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Frontiers in Endocrinology 2023Osteosarcoma is a highly aggressive and metastatic malignant tumor. It has the highest incidence of all malignant bone tumors and is one of the most common solid tumors... (Review)
Review
Osteosarcoma is a highly aggressive and metastatic malignant tumor. It has the highest incidence of all malignant bone tumors and is one of the most common solid tumors in children and adolescents. Osteosarcoma tissues are often richly infiltrated with inflammatory cells, including tumor-associated macrophages, lymphocytes, and dendritic cells, forming a complex immune microenvironment. The expression of immune checkpoint molecules is also high in osteosarcoma tissues, which may be involved in the mechanism of anti-tumor immune escape. Metabolism and senescence are closely related to the immune microenvironment, and disturbances in metabolism and senescence may have important effects on the immune microenvironment, thereby affecting immune cell function and immune responses. Metabolic modulation and anti-senescence therapy are gaining the attention of researchers as emerging immunotherapeutic strategies for tumors. Through an in-depth study of the interconnection of metabolism and anti- senescence in the tumor immune microenvironment and its regulatory mechanism on immune cell function and immune response, more precise therapeutic strategies can be developed. Combined with the screening and application of biomarkers, personalized treatment can be achieved to improve therapeutic efficacy and provide a scientific basis for clinical decision-making. Metabolic modulation and anti- senescence therapy can also be combined with other immunotherapy approaches, such as immune checkpoint inhibitors and tumor vaccines, to form a multi-level and multi-dimensional immunotherapy strategy, thus further enhancing the effect of immunotherapy. Multidisciplinary cooperation and integrated treatment can optimize the treatment plan and maximize the survival rate and quality of life of patients. Future research and clinical practice will further advance this field, promising more effective treatment options for patients with osteosarcoma. In this review, we reviewed metabolic and senescence characteristics in the immune microenvironment of osteosarcoma and related immunotherapies, and provide a reference for development of more personalized and effective therapeutic strategies.
Topics: Child; Humans; Adolescent; Quality of Life; Immunotherapy; Bone Neoplasms; Osteosarcoma; Tumor Microenvironment
PubMed: 37497349
DOI: 10.3389/fendo.2023.1217669 -
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 -
Current Molecular Pharmacology 2024Osteosarcoma is the most common primary bone malignancy and has a high tendency of local invasion. Although a lot of studies have focused on chemotherapy and combination... (Review)
Review
Osteosarcoma is the most common primary bone malignancy and has a high tendency of local invasion. Although a lot of studies have focused on chemotherapy and combination chemotherapy regimens in recent years, still, there is no particularly perfect regimen for the treatment of relapsed or metastatic OS, and the prognosis is still relatively poor. As a new therapeutic method, targeted therapy provides a new scheme for patients with osteosarcoma and has a wide application prospect. This article reviews the latest progress of targeted therapy for osteosarcoma, and summarizes the research on the corresponding targets of osteosarcoma through six major pathways. These studies can pave the way for new treatments for osteosarcoma patients who need them.
Topics: Humans; Osteosarcoma; Prognosis; Bone Neoplasms
PubMed: 37602543
DOI: 10.2174/1874467217666230821142839 -
Frontiers in Immunology 2023Osteosarcoma is a highly aggressive type of bone cancer with a poor prognosis. In the tumor immune microenvironment, T-cell exhaustion can occur due to various factors,...
BACKGROUND
Osteosarcoma is a highly aggressive type of bone cancer with a poor prognosis. In the tumor immune microenvironment, T-cell exhaustion can occur due to various factors, leading to reduced tumor-killing ability. The purpose of this study was to construct a prognostic model based on T-cell exhaustion-associated genes in osteosarcoma.
METHODS
Patient data for osteosarcoma were retrieved from the TARGET and GEO databases. Consensus clustering was employed to identify two novel molecular subgroups. The dissimilarities in the tumor immune microenvironment between these subgroups were evaluated using the "xCell" algorithm. GO and KEGG analyses were conducted to elucidate the underlying mechanisms of gene expression. Predictive risk models were constructed using the least absolute shrinkage and selection operator algorithm and Cox regression analysis. To validate the prognostic significance of the risk gene expression model at the protein level, immunohistochemistry assays were performed on osteosarcoma patient samples. Subsequently, functional analysis of the key risk gene was carried out through experimentation.
