-
Drug Delivery Dec 2023The clinical diagnosis and treatment of malignant bone tumors are still major clinical challenges due to their high incidence are difficulty. Targeted therapies have...
The clinical diagnosis and treatment of malignant bone tumors are still major clinical challenges due to their high incidence are difficulty. Targeted therapies have become a critical approach to treat bone tumors. In recent years, radiopharmaceuticals have been used widely and have shown potent and efficient results in treating bone tumors, among which P and the labeled radiopharmaceuticals play an essential role. In this study, the P-labeled hydroxyapatite (HA) was prepared through chemical synthesis (P-Hap) and physical adsorption (P-doped-Hap). The in vitro stability of P-labeled HA was analyzed to assess the superiority of the new-found chemical synthesis. The radiolabeling yield and stability of chemical synthesis (97.6 ± 0.5%) were significantly improved compared with physical adsorption (92.7 ± 0.4%). Furthermore, the CT results corroborate that P-Hap (100 μCi) +DOX group has the highest tumor suppression rate and can effectively reduce bone destruction. The results corroborate the effectiveness of the chemical synthesis and validate the application of P-Hap in bone tumors. Therefore, P-Hap (100 μCi) + DOX may be an effective strategy for bone metastasis treatments.
Topics: Humans; Durapatite; Radiopharmaceuticals; Nanoparticles; Bone and Bones; Bone Neoplasms
PubMed: 36688268
DOI: 10.1080/10717544.2023.2168791 -
Frontiers in Immunology 2023The advent of novel cancer immunotherapy approaches is revolutionizing the treatment for cancer. Current small animal models for most cancers are syngeneic or...
The advent of novel cancer immunotherapy approaches is revolutionizing the treatment for cancer. Current small animal models for most cancers are syngeneic or genetically engineered mouse models or xenograft models based on immunodeficient mouse strains. These models have been limited in evaluating immunotherapy regimens due to the lack of functional human immune system. Development of animal models for bone cancer faces another challenge in the accessibility of tumor engraftment sites. Here, we describe a protocol to develop an orthotopic humanized mouse model for a bone and soft tissue sarcoma, Ewing sarcoma, by transplanting fresh human cord blood CD34 hematopoietic stem cells into young NSG-SGM3 mice combined with subsequent Ewing sarcoma patient derived cell engraftment in the tibia of the humanized mice. We demonstrated early and robust reconstitution of human CD45 leukocytes including T cells, B cells, natural killer cells and monocytes. Ewing sarcoma xenograft tumors successfully orthotopically engrafted in the humanized mice with minimal invasive procedures. We validated the translational utility of this orthotopic humanized model by evaluating the safety and efficacy of an immunotherapy antibody, magrolimab. Treatment with magrolimab induces CD47 blockade resulting in significantly decreased primary tumor growth, decreased lung metastasis and prolonged animal survival in the established humanized model. Furthermore, the humanized model recapitulated the dose dependent toxicity associated with the CD47 blockade as observed in patients in clinical trials. In conclusion, this orthotopic humanized mouse model of Ewing sarcoma represents an improved platform for evaluating immunotherapy in bone and soft tissue sarcoma, such as Ewing sarcoma. With careful design and optimization, this model is generalizable for other bone malignancies.
Topics: Humans; Animals; Mice; Sarcoma, Ewing; CD47 Antigen; Bone Neoplasms; Immunotherapy; T-Lymphocytes; Osteosarcoma; Disease Models, Animal
PubMed: 37868989
DOI: 10.3389/fimmu.2023.1277987 -
Journal of Cancer Education : the... Oct 2023Bone metastases are common in advanced breast cancer (BC) patients and increase the risk for skeletal-related events (SREs), which present a significant health and...
