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BMC Musculoskeletal Disorders Jul 2023The objective of this study was to assess the expression profile of CD44v6, a potential cancer stem cell marker, and its diagnostic and predictive significance in three...
BACKGROUND
The objective of this study was to assess the expression profile of CD44v6, a potential cancer stem cell marker, and its diagnostic and predictive significance in three distinct types of primary bone tumors.
METHODS
In this study, we utilized real-time qRT-PCR and immunohistochemistry to examine the gene and protein levels of CD44v6 in a total of 138 fresh bone tissues. This included 69 tumor tissues comprising osteosarcoma (N = 23), chondrosarcoma (N = 23), and GCT (N = 23), as well as 69 corresponding non-cancerous tumor margins. Furthermore, we investigated the circulating level of CD44v6 by isolating peripheral blood mononuclear cells from 92 blood samples. Among these, 69 samples were obtained from patients diagnosed with primary bone tumors, while the remaining 23 samples were from healthy donors. The primary objectives of our investigation were to assess the correlation between CD44v6 expression levels and clinic-pathological features of the patients, as well as to evaluate the diagnostic and predictive values of CD44v6 in this context.
RESULTS
In patients with osteosarcoma and chondrosarcoma tumors, both the gene and protein expression of CD44v6 were found to be significantly higher compared to the GCT group. Furthermore, the circulating level of CD44v6 was notably elevated in patients diagnosed with osteosarcoma and chondrosarcoma in comparison to the GCT group and patients with malignant tumor characteristics. Additionally, we observed a strong correlation between the gene and protein levels of CD44v6 and important tumor indicators such as tumor grade, metastasis, recurrence, and size at the tumor site. CD44v6 shows potential in differentiating patients with bone tumors from both control groups and tumor groups with severe and invasive characteristics from those with non-severe features. Importantly, the expression level of CD44v6 also demonstrated predictive value for determining tumor grade and the likelihood of recurrence.
CONCLUSION
CD44v6 is likely to play a role in the development of primary bone tumors and has the potential to serve as a diagnostic biomarker for bone cancer. However, to obtain more accurate and conclusive findings, further mechanistic investigations involving larger population samples are necessary.
Topics: Humans; Clinical Relevance; Leukocytes, Mononuclear; Bone Neoplasms; Osteosarcoma; Chondrosarcoma; Biomarkers, Tumor
PubMed: 37491225
DOI: 10.1186/s12891-023-06738-7 -
Orthopaedic Surgery Sep 2023Osteosarcoma (OS) is a common malignant bone tumor that occurs mostly in children and adolescents. At present, surgery after chemotherapy or postoperative adjuvant... (Review)
Review
Osteosarcoma (OS) is a common malignant bone tumor that occurs mostly in children and adolescents. At present, surgery after chemotherapy or postoperative adjuvant chemotherapy is the main treatment plan. However, the efficacy of chemotherapeutic drugs is limited by the occurrence of chemotherapeutic resistance, toxicity to normal cells, poor pharmacokinetic performance, and drug delivery failure. The delivery of chemotherapy drugs to the bone to treat OS may fail for a variety of reasons, such as a lack of selectivity for OS cells, initial sudden release, short-term release, and the presence of biological barriers (such as the blood-bone marrow barrier). Nanomaterials are new materials with at least one dimension on the nanometer scale (1-100 nm) in three-dimensional space. These materials have the ability to penetrate biological barriers and can accumulate preferentially in tumor cells. Studies have shown that the effective combination of nanomaterials and traditional chemotherapy can significantly improve the therapeutic effect. Therefore, this article reviews the latest research progress on the use of nanomaterials in OS chemotherapy.
Topics: Child; Humans; Adolescent; Antineoplastic Agents; Osteosarcoma; Bone Neoplasms; Nanostructures; Drug Delivery Systems
PubMed: 37403654
DOI: 10.1111/os.13806 -
Aging Nov 2023Bone is the second most frequent site of metastasis for Liver hepatocellular carcinoma (LIHC), which leads to an extremely poor prognosis. Identifying novel biomarkers...
BACKGROUND
Bone is the second most frequent site of metastasis for Liver hepatocellular carcinoma (LIHC), which leads to an extremely poor prognosis. Identifying novel biomarkers and therapeutic targets for LIHC patients with bone metastasis is urgently needed.