RESULTS
Four gene expression signatures (PLEKHO2, GBP2, MPP1, and VSIG4) linked to osteosarcoma prognosis were identified within the TARGET-osteosarcoma cohort, categorizing patients into two subgroups. The resulting prognostic model showed strong predictive capability, with area under the receiver operating characteristic curve (AUC) values of 0.728/0.740, 0.781/0.658, and 0.788/0.642 for 1, 3, and 5-year survival in both training and validation datasets. Notably, patients in the low-risk group had significantly higher stromal, immune, and ESTIMATE scores compared to high-risk counterparts. Additionally, a nomogram was developed, exhibiting high accuracy in predicting the survival outcome of osteosarcoma patients. Immunohistochemistry, Kaplan-Meier, and time-dependent AUC analyses consistently supported the prognostic value of the risk model within our osteosarcoma patient cohort. experiments provided additional validation by demonstrating that the downregulation of GBP2 promoted the proliferation, migration, and invasion of osteosarcoma cells while inhibiting apoptosis.
CONCLUSION
The current study established a prognostic signature associated with TEX-related genes and elucidated the impact of the pivotal gene GBP2 on osteosarcoma cells via experiments. Consequently, it introduces a fresh outlook for clinical prognosis prediction and sets the groundwork for targeted therapy investigations in osteosarcoma.
Topics: Humans; T-Cell Exhaustion; Prognosis; Osteosarcoma; Bone Neoplasms; Gene Expression; Tumor Microenvironment
PubMed: 38169731
DOI: 10.3389/fimmu.2023.1265098 -
Journal of Immunology (Baltimore, Md. :... Oct 2023Osteosarcoma is a primary malignant bone tumor. Effective chemotherapy regimens for refractory disease are scarce, accounting for no improvement in survival.... (Review)
Review
Osteosarcoma is a primary malignant bone tumor. Effective chemotherapy regimens for refractory disease are scarce, accounting for no improvement in survival. Immune-based cell therapies have emerged as novel alternatives. However, advancements with these therapies have been seen mostly when immune cells are armed to target specific tumor Ags. Recent studies identified cluster of differentiation 70 (CD70) as a promising target to osteosarcoma particularly because CD70 is highly expressed in osteosarcoma lung metastases (Pahl et al. 2015. Cancer Cell Int. 15: 31), and its overexpression by tumors has been correlated with immune evasion and tumor proliferation (Yang et al. 2007. Blood 110: 2537-2544). However, the limited knowledge of the overall CD70 expression within normal tissues and the potential for off-target effect pose several challenges (Flieswasser et al. 2022. J. Exp. Clin. Cancer Res. 41: 12). Nonetheless, CD70-based clinical trials are currently ongoing and are preliminarily showing promising results for patients with osteosarcoma. The present review sheds light on the recent literature on CD70 as it relates to osteosarcoma and highlights the benefits and challenges of targeting this pathway.
Topics: Humans; Osteosarcoma; Cell- and Tissue-Based Therapy; Immune Evasion; Lung Neoplasms; Bone Neoplasms; CD27 Ligand
PubMed: 37722095
DOI: 10.4049/jimmunol.2200591 -
Cancer Research Nov 2023Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease...
UNLABELLED
Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.
SIGNIFICANCE
The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
Topics: Humans; Osteosarcoma; Whole Genome Sequencing; Genomics; Bone Neoplasms; Recurrence; DNA Copy Number Variations; Mutation
PubMed: 37812025
DOI: 10.1158/0008-5472.CAN-23-0385 -
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 -
Molecular Therapy : the Journal of the... May 2024Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and... (Review)
Review
Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment contributes unique signals that influence cancer growth, immunogenicity, and metastasis. Traditional cancer therapies have limited effectiveness due to off-target effects and poor distribution on bones. As a result, therapies with improved specificity and efficacy for treating bone tumors are highly needed. One of the most promising strategies involves the targeted delivery of pharmaceutical agents to the site of bone cancer by introduction of bone-targeting moieties, such as bisphosphonates or oligopeptides. These moieties have high affinities to the bone hydroxyapatite matrix, a structure found exclusively in skeletal tissue, and can enhance the targeting ability and efficacy of anticancer drugs when combating bone tumors. This review focuses on the engineering of small molecules and proteins with bone-targeting moieties for the treatment of bone tumors.
