Special Issue "Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: 30 September 2022.

Special Issue Editors

Dr. Françoise Rédini
E-Mail Website
Guest Editor
INSERM UMR1238, Nantes University, Nantes, France
Interests: osteosarcoma; Ewing sarcoma; microenvironment; macrophages; immune cells
Dr. Franck Verrecchia
E-Mail Website
Guest Editor
INSERM UMR1238, PHY-OS, Bone Sarcomas and Remodeling of Calcified Tissues, Nantes University, 44000 Nantes, France
Interests: osteosarcoma; Ewing sarcoma; cell signaling; TGF-beta; YAP; ionic channels

Special Issue Information

Dear Colleagues,

After hemopathies, brain and spinal cord cancers, bone sarcomas are among the most common primary malignant tumors in children and adolescents. Despite the introduction of neoadjuvant and adjuvant chemotherapy following surgical tumor resection, metastatic relapse and resistance to treatment remain the leading causes of death in patients. The progress made in the understanding of the molecular basis of bone tumor pathogenesis in parallel with the emergence of targeted strategies that specifically block signaling pathways associated with cancer progression seems to be of great interest.

We invite you to submit either an original research or a review article to this Special Issue on “Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting”. Specific topics covered in this issue include basic, translational and clinical research in the field of primary bone tumors. We would like to shed light on recent findings describing key molecular and cellular pathways driving primary tumor growth, metastatic development and resistance to treatment. In this context, we are interested in studies describing original works regarding not only tumor cells but also their microenvironment considering endothelial, immune and bone cells.

Dr. Françoise Rédini
Dr. Franck Verrecchia
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • primary bone tumors
  • microenvironment
  • cell signaling
  • therapeutic strategy
  • pediatric cancers
  • targeted therapy

Published Papers (4 papers)

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Research

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Article
Sphingosine Kinase-1 Is Overexpressed and Correlates with Hypoxia in Osteosarcoma: Relationship with Clinicopathological Parameters
Cancers 2022, 14(3), 499; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030499 - 19 Jan 2022
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Abstract
The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P1 [...] Read more.
The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P1 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P1, prevented HIF-1α accumulation, and also inhibited cell proliferation in both normoxia and hypoxia unlike conventional chemotherapy. In human biopsies, a significant increase of SphK1 activity was observed in cancer compared with normal bones. In all sets of TMA samples (130 cases of osteosarcoma), immunohistochemical analysis showed the hypoxic marker GLUT-1, SphK1 and S1P1 were expressed in tumors. SphK1 correlated with the GLUT-1 suggesting that SphK1 is overexpressed and correlates with intratumoral hypoxia. No correlation was found between GLUT-1 or SphK1 and response to chemotherapy, but a statistical difference was found with increased S1P1 expression in patients with poor response in long bone osteosarcomas. Importantly, multivariate analyses showed that GLUT-1 was associated with an increased risk of death in flat bone, whereas SphK1 and S1P1 were associated with an increased risk of death in long bones. Full article
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Article
Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
Cancers 2021, 13(22), 5869; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225869 - 22 Nov 2021
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Abstract
Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades. Purpose: Here, we investigated the effect of [...] Read more.
Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades. Purpose: Here, we investigated the effect of simvastatin as adjuvant therapy on chemotherapy. Methods: Cell viability was assessed by the MTT test, and a combination index was evaluated by an isobologram approach. Cell motility was assessed by wound-healing assay. Cell-derived xenograft models were established in mice. FFPE tumor samples were assessed by immunohistochemistry. Results: In vitro experiments indicate that simvastatin synergized the conventional chemotherapy drugs’ inhibitory effect on cell viability. Functional assays reveal that simvastatin supplementation favored the anticancer mechanism of action of the tested chemotherapy drugs, such as DNA damage through intercalation or direct alkylation and disorganization of microtubules. Additionally, we show that even though simvastatin alone did not modify tumor behavior, it potentiated the inhibitory effect of doxorubicin on primary tumor growth (+50%, p < 0.05) and metastatic spread (+50%, p < 0.05). Our results provide evidence that simvastatin exerted an anti-tumor effect combined with chemotherapy in the preclinical murine model and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials. Full article
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Article
Co-Treatment with the Epigenetic Drug, 3-Deazaneplanocin A (DZNep) and Cisplatin after DZNep Priming Enhances the Response to Platinum-Based Therapy in Chondrosarcomas
Cancers 2021, 13(18), 4648; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184648 - 16 Sep 2021
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Abstract
Background: We have previously shown that 3-Deazaneplanocin A (DZNep) induces apoptosis in chondrosarcomas. Herein, we tested whether the combination of this epigenetic drug to a standard anticancer therapy may enhance the response to each drug in these bone tumors. Methods: Two chondrosarcoma cell [...] Read more.
Background: We have previously shown that 3-Deazaneplanocin A (DZNep) induces apoptosis in chondrosarcomas. Herein, we tested whether the combination of this epigenetic drug to a standard anticancer therapy may enhance the response to each drug in these bone tumors. Methods: Two chondrosarcoma cell lines (SW1353 and JJ012) were cultured in the presence of DZNep and/or cisplatin. Cell growth was evaluated by counting viable cells, and apoptosis was determined by Apo2.7 expression by flow cytometry. In vivo, the antitumoral effect of the DZNep/cisplatin combination was assessed through measurements of tumor volume of JJ012 xenografts in nude mice. Results: In vitro, the DZNep/cisplatin combination reduced cell survival and increased apoptosis compared to each drug alone in chondrosarcomas, but not in normal cells (chondrocytes). This enhancement of the antitumoral effect of the DZNep/cisplatin combination required a priming incubation with DZNep before the co-treatment with DZNep/cisplatin. Furthermore, in the chondrosarcoma xenograft mice model, the combination of both drugs more strongly reduced tumor growth and induced more apoptosis in tumoral cells than each of the drugs alone. Conclusion: Our results show that DZNep exposure can presensitize chondrosarcoma cells to a standard anticancer drug, emphasizing the promising clinical utilities of epigenetic-chemotherapeutic drug combinations in the future treatment of chondrosarcomas. Full article
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Review

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Review
Metastatic Progression of Osteosarcomas: A Review of Current Knowledge of Environmental versus Oncogenic Drivers
Cancers 2022, 14(2), 360; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020360 - 12 Jan 2022
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Abstract
Metastases of osteosarcomas are heterogeneous. They may grow simultaneously with the primary tumor, during treatment or shortly after, or a long time after the end of the treatment. They occur mainly in lungs but also in bone and various soft tissues. They can [...] Read more.
Metastases of osteosarcomas are heterogeneous. They may grow simultaneously with the primary tumor, during treatment or shortly after, or a long time after the end of the treatment. They occur mainly in lungs but also in bone and various soft tissues. They can have the same histology as the primary tumor or show a shift towards a different differentiation path. However, the metastatic capacities of osteosarcoma cells can be predicted by gene and microRNA signatures. Despite the identification of numerous metastasis-promoting/predicting factors, there is no efficient therapeutic strategy to reduce the number of patients developing a metastatic disease or to cure these metastatic patients, except surgery. Indeed, these patients are generally resistant to the classical chemo- and to immuno-therapy. Hence, the knowledge of specific mechanisms should be extended to reveal novel therapeutic approaches. Recent studies that used DNA and RNA sequencing technologies highlighted complex relations between primary and secondary tumors. The reported results also supported a hierarchical organization of the tumor cell clones, suggesting that cancer stem cells are involved. Because of their chemoresistance, their plasticity, and their ability to modulate the immune environment, the osteosarcoma stem cells could be important players in the metastatic process. Full article
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