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Science Advances Jan 2024Bone 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...
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 () or mitochondrial mitofusin 2 () 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.
Topics: Humans; Osteocytes; Bone and Bones; Bone Neoplasms; GTP Phosphohydrolases; Mitochondria; Tumor Microenvironment
PubMed: 38232158
DOI: 10.1126/sciadv.adi4298 -
Redox Biology Jun 2023Bone cancer pain (BCP) impairs patients' quality of life. However, the underlying mechanisms are still unclear. This study investigated the role of spinal interneuron...
Bone cancer pain (BCP) impairs patients' quality of life. However, the underlying mechanisms are still unclear. This study investigated the role of spinal interneuron death using a pharmacological inhibitor of ferroptosis in a mouse model of BCP. Lewis lung carcinoma cells were inoculated into the femur, resulting in hyperalgesia and spontaneous pain. Biochemical analysis revealed that spinal levels of reactive oxygen species and malondialdehyde were increased, while those of superoxide dismutase were decreased. Histological analysis showed the loss of spinal GAD65+ interneurons and provided ultrastructural evidence of mitochondrial shrinkage. Pharmacologic inhibition of ferroptosis using ferrostatin-1 (FER-1, 10 mg/kg, intraperitoneal for 20 consecutive days) attenuated ferroptosis-associated iron accumulation and lipid peroxidation and alleviated BCP. Furthermore, FER-1 inhibited the pain-associated activation of ERK1/2 and COX-2 expression and prevented the loss of GABAergic interneurons. Moreover, FER-1 improved analgesia by the COX-2 inhibitor Parecoxib. Taken together, this study shows that pharmacological inhibition of ferroptosis-like cell death of spinal interneurons alleviates BCP in mice. The results suggest that ferroptosis is a potential therapeutic target in patients suffering on BCP and possibly other types of pain.
Topics: Mice; Animals; Hyperalgesia; Cancer Pain; Ferroptosis; Quality of Life; Pain; Bone Neoplasms; Cell Death
PubMed: 37084690
DOI: 10.1016/j.redox.2023.102700 -
Nature Communications Jun 2023Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as...
Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation.
Topics: Child; Humans; Immunotherapy, Adoptive; T-Lymphocytes; Immunotherapy; Osteosarcoma; Bone Neoplasms; Cell Line, Tumor; Alkaline Phosphatase
PubMed: 37291203
DOI: 10.1038/s41467-023-39097-x -
Endocrine-related Cancer Sep 2023Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has... (Review)
Review
Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling - produced by concerted actions of bone-building osteoblasts, bone-resorbing osteoclasts, and regulatory osteocytes - may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the entwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions.
Topics: Male; Humans; Prostatic Neoplasms; Bone Neoplasms; Androgen Antagonists; Bone and Bones; Treatment Outcome; Tumor Microenvironment
PubMed: 37226936
DOI: 10.1530/ERC-22-0360 -
JNCI Cancer Spectrum Oct 2023
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Bone Neoplasms; Radium; Magnetic Resonance Imaging
PubMed: 37952210
DOI: 10.1093/jncics/pkad083 -
International Journal of Molecular... Jul 2023Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most... (Review)
Review
Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, it has heterogeneous abnormalities, including somatic DNA copy number alteration, ploidy, chromosomal amplification, and chromosomal loss and gain. Unfortunately, clinical outcomes have not significantly improved in over 30 years. Currently, no effective molecularly targeted therapies are available for this disease. Several genomic studies showed inactivation in the tumor suppressor genes, including , , and and hyperactivation of the tumor promoter genes, including and , in OS. Alterations in the major signaling pathways, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, NOTCH, Hedgehog/Gli, TGF-β, RTKs, RANK/RANKL, and NF-κB signaling pathways, have been identified in OS development and metastasis. Although OS treatment is currently based on surgical excision and systematic multiagent therapies, several potential targeted therapies are in development. This review focuses on the major signaling pathways of OS, and we propose a biological rationale to consider novel and targeted therapies in the future.
Topics: Adolescent; Humans; Child; Phosphatidylinositol 3-Kinases; Hedgehog Proteins; Osteosarcoma; Carcinogenesis; Cell Transformation, Neoplastic; Bone Neoplasms
PubMed: 37511127
DOI: 10.3390/ijms241411367 -
Chinese Medical Journal Oct 2023Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is... (Review)
Review
Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.
Topics: Child; Adolescent; Humans; Bone Neoplasms; Signal Transduction; Bone and Bones; Treatment Outcome; Osteosarcoma; Tumor Microenvironment
PubMed: 37649421
DOI: 10.1097/CM9.0000000000002800 -
Advanced Science (Weinheim,... Jun 2023Bone is the second leading metastatic site for hepatocellular carcinoma (HCC). Patients with HCC and bone metastasis suffer poor quality of life and reduced survival...
