-
International Journal of Molecular... Sep 2020The bone microenvironment is an ideal fertile soil for both primary and secondary tumors to seed. The occurrence and development of osteosarcoma, as a primary bone... (Review)
Review
The bone microenvironment is an ideal fertile soil for both primary and secondary tumors to seed. The occurrence and development of osteosarcoma, as a primary bone tumor, is closely related to the bone microenvironment. Especially, the metastasis of osteosarcoma is the remaining challenge of therapy and poor prognosis. Increasing evidence focuses on the relationship between the bone microenvironment and osteosarcoma metastasis. Many elements exist in the bone microenvironment, such as acids, hypoxia, and chemokines, which have been verified to affect the progression and malignance of osteosarcoma through various signaling pathways. We thoroughly summarized all these regulators in the bone microenvironment and the transmission cascades, accordingly, attempting to furnish hints for inhibiting osteosarcoma metastasis via the amelioration of the bone microenvironment. In addition, analysis of the cross-talk between the bone microenvironment and osteosarcoma will help us to deeply understand the development of osteosarcoma. The cellular and molecular protagonists presented in the bone microenvironment promoting osteosarcoma metastasis will accelerate the exploration of novel therapeutic strategies towards osteosarcoma.
Topics: Animals; Bone Neoplasms; Humans; Neoplasm Metastasis; Osteosarcoma; Signal Transduction; Tumor Microenvironment
PubMed: 32977425
DOI: 10.3390/ijms21196985 -
Cells Apr 2020Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly... (Review)
Review
Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.
Topics: Animals; Bone Remodeling; Humans; Immune System; Mesenchymal Stem Cells; Molecular Targeted Therapy; Osteosarcoma; Tumor Microenvironment
PubMed: 32326444
DOI: 10.3390/cells9040976 -
British Journal of Pharmacology Jan 2022Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is... (Review)
Review
Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is highly predisposed in Paget's disease of the bone, and both have common characteristic skeletal features due to rapid bone remodelling. Osteosarcoma prognosis is location dependent, which further emphasizes the likely contribution of the bone microenvironment in its pathogenesis. Mechanobiology describes the processes involved when mechanical cues from the changing physical microenvironment of the bone are transduced to biological pathways through mechanosensitive cellular components. Mechanobiology-driven therapies have been used to curb tumour progression by direct alteration of the physical microenvironment or inhibition of metastasis-associated mechanosensitive proteins. This review emphasizes the contribution of mechanobiology to the progression of osteosarcoma and sheds light on current mechanobiology-based therapies and potential new targets for improving disease management. Additionally, the many different 3D models currently used to study osteosarcoma mechanobiology are summarized.
Topics: Biophysics; Bone Neoplasms; Humans; Osteitis Deformans; Osteosarcoma; Tumor Microenvironment
PubMed: 34679192
DOI: 10.1111/bph.15713 -
Frontiers in Immunology 2022Aging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary...
BACKGROUND
Aging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction.
METHODS
Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM.
RESULTS
Three molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score.
CONCLUSION
Aging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.
Topics: Humans; Osteosarcoma; Prognosis; Gene Ontology; Bone Neoplasms; Aging; Tumor Microenvironment
PubMed: 36275664
DOI: 10.3389/fimmu.2022.997765 -
Veterinary Pathology May 2022Osteosarcoma (OS) is the most common malignant bone tumor in children. Despite efforts to develop and implement new therapies, patient outcomes have not measurably... (Review)
Review
Osteosarcoma (OS) is the most common malignant bone tumor in children. Despite efforts to develop and implement new therapies, patient outcomes have not measurably improved since the 1980s. Metastasis continues to be the main source of patient mortality, with 30% of cases developing metastatic disease within 5 years of diagnosis. Research models are critical in the advancement of cancer research and include a variety of species. For example, xenograft and patient-derived xenograft (PDX) mouse models provide opportunities to study human tumor cells while transgenic models have offered significant insight into the molecular mechanisms underlying OS development. A growing recognition of naturally occurring cancers in companion species has led to new insights into how veterinary patients can contribute to studies of cancer biology and drug development. The study of canine cases, including the use of diagnostic tissue archives and clinical trials, offers a potential mechanism to further canine and human cancer research. Advancement in the field of OS research requires continued development and appropriate use of animal models. In this review, animal models of OS are described with a focus on the mouse and tumor-bearing pet dog as parallel and complementary models of human OS.
