of LPS-induced inflammatory bone loss. STA also inhibited the activities of NF-κB and NFATc1 in vivo. Together, these results suggest that STA effectively inhibits osteoclastogenesis both in vitro and in vivo and therefore is a potential option for treating osteoclast-related diseases.
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NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/tratamento farmacológico , Prolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Actinas/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Animais , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Osteólise/induzido quimicamente , Osteólise/diagnóstico por imagem , Osteólise/metabolismo , Prolina/farmacologia , Prolina/uso terapêutico , Ligante RANK/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios XRESUMO
Background: Ewing sarcoma (ES) is the second commonest primary malignant bone neoplasm. Metastatic status at diagnosis strongly predicted poor prognosis of Ewing sarcoma patients. Yet little was known about the underlying mechanism of ES metastasis. Purpose:This study intended to identify the relationship between key genes/pathways and metastasis/poor prognosis in Ewing's sarcoma patients by using bioinformatic method. Methods: In this study, multi-center sequencing data were obtained from the GEO database, including gene and miRNA expression profile and prognosis information of ES patients. Differentially expressed genes (DEGs) were identified between primary and metastasis ES samples by the GEO2R online tool. Gene ontology (Go) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses of DEGs were performed. And PPI network analyses were conducted. The ES patient's prognostic information was employed for survival analysis, and the potential relationship between miRNAs and key genes was analyzed. Results: The results showed that a total of 298 and 428 DEGs were screened out in metastasis samples based on GSE17618 and GSE12102 dataset compared to primary samples respectively. The most significantly enriched KEGG pathway was the mismatch repair (MMR) pathway. MSH2, MSH6, RPA2, and RFC2 that belong to the MMR pathway were identified as key genes. Moreover, the expression of key genes was increased in metastasis samples compared with primary ones and was associated with poor event-free and overall survival of ES patients. The negative correlation of the expression level of the key genes with patients prognosis also supported by TCGA sarcoma database. Furthermore, knockdown of EWSR/FLI1 fusion in ES cell line A673 down-regulates the expression of the 4 key genes was revealed by GDS4962. Conclusion: In conclusion, the present study indicated that the key genes promote our understanding of the molecular mechanisms underlying the development of ES metastasis, and might be used as molecular targets and diagnostic biomarkers for the treatment of ES.