Bone metastases are common in advanced breast cancer (BC) patients and increase the risk for skeletal-related events (SREs), which present a significant health and economic burden. Bone targeting agents (BTAs) can improve health-related quality of life by delaying or preventing SREs; nevertheless, a significant portion of eligible BC patients are not receiving this therapy. A bone health education needs assessment survey was conducted to examine cancer-related bone health awareness and to identify opportunities to improve bone health education. Direct-to-patient outreach was used to recruit adult BC patients in the USA self-reporting a diagnosis of bone metastasis within the past 3 years. Of the 200 patients, 59% experienced at least one SRE prior to survey participation (44% radiation to bone, 29% bone fracture, 17% spinal cord compression, 15% surgery to bone), and 83% were currently receiving a BTA. Awareness of general cancer bone health, protection strategies against SREs, and screening tests were low to moderate. Patients currently not receiving a BTA were least knowledgeable about cancer bone health, with only 40% aware of BTAs as a protective strategy, and only 26% were very or extremely satisfied with the information received from healthcare providers. Sixty-two percent of patients wanted to receive information by more than one mode of communication. Notable gaps in bone health education were observed in bone metastatic BC patients at risk for SREs, suggesting the need for earlier and more effective communication and education strategies to promote appropriate BTA use and better health outcomes.
Topics: Adult; Humans; United States; Female; Breast Neoplasms; Bone Density; Quality of Life; Bone Neoplasms; Spinal Cord Compression
PubMed: 37118404
DOI: 10.1007/s13187-023-02293-w -
Journal of Nanobiotechnology Jul 2023Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in...
Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in cancer therapy, their nontargeted accumulation and drug resistance remain nonnegligible limiting factors. Herein, we first found that icaritin had a strong synergistic effect with an epigenetic drug (JQ1) in the suppression of breast cancer, which could help to relieve drug resistance to JQ1. To improve tumor-targeted efficacy, we developed a hypoxia-cleavable, RGD peptide-modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (termed ARNP) for the targeted delivery of JQ1 and icaritin. The decoration of long cleavable PEG chains can shield RGD peptides during blood circulation and reduce cellular uptake at nonspecific sites. ARNP actively targets breast cancer cells via an RGD-αvβ3 integrin interaction after PEG chain cleavage by responding to hypoxic tumor microenvironment. In vitro and in vivo assays revealed that ARNP exhibited good biodistribution and effectively suppressed primary tumor and bone metastasis. Meanwhile, ARNP could alleviate bone erosion to a certain extent. Furthermore, ARNP significantly inhibited pulmonary metastasis secondary to bone metastasis. The present study suggests that ARNP has great promise in the treatment of breast cancer and bone metastasis due to its simple and practical potential.
Topics: Humans; Pharmaceutical Preparations; Nanomedicine; Tissue Distribution; Bone Neoplasms; Epigenesis, Genetic; Tumor Microenvironment
PubMed: 37438800
DOI: 10.1186/s12951-023-01939-7 -
Journal of Translational Medicine Dec 2023Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, with poor outcomes for patients with metastatic disease or chemotherapy...
BACKGROUND
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, with poor outcomes for patients with metastatic disease or chemotherapy resistance. Cirsiliol is a recently found flavonoid with anti-tumor effects in various tumors. However, the effects of cirsiliol in the regulation of aggressive behaviors of OS remain unknown.
METHODS
The effect of cirsiliol on the proliferation of OS cells was detected using a cell counting kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining, while cell apoptosis was detected using flow cytometry. Immunofluorescence was applied to visualize the expression level of the mitochondria, lysosomes and microtubule-associated protein light chain 3 (LC3). A computational molecular docking technique was used to predict the interaction between cirsiliol and the AKT protein. The impact of cirsiliol on resistance was investigated by comparing it between a methotrexate (MTX)-sensitive OS cell line, U2OS, and a MTX-resistant OS cell line, U2OS/MTX. Finally, in situ xenogeneic tumor models were used to validate the anti-tumor effect of cirsiliol in OS.
