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Communications Biology Aug 2023Canine osteosarcoma is increasingly recognized as an informative model for human osteosarcoma. Here we show in one of the largest clinically annotated canine...
Canine osteosarcoma is increasingly recognized as an informative model for human osteosarcoma. Here we show in one of the largest clinically annotated canine osteosarcoma transcriptional datasets that two previously reported, as well as de novo gene signatures devised through single sample Gene Set Enrichment Analysis (ssGSEA), have prognostic utility in both human and canine patients. Shared molecular pathway alterations are seen in immune cell signaling and activation including TH1 and TH2 signaling, interferon signaling, and inflammatory responses. Virtual cell sorting to estimate immune cell populations within canine and human tumors showed similar trends, predominantly for macrophages and CD8+ T cells. Immunohistochemical staining verified the increased presence of immune cells in tumors exhibiting immune gene enrichment. Collectively these findings further validate naturally occurring osteosarcoma of the pet dog as a translationally relevant patient model for humans and improve our understanding of the immunologic and genomic landscape of the disease in both species.
Topics: Humans; Animals; Dogs; Prognosis; Transcriptome; Genomics; Osteosarcoma; Bone Neoplasms
PubMed: 37591946
DOI: 10.1038/s42003-023-05208-z -
Journal of Cellular Physiology Mar 2024N6-methyladenosine (m A) is one of the main epitranscriptomic modifications that accelerates the progression of malignant tumors by modifying RNA. Methyltransferase-like...
N6-methyladenosine (m A) is one of the main epitranscriptomic modifications that accelerates the progression of malignant tumors by modifying RNA. Methyltransferase-like 16 (METTL16) is a newly identified methyltransferase that has been found to play an important oncogenic role in a few malignancies; however, its function in osteosarcoma (OS) remains unclear. In this study, METTL16 was found to be upregulated in OS tissues, and associated with poor prognosis in OS patients. Functionally, METTL16 substantially promoted OS cell proliferation, migration, and invasion in vitro and OS growth in vivo. Mechanistically, vacuolar protein sorting protein 33b (VPS33B) was identified as the downstream target of METTL16, which induced m A modification of VPS33B and impaired the stability of the VPS33B transcript, thereby degrading VPS33B. In addition, VPS33B was found to be downregulated in OS tissues, VPS33B knockdown markedly attenuated shMETTL16-mediated inhibition on OS progression. Finally, METTL16/VPS33B might facilitate OS progression through PI3K/AKT pathway. In summary, this study revealed an important role for the METTL16-mediated m A modification in OS progression, implying it as a promising target for OS treatment.
Topics: Humans; Bone Neoplasms; Methyltransferases; Osteosarcoma; Phosphatidylinositol 3-Kinases; Protein Transport; Vesicular Transport Proteins; Adenosine; Cell Line, Tumor
PubMed: 37357526
DOI: 10.1002/jcp.31068 -
International Journal of Molecular... Aug 2023Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have... (Review)
Review
Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.
Topics: Child; Young Adult; Humans; Phytoestrogens; Osteosarcoma; Apoptosis; Estrogens; Bone Neoplasms
PubMed: 37686148
DOI: 10.3390/ijms241713344 -
ACS Nano Nov 2023Catalytic tumor therapy based on two-dimensional (2D) nanomaterials is a burgeoning and promising tumor therapeutic modality. However, the inefficient utilization and...
