Dataset Information

Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

ABSTRACT: Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor ?B (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.

SUBMITTER: Fioramonti M

PROVIDER: S-EPMC5843583 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

Fioramonti M M Fausti V V Pantano F F Iuliani M M Ribelli G G Lotti F F Pignochino Y Y Grignani G G Santini D D Tonini G G Vincenzi B B

Scientific reports 20180308 1

Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested diffe ...[more]

PMID: 29520051

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Project description:BackgroundOsteosarcoma (OS), the commonest primary malignant bone tumor, is mainly seen in children and teenagers. LINC00960, a newly discovered long intergenic non-protein coding RNA, has been shown to be important in certain cancers. The objective of this study was to assess LINC00960's prognostic and therapeutic value and analyze its mechanism of action in osteosarcoma.MethodsWith the transcriptome information of 85 osteosarcomas from the TARGET database, the Cox regression analyses, K-M curve, and ROC curve, were conducted for survival and prognostic analysis. The functional analysis was conducted using GO, KEGG, GSEA, and GSVA. The ESTIMATE, ssGSEA, MCP-counter, ImmuCellAI algorithms, and immune checkpoint correlation analysis were performed for immune-related analysis. The single-cell RNA sequencing data of 6 osteosarcoma patients was obtained from the Gene Expression Omnibus database. The Tumor Immune Dysfunction and Exclusion algorithm and the "pRRophetic" R package were performed to predict the response to immunotherapy and chemotherapy.ResultsLINC00960 overexpression is associated with osteosarcoma metastasis and poor prognosis. Based on the LINC00960 expression, the nomogram prediction model was created, which showed good accuracy and precision to predict the overall survival of osteosarcoma. Single-cell and immune-related analysis showed that LINC00960 is mainly highly expressed in the tumor-exhausted CD8 T cells in osteosarcoma. In osteosarcoma, the expression of LIC00960 was favorably connected with immune checkpoint-related genes and negatively correlated with immune infiltration. TIDE analysis indicated that low LINC00960 expression patients might have a better response to immunotherapy. Drug sensitivity analysis showed that high LINC00960 expression patients might have better responses to Bleomycin and Doxorubicin.ConclusionLINC00960 has the potential to be a novel biomarker for predicting overall survival in osteosarcoma patients and to guide more individualized treatment and clinical decision-making.

Dataset Information

Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

Publications

Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

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