METHODS
In this study, we used multiple databases for comprehensive bioinformatics analysis, including TCGA, GEO, ICGC, GTEx, TISIDB, and TIMER, to identify key genes related to bone metastasis of LIHC. Clinical tissues and tissue microarray were adopted to assess the expression of TOP2A through qRT-PCR and immunohistochemistry analyses in LIHC. Gene enrichment analysis, DNA methylation, gene mutation, prognosis, and tumor immunity associated with TOP2A in LIHC were investigated. and experiments were performed to explore the functional role of TOP2A in LIHC bone metastasis.
RESULTS
We identified that TOP2A was involved in LIHC bone metastasis. Clinically, TOP2A was highly expressed in LIHC tumoral specimens, with the highest level in the bone metastasis lesions. TOP2A was an independent prognostic factor that higher expression of TOP2A was markedly associated with poorer prognosis in LIHC. Moreover, the abnormal expression of TOP2A might be related to DNA hypomethylation, often accompanied by TP53 mutation, immune escape and immunotherapy failure. Enrichment analysis and validation experiments unveiled that TOP2A stimulated the Hippo-YAP signaling pathway in LIHC. Functional assays confirmed that TOP2A could promote bone-specific metastatic potential and tumor-induced osteolysis in LIHC.
CONCLUSIONS
These findings unveil that TOP2A might be a novel prognostic biomarker and therapeutic target for LIHC bone metastasis.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Bone Neoplasms; Biological Assay; Prognosis
PubMed: 37980167
DOI: 10.18632/aging.205216 -
Cell Death & Disease Sep 2023The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS,...
The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS, but there is a lack of safe and efficient delivery systems to encapsulate siRNAs for in vivo administration. This study presented a synthetic biological strategy that remolds the host liver with synthesized genetic circuits for efficient in vivo VEGFR2 siRNA delivery. After being taken-up by hepatocytes, the genetic circuit (in the form of a DNA plasmid) reprogrammed the liver to drive the autonomous intrahepatic assembly and encapsulation of VEGFR2 siRNAs into secretory small extracellular vesicles (sEVs), thus allowing for the transport of self-assembled VEGFR2 siRNAs towards the lung. The results showed that our strategy was superior to the positive medicine (Apatinib) for OS lung metastasis in terms of therapeutic efficacy and toxic adverse effects and may provide a feasible and viable therapeutic solution for lung metastatic OS.
Topics: Humans; RNA, Small Interfering; Extracellular Vesicles; Osteosarcoma; Bone Neoplasms; Lung
PubMed: 37739958
DOI: 10.1038/s41419-023-06159-3 -
Seminars in Nuclear Medicine May 2024Recent developments in hybrid SPECT/CT systems and the use of cadmium-zinc-telluride (CZT) detectors have improved the diagnostic accuracy of bone scintigraphy. These... (Review)
Review
Recent developments in hybrid SPECT/CT systems and the use of cadmium-zinc-telluride (CZT) detectors have improved the diagnostic accuracy of bone scintigraphy. These advancements have paved the way for novel quantitative approaches to accurate and reproducible treatment monitoring of bone metastases. PET/CT imaging using [F]F-FDG and [F]F-NaF have shown promising clinical utility in bone metastases assessment and monitoring response to therapy and prediction of treatment response in a broad range of malignancies. Additionally, specific tumor-targeting tracers like [Tc]Tc-PSMA, [Ga]Ga-PSMA, or [C]C- or [F]F-Choline revealed high diagnostic performance for early assessment and prognostication of bone metastases, particularly in prostate cancer. PET/MRI appears highly accurate imaging modality, but has associated limitations notably, limited availability, more complex logistics and high installation costs. Advances in artificial intelligence (Al) seem to improve the accuracy of imaging modalities and provide an assistant role in the evaluation of treatment response of bone metastases.
Topics: Humans; Bone Neoplasms; Positron Emission Tomography Computed Tomography; Magnetic Resonance Imaging; Single Photon Emission Computed Tomography Computed Tomography; Treatment Outcome
PubMed: 38172001
DOI: 10.1053/j.semnuclmed.2023.11.005 -
Clinical and Translational Medicine May 2024Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma...
BACKGROUND
Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival.
METHODS
Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target.
RESULTS
In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression.
CONCLUSIONS
Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients.
KEY POINTS
WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.
Topics: Osteosarcoma; Humans; Drug Resistance, Neoplasm; Wnt Proteins; Animals; Mice; Bone Neoplasms; Neoplasm Metastasis; Neoplastic Stem Cells; Cell Line, Tumor
PubMed: 38689429
DOI: 10.1002/ctm2.1670 -
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