Mechanisms of Resistance to Conventional Therapies for Osteosarcoma

Marchandet, Louise; Lallier, Morgane; Charrier, Céline; Baud’huin, Marc; Ory, Benjamin; Lamoureux, François

doi:10.3390/cancers13040683

Cited by 91 publications

(88 citation statements)

References 219 publications

(245 reference statements)

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“…The combination of surgery and chemotherapy markedly improves patients' prognosis [18]. However, local invasion, metastasis, and drug resistance are still to be improved [18,19]. Exploring an effective therapeutic target is an urgent and critical issue.…”

Section: Discussionmentioning

confidence: 99%

Circusp34 Promotes Osteosarcoma Proliferation and Invasion by Sponging Mir-16-5p: An in Vivo and in Vitro Analysis

J¹,

Zhang²,

Xu³

et al. 2021

Preprint

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Background Osteosarcoma (OS) is a primary and highly malignant mesenchymal tissue tumor. Although it has achieved a significant breakthrough in therapeutic administration, the specific pathological mechanism remains unclear. CircRNAs are a type of covalently circular RNA with a head-to-tail junction site. Several studies have reported that abnormal expression of circRNAs is closely associated with tumorigenesis and progression. CircRNAs promote or inhibit the progression of OS by sponging miRNAs. In this study, we aimed to investigate the endogenous competition between circRNAs and miRNAs in OS. Methods CircUSP34 expression was detected by qRT-PCR in KHOS and 143B cells. To confirm the effect of circRNAs and miRNAs, function assays including CCK8, EdU, wound healing, transwell, and western blot were performed in OS cells. FISH and dual-luciferase reporter assays were performed to confirm the sponging mechanism of circUSP34 and miR-16-5p. Additionally, qRT-PCR, immunohistochemistry, HE staining, and western blot were used to confirm the expression of proteins and genes in tumor tissues from mice. Results In the present study, we found that circUSP34 promoted OS proliferation, migration, and invasion in vitro and in vivo. circUSP34 and miR-16-5p were upregulated and downregulated, respectively, in OS cells. OS cells’ biological behaviors, such as proliferation, migration, and invasion, were inhibited after circUSP34 knockdown. Western blot results also showed that Vimentin and Ki-67 expression levels were decreased. Similarly, miR-16-5p mimic compromised OS cell proliferation and migration. FISH assay indicated that circUSP34 and miR-16-5p were colocalized in the cytoplasm. The dual-luciferase reporter assay showed that miR-16-5p was sponged by circUSP34. Interestingly, the miR-16-5p mimic partly reversed the inhibitory effect of sh-circUSP34 on the malignancy of OS cells. Finally, animal experiment results about IHC indicated that Vimentin, N-cadherin, and Ki-67 protein expression decreased, but E-cadherin protein expression increased. Conclusion Collectively, circUSP34 promoted OS proliferation, migration, and invasion by sponging miR-16-5p. It can serve as a potential therapeutic target and biomarker.

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Section: Discussionmentioning

confidence: 99%

Circusp34 Promotes Osteosarcoma Proliferation and Invasion by Sponging Mir-16-5p: An in Vivo and in Vitro Analysis

J¹,

Zhang²,

Xu³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Despite improved outcomes from neoadjuvant chemotherapy in the treatment of osteosarcoma, the average survival of patients with metastasis has remained poor over the last three decades [ 5 , 6 , 7 ]. Immunotherapy and targeted therapy have recently demonstrated significant results in the treatment of certain cancer types [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Data-Driven Mathematical Model of Osteosarcoma

Kirshtein

et al. 2021

Cancers

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As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN-γ, switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments.

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“…Osteosarcoma (OS) is the most aggressive bone malignancy in children and adolescents, resulting in significant morbidity and mortality [ 1 ]. Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the overall survival rates of OS have reached a plateau [ 2 ]. However, these treatments still leave much to be improved, such as multi-drug resistance and severe side effects [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy

Yang

Liang

et al. 2021

J Nanobiotechnol

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Background Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. Methods and results A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica–coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. Conclusion All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.

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Mechanisms of Resistance to Conventional Therapies for Osteosarcoma

Cited by 91 publications

References 219 publications

Circusp34 Promotes Osteosarcoma Proliferation and Invasion by Sponging Mir-16-5p: An in Vivo and in Vitro Analysis

Circusp34 Promotes Osteosarcoma Proliferation and Invasion by Sponging Mir-16-5p: An in Vivo and in Vitro Analysis

Data-Driven Mathematical Model of Osteosarcoma

Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy

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