International Journal of Molecular Sciences

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19 pages, 32022 KiB

Open AccessArticle

Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma

by Gemma Di Pompo, Margherita Cortini, Roberto Palomba, Valentina Di Francesco, Elena Bellotti, Paolo Decuzzi, Nicola Baldini and Sofia Avnet

Int. J. Mol. Sci. 2021, 22(11), 5760; https://doi.org/10.3390/ijms22115760 - 28 May 2021

Cited by 16 | Viewed by 2931

Abstract

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated [...] Read more.

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from Curcuma longa, acts as an NF-κB inhibitor with anti-inflammatory properties. In this work, highly proliferating osteosarcoma cells were used to study the ability of curcumin to reduce the supportive effect of MSCs when stimulated by acidosis. Due to the poor solubility of curcumin in biological fluids, we used spherical polymeric nanoparticles as carriers (SPN-curc) to optimize its uptake by MSCs. We showed that SPN-curc inhibited the release of inflammatory cytokines (IL6 and IL8) by acidity-stimulated MSCs at a higher extent than by free curcumin. SPN-curc treatment was also successful in blocking tumor stemness, migration, and invasion that were driven by the secretome of acid-stressed MSCs. Overall, these data encourage the use of lipid–polymeric nanoparticles encapsulating NF-κB inhibitors such as curcumin to treat cancers whose progression is stimulated by an activated mesenchymal stroma. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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27 pages, 7771 KiB

Open AccessArticle

Analysis of a Preliminary microRNA Expression Signature in a Human Telangiectatic Osteogenic Sarcoma Cancer Cell Line

by Gaia Palmini, Cecilia Romagnoli, Simone Donati, Roberto Zonefrati, Gianna Galli, Francesca Marini, Teresa Iantomasi, Alessandra Aldinucci, Gigliola Leoncini, Alessandro Franchi, Giovanni Beltrami, Domenico Andrea Campanacci, Rodolfo Capanna and Maria Luisa Brandi

Int. J. Mol. Sci. 2021, 22(3), 1163; https://doi.org/10.3390/ijms22031163 - 25 Jan 2021

Cited by 2 | Viewed by 2749

Abstract

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not [...] Read more.

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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18 pages, 4795 KiB

Open AccessArticle

Optimizing an Osteosarcoma-Fibroblast Coculture Model to Study Antitumoral Activity of Magnesium-Based Biomaterials

by Philipp Globig, Regine Willumeit-Römer, Fernanda Martini, Elisa Mazzoni and Bérengère J.C. Luthringer-Feyerabend

Int. J. Mol. Sci. 2020, 21(14), 5099; https://doi.org/10.3390/ijms21145099 - 19 Jul 2020

Cited by 12 | Viewed by 3351

Abstract

Osteosarcoma is among the most common cancers in young patients and is responsible for one-tenth of all cancer-related deaths in children. Surgery often leads to bone defects in excised tissue, while residual cancer cells may remain. Degradable magnesium alloys get increasing attention as [...] Read more.

Osteosarcoma is among the most common cancers in young patients and is responsible for one-tenth of all cancer-related deaths in children. Surgery often leads to bone defects in excised tissue, while residual cancer cells may remain. Degradable magnesium alloys get increasing attention as orthopedic implants, and some studies have reported potential antitumor activity. However, most of the studies do not take the complex interaction between malignant cells and their surrounding stroma into account. Here, we applied a coculture model consisting of green fluorescent osteosarcoma cells and red fluorescent fibroblasts on extruded Mg and Mg–6Ag with a tailored degradation rate. In contrast to non-degrading Ti-based material, both Mg-based materials reduced relative tumor cell numbers. Comparing the influence of the material on a sparse and dense coculture, relative cell numbers were found to be statistically different, thus relevant, while magnesium alloy degradations were observed as cell density-independent. We concluded that the sparse coculture model is a suitable mechanistic system to further study the antitumor effects of Mg-based material. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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19 pages, 3559 KiB

Open AccessArticle

An Innovative Therapeutic Option for the Treatment of Skeletal Sarcomas: Elimination of Osteo- and Ewing’s Sarcoma Cells Using Physical Gas Plasma

by Josephine M. Jacoby, Silas Strakeljahn, Andreas Nitsch, Sander Bekeschus, Peter Hinz, Alexander Mustea, Axel Ekkernkamp, Mladen V. Tzvetkov, Lyubomir Haralambiev and Matthias B. Stope

Int. J. Mol. Sci. 2020, 21(12), 4460; https://doi.org/10.3390/ijms21124460 - 23 Jun 2020

Cited by 18 | Viewed by 3114

Abstract

Osteosarcoma and Ewing’s sarcoma are the most common malignant bone tumors. Conventional therapies such as polychemotherapy, local surgery, and radiotherapy improve the clinical outcome for patients. However, they are accompanied by acute and chronic side effects that affect the quality of life of [...] Read more.

