Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Hattinger, Claudia Maria; Patrizio, Maria Pia; Fantoni, Leonardo; Casotti, Chiara; Riganti, Chiara; Serra, Massimo

doi:10.3390/cancers13122878

Cited by 67 publications

(65 citation statements)

References 150 publications

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“…The median 5-year survival rate is reported around 68%; however, it is highly dependent on the SEER stage, as follows: localized-74%, regional-66%, distant-27% [25][26][27]. Particularly, chemoresistance and preventing metastasis are still important challenges impeding successful osteosarcoma therapy [15,19].…”

Section: Osteosarcomamentioning

confidence: 99%

“…Intensified treatments with combinations of cytotoxic drugs have also failed to improve the cure rates of conventional high-grade osteosarcoma significantly. The main cause is the inherent or acquired drug resistance, which, coupled with metastasis development, causes the dismal prognosis of relapsed patients, for whom cure probability is at most 20-25% [15,51].…”

Section: Chemotherapymentioning

confidence: 99%

“…To avoid using small systemic dose or large local dose of plain chemotherapeutics, nanocarrier systems with controlled drug release can be employed. Particularly, bonetargeted drug delivery systems aim to concentrate drugs in tumor sites, protect drugs from rapid clearance, prolong their circulation times, enhance therapeutic efficacy, and reduce the systemic adverse effects [9,15,88,89].…”

Section: Drug Deliverymentioning

confidence: 99%

“…Nonetheless, currently available studies of this material have only been performed on animal models, with no research being published on human subjects [13]. Polymeric micelles can also be a transportation alternative for overcoming drug resistance [15]. While the core can incorporate poorly water-soluble agents, the shell can stabilize the micelles in the aqueous environment and can be modified with stimuliresponsive or tumor-targeting moieties [93].…”

Section: Carrier Systemsmentioning

confidence: 99%

“…Particularly, the delivery of desired compounds via micro-and nanostructured carriers has gained tremendous interest in recent years. It aids in the bioaccumulation of drugs at the target site, enhances therapeutic efficacy, and reduces systemic side effects [9,15].…”

Section: Introductionmentioning

confidence: 99%

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Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

Bădilă

Rădulescu

Niculescu

et al. 2021

Cancers

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In the last decades, the treatment of primary and secondary bone tumors has faced a slow-down in its development, being mainly based on chemotherapy, radiotherapy, and surgical interventions. However, these conventional therapeutic strategies present a series of disadvantages (e.g., multidrug resistance, tumor recurrence, severe side effects, formation of large bone defects), which limit their application and efficacy. In recent years, these procedures were combined with several adjuvant therapies, with different degrees of success. To overcome the drawbacks of current therapies and improve treatment outcomes, other strategies started being investigated, like carrier-mediated drug delivery, bone substitutes for repairing bone defects, and multifunctional scaffolds with bone tissue regeneration and antitumor properties. Thus, this paper aims to present the types of bone tumors and their current treatment approaches, further focusing on the recent advances in new therapeutic alternatives.

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Section: Osteosarcomamentioning

confidence: 99%

Section: Chemotherapymentioning

confidence: 99%

Section: Drug Deliverymentioning

confidence: 99%

Section: Carrier Systemsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

Bădilă

Rădulescu

Niculescu

et al. 2021

Cancers

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WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Perkins,

Murray,

Suthon

et al. 2024

Clinical & Translational Med

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BackgroundTreatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival.MethodsUsing tumor‐spheroids to model cancer stem‐like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem‐like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target.ResultsIn osteosarcoma cell lines and patient‐derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere‐forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient‐derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression.ConclusionsTogether, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients.Key points WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

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Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

Li,

Meng,

Liu

et al. 2023

J Biochem & Molecular Tox

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Increasing evidence indicated that protein arginine methyltransferase‐1 (PRMT1) is an oncogene in multiple malignant tumors, including osteosarcoma (OS). The aim of this study was to investigate the underlying mechanism of PRMT1 in OS. The effects of PRMT1 or BCAT1, branched‐chain amino acid transaminase 1 (BCAT1) on OS cell proliferation, invasion, autophagy, and apoptosis in vitro were examined. Moreover, molecular control of PRMT1 on c‐Myc or transactivation of BCAT1 on c‐Myc was assessed by chromatin immunoprecipitation and quantitative reverse transcription PCR assays. The effects of PRMT1 in vivo were examined with a xenograft tumor model. The results showed that PRMT1 was potently upregulated in OS tissues and cells. Upregulation of PRMT1 markedly increased OS cell proliferation and invasion in vitro and reduced cell apoptosis, whereas PRMT1 silencing showed the opposite effects. Cisplatin, one of the most effective chemotherapeutic drugs, improved cell survival rate by inducing the expression of PRMT1 to downregulate the cisplatin sensitivity. Meanwhile, the cisplatin‐induced upregulation of PRMT1 expression caused dramatically autophagy induction and autophagy‐mediated apoptosis by inactivating the mTOR signaling pathway, which could be reversed by 3‐methyladenine, an autophagy inhibitor, or PRMT1 silencing. PRMT1 could activate c‐Myc transcription and increase c‐Myc‐mediated expression of BCAT1. Furthermore, BCAT1 overexpression counteracted the effects of PRMT1 knockdown on cell proliferation, invasion, and apoptosis. Of note, deficiency of PRMT1 suppressed tumor growth in vivo. PRMT1 facilitated the proliferation and invasion of OS cells, inhibited cell apoptosis, and decreased chemotherapy sensitivity through c‐Myc/BCAT1 axis, which may become potential target in treating OS.

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Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Cited by 67 publications

References 150 publications

Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis

Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

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