Topics: Animals; Bone Neoplasms; Disease Models, Animal; Dog Diseases; Dogs; Humans; Mice; Osteosarcoma
PubMed: 35341404
DOI: 10.1177/03009858221083038 -
Biomedical Engineering Online Mar 2021Osteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong... (Review)
Review
Osteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong invasiveness, rapid disease progression, and extremely high mortality rate; it is considered as a serious threat to the human health globally. The incidence of OS is common in the metaphysis of long tubular bones, but rare in the spine, pelvis, and sacrum areas; moreover, majority of the OS patients present with only a single lesion. OS has a bimodal distribution pattern, that is, its incidence peaks in the second decade of life and in late adulthood. We examine historical and current literature to present a succinct review of OS. In this review, we have discussed the types, clinical diagnosis, and modern and future treatment methods of OS. The purpose of this article is to inspire new ideas to develop more effective therapeutic options.
Topics: Antineoplastic Agents; Bone Neoplasms; Disease Progression; Genetic Therapy; Humans; Immunotherapy; Magnetic Resonance Imaging; Neoplasm Staging; Osteosarcoma; Radiotherapy; Tomography, X-Ray Computed
PubMed: 33653371
DOI: 10.1186/s12938-021-00860-0 -
Clinical Cancer Research : An Official... Nov 2022Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis....
PURPOSE
Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis. Although effective for some soft tissue sarcomas, current immunotherapeutic approaches for the treatment of bone sarcomas have been largely ineffective, necessitating a deeper understanding of bone sarcoma immunobiology.
EXPERIMENTAL DESIGN
Multiplex immunofluorescence analysis of immune infiltration in relapsed versus primary disease was conducted. To better understand immune states and drivers of immune infiltration, especially during disease progression, we performed single-cell RNA sequencing (scRNAseq) of immune populations from paired blood and bone sarcoma tumor samples.
RESULTS
Our multiplex immunofluorescence analysis revealed increased immune infiltration in relapsed versus primary disease in both Ewing sarcoma and osteosarcoma. scRNAseq analyses revealed terminally exhausted CD8+ T cells expressing co-inhibitory receptors in osteosarcoma and an effector T-cell subpopulation in Ewing sarcoma. In addition, distinct subsets of CD14+CD16+ macrophages were present in Ewing sarcoma and osteosarcoma. To determine pathways driving tumor immune infiltration, we conducted intercellular communication analyses and uncovered shared mechanisms of immune infiltration driven by CD14+CD16+ macrophages and unique pathways of immune infiltration driven by CXCL10 and CXCL12 in osteosarcoma.
CONCLUSIONS
Our study provides preclinical rationale for future investigation of specific immunotherapeutic targets upon relapse and provides an invaluable resource of immunologic data from bone sarcomas.
Topics: Adolescent; Humans; Sarcoma, Ewing; Neoplasm Recurrence, Local; Osteosarcoma; Bone Neoplasms; Sarcoma; Cell Communication
PubMed: 36074145
DOI: 10.1158/1078-0432.CCR-22-1471 -
International Journal of Molecular... Jul 2020Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after... (Review)
Review
Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
Topics: Bone Neoplasms; Humans; Neoplasm Metastasis; Osteosarcoma; Signal Transduction; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 32717819
DOI: 10.3390/ijms21155207 -
The Lancet. Oncology Mar 2020Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been...
BACKGROUND
Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma.
METHODS
We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605.
FINDINGS
Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects.
INTERPRETATION
Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation.
FUNDING
Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.
Topics: Adult; Anilides; Bone Neoplasms; Case-Control Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Prognosis; Protein Kinase Inhibitors; Pyridines; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Sarcoma, Ewing; Survival Rate; Young Adult
PubMed: 32078813
DOI: 10.1016/S1470-2045(19)30825-3 -
International Journal of Molecular... Sep 2020Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure.... (Review)
Review
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Osteosarcoma; Survival Rate
PubMed: 32961800
DOI: 10.3390/ijms21186885