Osteosarcoma and Ewing’s sarcoma are the most common malignant bone tumors. Conventional therapies such as polychemotherapy, local surgery, and radiotherapy improve the clinical outcome for patients. However, they are accompanied by acute and chronic side effects that affect the quality of life of patients, motivating novel research lines on therapeutic options for the treatment of sarcomas. Previous experimental work with physical plasma operated at body temperature (cold atmospheric plasma, CAP) demonstrated anti-oncogenic effects on different cancer cell types. This study investigated the anti-cancer effect of CAP on two bone sarcoma entities, osteosarcoma and Ewing’s sarcoma, which were represented by four cell lines (U2-OS, MNNG/HOS, A673, and RD-ES). A time-dependent anti-proliferative effect of CAP on all cell lines was observed. CAP-induced alterations in cell membrane functionality were detected by performing a fluorescein diacetate (FDA) release assay and an ATP release assay. Additionally, modifications of the cell membrane and modifications in the actin cytoskeleton composition were examined using fluorescence microscopy monitoring dextran-uptake assay and G-/F-actin distribution. Furthermore, the CAP-induced induction of apoptosis was determined by TUNEL and active caspases assays. The observations suggest that a single CAP treatment of bone sarcoma cells may have significant anti-oncogenic effects and thus may be a promising extension to existing applications. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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Review

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19 pages, 350 KiB

Open AccessReview

Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

by Isabel Fernandes, Cecília Melo-Alvim, Raquel Lopes-Brás, Miguel Esperança-Martins and Luís Costa

Int. J. Mol. Sci. 2021, 22(2), 813; https://doi.org/10.3390/ijms22020813 - 15 Jan 2021

Cited by 24 | Viewed by 3903

Abstract

Osteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some [...] Read more.

Osteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some promising results for these patients. This article reviews OS pathogenesis and new potential therapeutic targets. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

55 pages, 2066 KiB

Open AccessReview

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

by Ingrid Lilienthal and Nikolas Herold

Int. J. Mol. Sci. 2020, 21(18), 6885; https://doi.org/10.3390/ijms21186885 - 19 Sep 2020

Cited by 189 | Viewed by 9177

Abstract

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, [...] Read more.

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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20 pages, 1234 KiB

Open AccessReview

Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy

by Francesca Cersosimo, Silvia Lonardi, Giulia Bernardini, Brian Telfer, Giulio Eugenio Mandelli, Annalisa Santucci, William Vermi and Emanuele Giurisato

Int. J. Mol. Sci. 2020, 21(15), 5207; https://doi.org/10.3390/ijms21155207 - 23 Jul 2020

Cited by 145 | Viewed by 9879

Abstract

Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a [...] Read more.

Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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16 pages, 2162 KiB

Open AccessReview

A Review of T-Cell Related Therapy for Osteosarcoma

by Kazushige Yoshida, Masanori Okamoto, Kaoru Aoki, Jun Takahashi and Naoto Saito

Int. J. Mol. Sci. 2020, 21(14), 4877; https://doi.org/10.3390/ijms21144877 - 10 Jul 2020

Cited by 8 | Viewed by 3733

Abstract

Osteosarcoma is one of the most common primary malignant tumors of bone. The combination of chemotherapy and surgery makes the prognosis better than before, but therapy has not dramatically improved over the last three decades. This is partially because of the lack of [...] Read more.

Osteosarcoma is one of the most common primary malignant tumors of bone. The combination of chemotherapy and surgery makes the prognosis better than before, but therapy has not dramatically improved over the last three decades. This is partially because of the lack of a novel specialized drug for osteosarcoma, which is known as a tumor with heterogeneity. On the other hand, immunotherapy has been one of the most widely used strategies for many cancers over the last ten years. The therapies related to T-cell response, such as immune checkpoint inhibitor and chimeric antigen receptor T-cell therapy, are well-known options for some cancers. In this review, we offer the accumulated knowledge of T-cell-related immunotherapy for osteosarcoma, and discuss the future of the therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Osteosarcoma)

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