Catalytic tumor therapy based on two-dimensional (2D) nanomaterials is a burgeoning and promising tumor therapeutic modality. However, the inefficient utilization and conversion of exogenous stimulation, single catalytic modality, and unsatisfactory therapeutic efficiency in the tumor microenvironment (TME) have seriously restricted their further application in tumor therapy. Herein, the heterogeneous carbon nitride-based nanoagent named T-HCN@CuMS was successfully developed, which dramatically improved the efficiency of the tumor therapeutic modality. Benefiting from the donor-acceptor (triazine-heptazine) structure within the heterogeneous carbon nitride nanosheets (HCN) and the construction of interplanar heterostructure with copper loaded metallic molybdenum bisulfide nanosheets (CuMS), T-HCN@CuMS presented a favorable photo-induced catalytic property to generate abundant reactive oxygen species (ROS) under near-infrared (NIR) light irradiation. Besides, the choice of CuMS simultaneously enabled this nanoagent to efficiently catalyze the Fenton-like reaction and trigger cell cuproptosis, a recently recognized regulated cell death mode characterized by imbalanced intracellular copper homeostasis and aggregation of lipoylated mitochondrial proteins. Moreover, upon surface modification with cRGD-PEG-DSPE, T-HCN@CuMS was prepared and endowed with improved dispersibility and αβ integrins targeting ability. In general, through the rational design, T-HCN@CuMS was facilely prepared and had achieved satisfactory antitumor and antimetastasis outcomes both and in a high-metastatic orthotopic osteosarcoma model. This strategy could offer an idea to treat malignant diseases based on 2D nanomaterials.
Topics: Humans; Copper; Oxidative Stress; Neoplasms; Osteosarcoma; Bone Neoplasms; Tumor Microenvironment; Cell Line, Tumor; Nitriles
PubMed: 37902237
DOI: 10.1021/acsnano.3c04903 -
Cancer Research Jul 2023Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These...
UNLABELLED
Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. Survival significantly decreased and metastatic incidence increased in mice expressing p53 mutants compared with p53-null mice, suggesting GOF. RNA sequencing of primary osteosarcomas revealed vastly different gene expression profiles between tumors expressing the missense mutants and p53-null tumors. Further, p53R172H and p53R245W each regulated unique transcriptomes and pathways through interactions with a distinct repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines and promotes metastasis in allogeneic transplantation models. In addition, analyses of p53R248W chromatin immunoprecipitation peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53.
SIGNIFICANCE
The p53 DNA binding domain contact mutant p53R245W, but not the structural mutant p53R172H, interacts with KLF15 to drive metastasis in somatic osteosarcoma, providing a potential vulnerability in tumors expressing p53R245W mutation.
Topics: Mice; Humans; Animals; Tumor Suppressor Protein p53; Osteosarcoma; Mutation; Mice, Knockout; Bone Neoplasms; Transcription Factors; DNA; Cell Line, Tumor
PubMed: 37205631
DOI: 10.1158/0008-5472.CAN-22-3464 -
PloS One 2023Immune checkpoint inhibitors (ICIs) have been developed for canine tumour treatment, and pilot clinical studies have demonstrated their antitumour efficacy in dogs with...
Immune checkpoint inhibitors (ICIs) have been developed for canine tumour treatment, and pilot clinical studies have demonstrated their antitumour efficacy in dogs with oral malignant melanoma (OMM). Although ICIs have been approved for various human malignancies, their clinical benefits in other tumour types remain to be elucidated in dogs. Here, we conducted a clinical study of c4G12, a canine chimeric anti-PD-L1 antibody, to assess its safety and efficacy in dogs with various advanced malignant tumours (n = 12) at the Veterinary Teaching Hospital of Hokkaido University from 2018 to 2023. Dogs with digit or foot pad malignant melanoma (n = 4), osteosarcoma (n = 2), hemangiosarcoma (n = 1), transitional cell carcinoma (n = 1), nasal adenocarcinoma (n = 1), B-cell lymphoma (n = 1), or undifferentiated sarcoma (n = 2) were treated with 2 or 5 mg/kg c4G12 every 2 weeks. Treatment-related adverse events of any grade were observed in eight dogs (66.7%), including elevated aspartate aminotransferase (grade 3) in one dog (8.3%) and thrombocytopenia (grade 4) in another dog (8.3%). Among dogs with target disease at baseline (n = 8), as defined by the response evaluation criteria for solid tumours in dogs (cRECIST), one dog with nasal adenocarcinoma and another with osteosarcoma experienced a partial response (PR), with an objective response rate of 25.0% (2 PR out of 8 dogs; 95% confidence interval: 3.2-65.1%). These results suggest that c4G12 is safe and tolerable and shows antitumor effects in dogs with malignant tumours other than OMM. Further clinical studies are warranted to identify the tumour types that are most likely to benefit from c4G12 treatment.