Bone is the second leading metastatic site for hepatocellular carcinoma (HCC). Patients with HCC and bone metastasis suffer poor quality of life and reduced survival time. Extracellular vesicles (EVs) are widely involved in HCC formation and metastasis. However, the communication between primary HCC and bone lesions mediated by EVs remains unclear and the possible effect of bone metastasis on the progression of HCC remains largely unknown. Here, bone-metastasized HCC-derived EVs (BM-EVs) are found to localize to orthotropic HCC cells and promote HCC progression. Mechanistically, miR-3190-5p (miR-3190) is upregulated in intracellular HCC cells isolated from bone lesions as well as in their derived EVs. miR-3190 in BM-EVs is transferred into orthotopic tumor cells and enhances their metastatic capacity by downregulating AlkB homolog 5 (ALKBH5) expression. Decreased level of ALKBH5 exacerbates the prometastatic characteristics of HCC by modulating gene expression in N6-methyladenosine-dependent and -independent ways. Finally, antagomir-miR-3190-loaded liposomes with HCC affinity successfully suppress HCC progression in mice treated with BM-EVs. These findings reveal that BM-EVs initiate prometastatic cascades in orthotopic HCC by transferring ALKBH5-targeting miR-3190 and miR-3190 is serving as a promising therapeutic target for inhibiting the progression of HCC in patients with bone metastasis.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Liver Neoplasms; MicroRNAs; Quality of Life; Extracellular Vesicles; Cell Line, Tumor; Bone Neoplasms
PubMed: 37096833
DOI: 10.1002/advs.202207080 -
Deutsches Arzteblatt International Jun 2023Osteosarcoma and Ewing's sarcoma in children and adolescents require age-specific interdisciplinary diagnosis and treatment to achieve optimal therapeutic outcomes.
BACKGROUND
Osteosarcoma and Ewing's sarcoma in children and adolescents require age-specific interdisciplinary diagnosis and treatment to achieve optimal therapeutic outcomes.
METHODS
The diagnosis and treatment of malignant bone tumors in childhood and adolescence are presented in the light of publications retrieved by a selective search, pertinent guidelines, and the authors' extensive experience in an interdisciplinary cancer center.
RESULTS
Bone sarcomas make up approximately 5% of all malignancies in children and adolescents; the most common types are Ewing's sarcoma and osteosarcoma. Patients are often not referred to a specialized center until long after the onset of symptoms, as they and their physicians rarely consider the possibility of a bone tumor, and the symptoms are often trivialized. Bone pain of unknown origin, swelling, and functional limitations should be investigated with conventional x-rays. Lesions of unclear origin should be biopsied after a meticulous clinical and radiologic evaluation. Multimodal treatment consists of neo - adjuvant chemotherapy, limb-preserving resection if possible, and radiotherapy where indicated. In multicenter studies, patients with osteosarcoma achieve event-free survival in 64% of cases if their disease is localized, and 28% if it is metastatic; the corresponding figures for patients with Ewing's sarcoma are 80% and 27%, respectively.
CONCLUSION
With implementation of the current treatment recommendations, most children and adolescents with malignant bone tumors can be treated successfully with curative intent. These patients should be referred to a sarcoma center for diagnosis and treatment.
Topics: Humans; Child; Adolescent; Sarcoma, Ewing; Osteosarcoma; Bone Neoplasms; Combined Modality Therapy
PubMed: 37097079
DOI: 10.3238/arztebl.m2023.0079 -
Journal of Orthopaedic Surgery and... Mar 2024Osteofibrous dysplasia (OFD) is a rare, benign, self-limited bone disorder with a relatively low incidence, accounting for approximately 0.2% of all primary bone tumors.... (Review)
Review
Osteofibrous dysplasia (OFD) is a rare, benign, self-limited bone disorder with a relatively low incidence, accounting for approximately 0.2% of all primary bone tumors. It was frequently found intra-cortical of the mid-shaft of the tibia. OFD can also occur in other skeletal regions, including the fibula, ulna, radius, femur, humerus, ischium, rib, tarsus, metatarsals, vertebral, and capitate. OFD can present with asymptomatic, mass, pain, swelling, deformity, and even pathological fracture. OFD might be misdiagnosed as adamantinoma (AD) and because they are three subtypes origin from the same family of bone tumors and have similar imaging features. Moreover, pathology could provide evidence for an accurate diagnosis of OFD, but misdiagnosis may occur due to small sampling materials. To date, few studies have comprehensively introduced the epidemiology, clinical manifestations, pathogenesis, radiological features, pathology, and treatment for OFD. We herein discuss clinical signs, diagnosis methods, and treatment options of OFD to improve the understanding of OFD, which is helpful for accurate diagnosis and appropriate treatment.
Topics: Humans; Adamantinoma; Bone Neoplasms; Tibia; Bone Diseases, Developmental; Fibrous Dysplasia of Bone
PubMed: 38539216
DOI: 10.1186/s13018-024-04682-3