Topics: Humans; Bone Neoplasms; Antineoplastic Agents; Animals; Diphosphonates; Drug Delivery Systems; Osteosarcoma; Sarcoma, Ewing; Molecular Targeted Therapy; Tumor Microenvironment
PubMed: 38449313
DOI: 10.1016/j.ymthe.2024.03.001 -
Advanced Science (Weinheim,... Aug 2023Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative...
Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor-targeting and enzyme-activatable cell-material interface system based on DDDEEK-pY-phenylboronic acid (SAP-pY-PBA) conjugates. Using this tandem-activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP-pY-PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme-responsive biointerface combining supramolecular hydrogels with biomineralization.
Topics: Child; Humans; Adolescent; Biomineralization; Osteosarcoma; Hydrogels; Bone Neoplasms; Biomarkers
PubMed: 37211693
DOI: 10.1002/advs.202302272 -
BMC Cancer Sep 2023Novel and effective immunotherapies are required for refractory or recurrent sarcomas. Transforming growth factor-beta (TGF-β) is a diverse regulatory and fibrogenic...
Exploratory study of an anti-PD-L1/TGF-β antibody, TQB2858, in patients with refractory or recurrent osteosarcoma and alveolar soft part sarcoma: a report from Chinese sarcoma study group (TQB2858-Ib-02).
BACKGROUND
Novel and effective immunotherapies are required for refractory or recurrent sarcomas. Transforming growth factor-beta (TGF-β) is a diverse regulatory and fibrogenic protein expressed in multiple sarcoma tumors that promotes epithelial-mesenchymal transition and excessive deposition of extracellular matrix. This study evaluated the efficacy and safety of the anti-PD-L1/TGF-β antibody TQB2858 in patients with refractory osteosarcoma and alveolar soft part sarcoma (ASPS).
METHODS
This single-arm phase 1b exploratory study included patients with refractory osteosarcoma or ASPS who had previously undergone at least two lines of systemic therapy. Patients were administered 1200 mg of TQB2858 once every 3 weeks. The primary endpoint was objective response rate (ORR), with null and alternative hypotheses of ORR ≤5% and ≥20%, respectively. Exploratory biomarker analyses using immunohistochemistry (IHC) staining (for PD-L1 and TGF-β) were performed on pre-treatment tumor samples.
RESULTS
Eleven eligible patients were included in this study. TQB2858 did not demonstrate evidence of efficacy as 0/5 osteosarcomas had any objective response, while 2/6 ASPS showed a partial response. The median progression-free survivals were 1.51 (1.38, Not Evaluable) and 2.86 (1.38, Not Evaluable) months for the osteosarcoma and ASPS groups, respectively. None of the administered cycles met the criteria for unacceptable toxicity. Other Grade 3 toxicities included abnormal liver function and elevation of γ-glutamyl transferase. IHC analysis revealed that functional enrichment in the TGF-β pathway or PD-L1 was not associated with treatment outcomes.
CONCLUSIONS
The combination of PD-L1 and TQB2858 did not significantly improve the ORR in patients with recurrent osteosarcoma. However, it improved immunogenic responses in ASPS, even after progression upon anti-PD-1/PD-L1 therapy, with an acceptable safety profile. IHC profiling with pathway enrichment analysis may not have any predictive value for survival outcomes.
TRIAL REGISTRATION
Prospectively registered in the Ethical Review Committee of Peking University People's Hospital. The trial registration number is 2021PHA105-001 and 2021PHA140-001 and the registration date was March 2, 2022.
CLINICALTRIALS
gov Identifier CTR20213001 and CTR20220390.
Topics: Humans; Asian People; Bone Neoplasms; East Asian People; Osteosarcoma; Sarcoma, Alveolar Soft Part; Soft Tissue Neoplasms; Transforming Growth Factor beta; B7-H1 Antigen; Antineoplastic Agents, Immunological; Antibodies
PubMed: 37715133
DOI: 10.1186/s12885-023-11390-4