Topics: Humans; Dogs; Animals; Hospitals, Animal; Hospitals, Teaching; Melanoma; Treatment Outcome; Mouth Neoplasms; Adenocarcinoma; Osteosarcoma; Melanoma, Cutaneous Malignant
PubMed: 37792729
DOI: 10.1371/journal.pone.0291727 -
Clinical Orthopaedics and Related... Nov 2023Osteosarcoma is the most common secondary malignancy among survivors of retinoblastoma. Most previous reports on secondary malignancy of retinoblastoma included all... (Review)
Review
BACKGROUND
Osteosarcoma is the most common secondary malignancy among survivors of retinoblastoma. Most previous reports on secondary malignancy of retinoblastoma included all types of secondary malignancies without a focus on osteosarcoma, owing to its rarity. In addition, there are few studies suggesting tools for regular surveillance for early detection.
QUESTIONS/PURPOSES
(1) What are the radiologic and clinical characteristics of secondary osteosarcoma after retinoblastoma? (2) What is the clinical survivorship? (3) Is a radionuclide bone scan a reasonable imaging modality for early detection in patients with retinoblastoma?
METHODS
Between February 2000 and December 2019, we treated 540 patients for retinoblastoma. Twelve patients (six male, six female) subsequently developed an osteosarcoma in the extremities; two of these patients had two sites of osteosarcoma (10 femurs, four tibiae) . A Technetium-99m bone scan image was examined annually in all patients for regular surveillance after the treatment of retinoblastoma as per our hospital's policy. All patients were treated with the same strategy as that used for primary conventional osteosarcoma, namely neoadjuvant chemotherapy, wide excision, and adjuvant chemotherapy. The median follow-up period was 12 years (range 8 to 21 years). The median age at the time of diagnosis of osteosarcoma was 9 years (range 5 to 15 years), and the median interval from retinoblastoma diagnosis to osteosarcoma diagnosis was 8 years (range 5 to 15 years). Radiologic characteristics were assessed with plain radiographs and MRI, while clinical characteristics were assessed through a retrospective review of medical records. For clinical survivorship, we evaluated overall survival, local recurrence-free survival, and metastasis-free survival. We reviewed the results of bone scans and clinical symptoms at the time of diagnosis for osteosarcoma after retinoblastoma.
RESULTS
In nine of 14 patients, the tumor had a diaphyseal center, and five of the tumors were located at the metaphysis. The femur was the most common site (n = 10), followed by the tibia (n = 4). The median tumor size was 9 cm (range 5 to 13 cm). There was no local recurrence after surgical resection of the osteosarcoma, and the 5-year overall survival rate after the diagnosis of osteosarcoma was 86% (95% CI 68% to 100%). In all 14 tumors, the Technetium bone scan showed increased uptake in the lesions. Ten of 14 tumors were examined in clinic because of patient complaints of pain in the affected limb. Four patients showed no clinical symptoms detected by abnormal uptake on bone scan.
CONCLUSION
For unclear reasons, secondary osteosarcomas in patients who were alive after the treatment of retinoblastoma had a slight predilection for the diaphysis of the long bone compared with patients with spontaneous osteosarcoma in other reports. The clinical survivorship of osteosarcoma as a secondary malignancy after retinoblastoma may not be inferior to that of conventional osteosarcoma. Close follow-up with at least yearly clinical assessment and bone scans or other imaging modalities appears to be helpful in detecting secondary osteosarcoma after the treatment of patients with retinoblastoma. Larger multi-institutional studies will be needed to substantiate these observations.Level of Evidenc e Level IV, therapeutic study.