RESULTS
Cirsiliol inhibited cell proliferation and induced apoptosis in both U2OS and U2OS/MTX300 OS cells. In addition, treatment with cirsiliol resulted in G2 phase arrest in U2OS/MTX300 and U2OS cells. Cell fluorescence probe staining results showed impaired mitochondria and increased autophagy in OS cells after treatment with cirsiliol. Mechanistically, it was found that cirsiliol targeted AKT by reducing the phosphorylation of AKT, which further activated the transcriptional activity of forkhead Box O transcription factor 1 (FOXO1), ultimately affecting the function of OS cells. Moreover, in situ tumorigenesis experiments showed that cirsiliol inhibited the tumorigenesis and progression of OS in vivo.
CONCLUSIONS
Cirsiliol inhibits OS cell growth and induces cell apoptosis by reducing AKT phosphorylation and further promotes FOXO1 expression. These phenomena indicate that cirsiliol is a promising treatment option for OS.
Topics: Child; Humans; Adolescent; Methotrexate; Proto-Oncogene Proteins c-akt; Molecular Docking Simulation; Cell Line, Tumor; Osteosarcoma; Apoptosis; Cell Proliferation; Bone Neoplasms; Carcinogenesis; Autophagy; Mitochondria; Forkhead Box Protein O1
PubMed: 38087310
DOI: 10.1186/s12967-023-04682-7 -
International Journal of Molecular... Feb 2024The treatment of patients with advanced cancer poses clinical problems due to the complications that arise as the disease progresses. Bone metastases are a common... (Review)
Review
The treatment of patients with advanced cancer poses clinical problems due to the complications that arise as the disease progresses. Bone metastases are a common problem that cancer patients may face, and currently, there are no effective drugs to treat these individuals. Prostate, breast, and lung cancers often spread to the bone, causing significant and disabling health conditions. The bone is a highly active and dynamic tissue and is considered a favorable environment for the growth of cancer. The role of osteoblasts and osteoclasts in the process of bone remodeling and the way in which their interactions change during the progression of metastasis is critical to understanding the pathophysiology of this disease. These interactions create a self-perpetuating loop that stimulates the growth of metastatic cells in the bone. The metabolic reprogramming of both cancer cells and cells in the bone microenvironment has serious implications for the development and progression of metastasis. Insight into the process of bone remodeling and the systemic elements that regulate this process, as well as the cellular changes that occur during the progression of bone metastases, is critical to the discovery of a cure for this disease. It is crucial to explore different therapeutic options that focus specifically on malignancy in the bone microenvironment in order to effectively treat this disease. This review will focus on the bone remodeling process and the effects of metabolic disorders as well as systemic factors like hormones and cytokines on the development of bone metastases. We will also examine the various therapeutic alternatives available today and the upcoming advances in novel treatments.
Topics: Male; Humans; Bone Neoplasms; Bone and Bones; Osteoclasts; Osteoblasts; Cytokines; Tumor Microenvironment
PubMed: 38474093
DOI: 10.3390/ijms25052846 -
Bioengineered Dec 2023Extracellular vehicles play crucial function in osteosarcoma tumorigenesis.Extracellular vehicles mediated the intercellular communication of osteosarcoma cells with... (Review)
Review
Extracellular vehicles play crucial function in osteosarcoma tumorigenesis.Extracellular vehicles mediated the intercellular communication of osteosarcoma cells with other types cells in tumor microenvironment.Extracellular vehicles have potential utility in osteosarcoma diagnosis and treatment.
