Clinical significance and in vitro cellular regulation of hypoxia mimicry on HIF-1α and downstream genes in canine appendicular osteosarcoma

Gola, Cecilia; Iussich, Selina; Noury, S.; Martano, Manuela; Gattino, Francesca; Morello, Emanuela; Martignani, Eugenio; Maniscalco, Lorella; Accornero, Paolo; Buracco, Paolo; Aresu, Luca; Maria, Raffaella De

doi:10.1016/j.tvjl.2020.105538

Cited by 11 publications

(10 citation statements)

References 49 publications

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“…Current reports have shown the crucial effect of hypoxia on cell proliferation, tumor growth, and cell differentiation [10]. Bone is one of the most vulnerable organs to hypoxia and has been shown to play a major role in metastasis, weak prognosis, and radiation tolerance of osteosarcoma [11,12]. Nonetheless, the regulatory structure remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

A Hypoxia Gene-Based Signature to Predict the Survival and Affect the Tumor Immune Microenvironment of Osteosarcoma in Children

Jiang

Miao

Zhang

et al. 2021

Journal of Immunology Research

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Osteosarcoma is a quickly developing, malignant cancer of the bone, which is associated with a bad prognosis. In osteosarcoma, hypoxia promotes the malignant phenotype, which results in a cascade of immunosuppressive processes, poor prognosis, and a high risk of metastasis. Nonetheless, additional methodologies for the study of hyperoxia in the tumor microenvironment also need more analysis. We obtained 88 children patients with osteosarcoma from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and 53 children patients with RNA sequence and clinicopathological data from the Gene Expression Omnibus (GEO). We developed a four-gene signature related to hypoxia to reflect the immune microenvironment in osteosarcoma that predicts survival. A high-risk score indicated a poor prognosis and immunosuppressive microenvironment. The presence of the four-gene signature related to hypoxia was correlated with clinical and molecular features and was an important prognostic predictor for pediatric osteosarcoma patients. In summary, we established and validated a four-gene signature related to hypoxia to forecast recovery and presented an independent prognostic predictor representing overall immune response strength within the osteosarcoma microenvironment.

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Section: Introductionmentioning

confidence: 99%

A Hypoxia Gene-Based Signature to Predict the Survival and Affect the Tumor Immune Microenvironment of Osteosarcoma in Children

Jiang

Miao

Zhang

et al. 2021

Journal of Immunology Research

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“…Specifically, two commercial and six primary cOSA cell lines established and validated in our laboratory were analyzed. The assorted cell lines were previously used in several studies to investigate cOSA pathogenetic mechanisms and response to therapies (11,12,14,(36)(37)(38). So far, only the D17 cell line has been characterized at the genomic level by Das et al in 2019 (13).…”

Section: Discussionmentioning

confidence: 99%

Genomic and Transcriptomic Characterization of Canine Osteosarcoma Cell Lines: A Valuable Resource in Translational Medicine

et al. 2021

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Osteosarcoma (OSA) represents the most common primary bone tumor in dogs and is characterized by a highly aggressive behavior. Cell lines represent one of the most suitable and reproducible pre-clinical models, and therefore the knowledge of their molecular landscape is mandatory to investigate oncogenic mechanisms and drug response. The present study aims at determining variants, putative driver genes, and gene expression aberrations by integrating whole-exome and RNA sequencing. For this purpose, eight canine OSA cell lines and one matched pair of primary tumor and normal tissue were analyzed. Overall, cell lines revealed a mean tumor mutational burden of 9.6 mutations/Mb (range 3.9–16.8). Several known oncogenes and tumor suppressor genes, such as ALK, MYC, and MET, were prioritized as having a likely role in canine OSA. Mutations in eight genes, previously described as human OSA drivers and including TP53, PTCH1, MED12, and PI3KCA, were retrieved in our cell lines. When variants were cross-referenced with human OSA driver mutations, the E273K mutation of TP53 was identified in the Wall cell line and tumor sample. The transcriptome profiling detected two possible p53 inactivation mechanisms in the Wall cell line on the one hand, and in D17 and D22 on the other. Moreover, MET overexpression, potentially leading to MAPK/ERK pathway activation, was observed in D17 and D22 cell lines. In conclusion, our data provide the molecular characterization of a large number of canine OSA cell lines, allowing future investigations on potential therapeutic targets and associated biomarkers. Notably, the Wall cell line represents a valuable model to empower prospective in vitro studies both in human and in dogs, since the TP53 driver mutation was maintained during cell line establishment and was widely reported as a mutation hotspot in several human cancers.

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“…As far as VEGF/VEGFR axis in veterinary oncology is concerned, VEGF family members were identified in several canine cancers ( 76 ), as well as OSA tissue, serum, and cultured cells ( 77 – 79 ). A relation between VM and VERGFR was found in D17 canine OSA cells cultured on type I collagen where malignant cancer cells with endothelial morphology express VEGFR1 ( 14 ).…”

Section: Endothelial Mediatorsmentioning

confidence: 99%

“…It has been also demonstrated that VEGFα is the direct target of miR34a, which is less expressed in OSA cell lines with respect to normal osteoblast; OSA cells that have been induced to overexpressing miR34a show decreased motility and invasion ability on Matrigel and increased levels of VEGFα ( 85 ). On the other hand, a correlation between VEGFα transcript and chemical hypoxia was not observed ( 77 ).…”

Section: Endothelial Mediatorsmentioning

confidence: 99%

“…As far as OSA ex vivo samples are concerned, literature data regarding VEGF axis and VM are lacking. Moreover, no correlation was observed between VEGF expression and clinicopathological parameters or hypoxia markers, which are often related to VM ( 77 ). On the contrary, its serum concentration has been previously correlated with poor prognosis in canine OSA ( 86 ).…”

Section: Endothelial Mediatorsmentioning

confidence: 99%

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An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology

et al. 2021

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Canine tumors are valuable comparative models for human counterparts, especially to explore novel biomarkers and to understand pathways and processes involved in metastasis. Vasculogenic mimicry (VM) is a unique property of malignant cancer cells which promote metastasis. Thus, it represents an opportunity to investigate both the molecular mechanisms and the therapeutic targets of a crucial phenotypic malignant switch. Although this biological process has been largely investigated in different human cancer types, including osteosarcoma, it is still largely unknown in veterinary pathology, where it has been mainly explored in canine mammary tumors. The presence of VM in human osteosarcoma is associated with poor clinical outcome, reduced patient survival, and increased risk of metastasis and it shares the main pathways involved in other type of human tumors. This review illustrates the main findings concerning the VM process in human osteosarcoma, search for the related current knowledge in canine pathology and oncology, and potential involvement of multiple pathways in VM formation, in order to provide a basis for future investigations on VM in canine tumors.

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Clinical significance and in vitro cellular regulation of hypoxia mimicry on HIF-1α and downstream genes in canine appendicular osteosarcoma

Cited by 11 publications

References 49 publications

A Hypoxia Gene-Based Signature to Predict the Survival and Affect the Tumor Immune Microenvironment of Osteosarcoma in Children

A Hypoxia Gene-Based Signature to Predict the Survival and Affect the Tumor Immune Microenvironment of Osteosarcoma in Children

Genomic and Transcriptomic Characterization of Canine Osteosarcoma Cell Lines: A Valuable Resource in Translational Medicine

An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology

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