Topics: Humans; Male; Female; Child, Preschool; Child; Adolescent; Retinoblastoma; Technetium; Bone Neoplasms; Osteosarcoma; Neoplasms, Second Primary; Retinal Neoplasms; Retrospective Studies
PubMed: 37145140
DOI: 10.1097/CORR.0000000000002667 -
Pediatric Blood & Cancer Sep 2023The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the...
The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the committee has leveraged the Childhood Cancer Research Network, and now more recently Project:EveryChild (PEC), to conduct epidemiologic assessments of various childhood cancers, including osteosarcoma, neuroblastoma, germ cell tumors, Ewing sarcoma, rhabdomyosarcoma, and Langerhans cell histiocytosis. More recent studies have utilized questionnaire data collected as part of PEC to focus on specific characteristics and/or features, including the presence of congenital disorders and the availability of stored cord blood. Members of the COG Epidemiology Committee have also been involved in other large-scale National Institutes of Health efforts, including the Childhood Cancer Data Initiative and the Gabriella Miller Kids First Pediatric Research Program, which are improving our understanding of the factors associated with childhood cancer risk. Future plans will focus on addressing questions surrounding health disparities, utilizing novel biospecimens in COG epidemiology studies, exploring the role of environmental factors on the etiologies and outcomes of childhood cancer, collaborating with other COG committees to expand the role of epidemiology in childhood cancer research, and building new epidemiologic studies from the Molecular Characterization Initiative-all with the ultimate goal of developing novel prevention and intervention strategies for childhood cancer.
Topics: Child; Humans; Neoplasms; Sarcoma, Ewing; Medical Oncology; Rhabdomyosarcoma; Osteosarcoma; Bone Neoplasms
PubMed: 37449937
DOI: 10.1002/pbc.30566 -
Applied Biochemistry and Biotechnology Sep 2023The size-dependent bioactivities of castalin were analyzed by comparing the cytotoxic effects of native castalin and castalin nanoparticles on osteosarcoma in vitro and...
The size-dependent bioactivities of castalin were analyzed by comparing the cytotoxic effects of native castalin and castalin nanoparticles on osteosarcoma in vitro and in vivo. In vitro experiments indicated that castalin nanoparticles induced apoptosis of an osteosarcoma cell line more efficiently than native castalin. The more potent effects of castalin nanoparticles, relative to native castalin, were confirmed in vivo using a xenograft osteosarcoma model. Caco-2 cell transport studies showed that permeation of castalin nanoparticles was higher than native castalin. The higher bioactivity and superior bioavailability of castalin nanoparticles could potentially be utilised to develop novel therapies for osteosarcoma.
Topics: Humans; Caco-2 Cells; Cell Line, Tumor; Antineoplastic Agents; Osteosarcoma; Nanoparticles; Apoptosis; Bone Neoplasms; Xenograft Model Antitumor Assays; Cell Proliferation
PubMed: 35226253
DOI: 10.1007/s12010-022-03846-3 -
Journal For Immunotherapy of Cancer Jan 2024The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to...
Cell membrane-anchored and tumor-targeted IL-12 T-cell therapy destroys cancer-associated fibroblasts and disrupts extracellular matrix in heterogenous osteosarcoma xenograft models.
BACKGROUND
The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma.
METHOD
In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors.
RESULTS
RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment, and CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL-12-targeted or tumor-targeted IL-12-T cells, did not disrupt the ECM because this effect depended on the engagement between CSV on the tumor cell and its ligand on the attIL12-T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV tumor cells, suppressing transforming growth factor beta secretion and in turn upregulating FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T-cell infiltration and tumor inhibition.
CONCLUSIONS
This study unveiled a novel therapy-attIL12-T cells-for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.
Topics: Animals; Humans; Interleukin-12; Cancer-Associated Fibroblasts; Heterografts; Osteosarcoma; Cell Membrane; Extracellular Matrix; Disease Models, Animal; Bone Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 38199607
DOI: 10.1136/jitc-2023-006991