Topics: Humans; Cell Communication; Osteosarcoma; Extracellular Vesicles; Carcinogenesis; Cell Transformation, Neoplastic; Bone Neoplasms; Tumor Microenvironment
PubMed: 37377390
DOI: 10.1080/21655979.2022.2161711 -
Journal of Cancer Research and... Apr 2024Bone sarcomas encompass a group of spontaneous mesenchymal malignancies, among which osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma are the most common... (Review)
Review
Bone sarcomas encompass a group of spontaneous mesenchymal malignancies, among which osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma are the most common subtypes. Chondrosarcoma, a relatively prevalent malignant bone tumor that originates from chondrocytes, is characterized by endogenous cartilage ossification within the tumor tissue. Despite the use of aggressive treatment approaches involving extensive surgical resection, chemotherapy, and radiotherapy for patients with osteosarcoma, chondrosarcoma, and chordoma, limited improvements in patient outcomes have been observed. Furthermore, resistance to chemotherapy and radiation therapy has been observed in chondrosarcoma and chordoma cases. Consequently, novel therapeutic approaches for bone sarcomas, including chondrosarcoma, need to be uncovered. Recently, the emergence of immunotherapy and immune checkpoint inhibitors has garnered attention given their clinical success in various diverse types of cancer, thereby prompting investigations into their potential for managing chondrosarcoma. Considering that circumvention of immune surveillance is considered a key factor in the malignant progression of tumors and that immune checkpoints play an important role in modulating antitumor immune effects, blockers or inhibitors targeting these immune checkpoints have become effective therapeutic tools for patients with tumors. One such checkpoint receptor implicated in this process is programmed cell death protein-1 (PD-1). The association between PD-1 and programmed cell death ligand-1 (PD-L1) and cancer progression in humans has been extensively studied, highlighting their remarkable potential as biomarkers for cancer treatment. This review comprehensively examines available studies on current chondrosarcoma treatments and advancements in anti-PD-1/PD-L1 blockade therapy for chondrosarcoma.
Topics: Humans; Chondrosarcoma; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Bone Neoplasms; Immune Checkpoint Inhibitors; Immunotherapy
PubMed: 38687921
DOI: 10.4103/jcrt.jcrt_2269_23 -
Frontiers in Immunology 2023
Topics: Humans; Bone Marrow Diseases; Bone Neoplasms
PubMed: 37614231
DOI: 10.3389/fimmu.2023.1265434 -
European Journal of Medical Research Sep 2023Osteosarcoma is the most prevalent and fatal type of bone tumor. Despite advancements in the treatment of other cancers, overall survival rates for patients with... (Review)
Review
Osteosarcoma is the most prevalent and fatal type of bone tumor. Despite advancements in the treatment of other cancers, overall survival rates for patients with osteosarcoma have stagnated over the past four decades Multiple-drug resistance-the capacity of cancer cells to become simultaneously resistant to multiple drugs-remains a significant obstacle to effective chemotherapy. The recent studies have shown that noncoding RNAs can regulate the expression of target genes. It has been proposed that "competing endogenous RNA" activity forms a large-scale regulatory network across the transcriptome, playing important roles in pathological conditions such as cancer. Numerous studies have highlighted that circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) can bind to microRNA (miRNA) sites as competitive endogenous RNAs, thereby affecting and regulating the expression of mRNAs and target genes. These circRNA/lncRNA-associated competitive endogenous RNAs are hypothesized to play significant roles in cancer initiation and progression. Noncoding RNAs (ncRNAs) play an important role in tumor resistance to chemotherapy. However, the molecular mechanisms of the lncRNA/circRNA-miRNA-mRNA competitive endogenous RNA network in drug resistance of osteosarcoma remain unclear. An in-depth study of the molecular mechanisms of drug resistance in osteosarcoma and the elucidation of effective intervention targets are of great significance for improving the overall recovery of patients with osteosarcoma. This review focuses on the molecular mechanisms underlying chemotherapy resistance in osteosarcoma in circRNA-, lncRNA-, and miRNA-mediated competitive endogenous networks.
Topics: Humans; MicroRNAs; RNA, Circular; RNA, Long Noncoding; Drug Resistance, Neoplasm; Osteosarcoma; RNA, Messenger; Bone Neoplasms
PubMed: 37717007
DOI: 10.1186/s40001-023-01309-x