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Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 22332

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Special Issue Editors

Dr. Françoise Rédini

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Guest Editor

INSERM UMR1238, Nantes University, Nantes, France
Interests: osteosarcoma; Ewing sarcoma; microenvironment; macrophages; immune cells

Dr. Franck Verrecchia

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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 submissions that pass pre-check are 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 2900 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 (7 papers)

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Research

Jump to: Review

17 pages, 2863 KiB

Open AccessArticle

TRAIL-Based Therapies Efficacy in Pediatric Bone Tumors Models Is Modulated by TRAIL Non-Apoptotic Pathway Activation via RIPK1 Recruitment

by Régis Brion, Malika Gantier, Kevin Biteau, Julien Taurelle, Bénédicte Brounais-Le Royer, Franck Verrecchia, Françoise Rédini and Romain Guiho

Cancers 2022, 14(22), 5627; https://doi.org/10.3390/cancers14225627 - 16 Nov 2022

Cited by 1 | Viewed by 1232

Abstract

Despite advances in clinical management, osteosarcoma and Ewing sarcoma, the two most frequent malignant primary bone tumors at pediatric age, still have a poor prognosis for high-risk patients (i.e., relapsed or metastatic disease). Triggering a TRAIL pro-apoptotic pathway represents a promising therapeutic approach, but previous studies have described resistance mechanisms that could explain the declining interest of such an approach in clinical trials. In this study, eight relevant human cell lines were used to represent the heterogeneity of the response to the TRAIL pro-apoptotic effect in pediatric bone tumors and two cell-derived xenograft models were developed, originating from a sensitive and a resistant cell line. The DR5 agonist antibody AMG655 (Conatumumab) was selected as an example of TRAIL-based therapy. In both TRAIL-sensitive and TRAIL-resistant cell lines, two signaling pathways were activated following AMG655 treatment, the canonical extrinsic apoptotic pathway and a non-apoptotic pathway, involving the recruitment of RIPK1 on the DR5 protein complex, activating both pro-survival and pro-proliferative effectors. However, the resulting balance of these two pathways was different, leading to apoptosis only in sensitive cells. In vivo, AMG655 treatment reduced tumor development of the sensitive model but accelerated tumor growth of the resistant one. We proposed two independent strategies to overcome this issue: (1) a proof-of-concept targeting of RIPK1 by shRNA approach and (2) the use of a novel highly-potent TRAIL-receptor agonist; both shifting the balance in favor of apoptosis. These observations are paving the way to resurrect TRAIL-based therapies in pediatric bone tumors to help predict the response to treatment, and propose a relevant adjuvant strategy for future therapeutic development. Full article

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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17 pages, 4687 KiB

Open AccessArticle

Together Intra-Tumor Hypoxia and Macrophagic Immunity Are Driven Worst Outcome in Pediatric High-Grade Osteosarcomas

by Charlotte Nazon, Marina Pierrevelcin, Thibault Willaume, Benoît Lhermitte, Noelle Weingertner, Antonio Di Marco, Laurent Bund, Florence Vincent, Guillaume Bierry, Anne Gomez-Brouchet, Françoise Redini, Nathalie Gaspar, Monique Dontenwill and Natacha Entz-Werle

Cancers 2022, 14(6), 1482; https://doi.org/10.3390/cancers14061482 - 14 Mar 2022

Cited by 5 | Viewed by 2062

Abstract

Background: Osteosarcomas (OTS) represent the most common primary bone cancer diagnosed in adolescents and young adults. Despite remarkable advances, there are no objective molecular or imaging markers able to predict an OTS outcome at diagnosis. Focusing on biomarkers contributing broadly to treatment resistance, we examine the interplay between the tumor-associated macrophages and intra-tumor hypoxia. Methods: Radiological and immunohistochemical (IHC) data were correlated with the outcome in a retrospective and monocentric cohort of 30 pediatric OTS. We studied hypoxic (pS6, phospho-mTor, HIF-1α and carbonic anhydrase IX (CAIX)) and macrophagic (CD68 and CD163) biomarkers. Results: The imaging analyses were based on MRI manual volumetric measures on axial post-contrast T1 weighted images, where, for each tumor, we determined the necrotic volume and its ratio to the entire tumor volume. When they were above 50 cm³ and 20%, respectively, they correlated with a worse overall survival (p = 0.0072 and p = 0.0136, respectively) and event-free survival (p = 0.0059 and p = 0.0143, respectively). IHC assessments enable a significant statistical link between HIF-1α/CAIX hyper-expressions, CD68+ cells and a worse outcome, whereas activation of mTor pathway was linked to a better survival rate and CD163+ cells. Conclusions: This study evidenced the links between hypoxia and immunity in OTS, as their poor outcome may be related to a larger necrotic volume on diagnostic MRI and, in biopsies, to a specific IHC profile. Full article

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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17 pages, 1879 KiB

Open AccessArticle

Sphingosine Kinase-1 Is Overexpressed and Correlates with Hypoxia in Osteosarcoma: Relationship with Clinicopathological Parameters

by Anne Gomez-Brouchet, Claire Illac, Adeline Ledoux, Pierre-Yves Fortin, Sandra de Barros, Clémentine Vabre, Fabien Despas, Sophie Peries, Christelle Casaroli, Corinne Bouvier, Sébastien Aubert, Gonzague de Pinieux, Frédérique Larousserie, Louise Galmiche, Franck Talmont, Stuart Pitson, Marie-Lise Maddelein and Olivier Cuvillier

Cancers 2022, 14(3), 499; https://doi.org/10.3390/cancers14030499 - 19 Jan 2022

Cited by 2 | Viewed by 2445

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 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P_1, 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

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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19 pages, 5795 KiB

Open AccessArticle

Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma

by Adèle Mangelinck, Nadia Habel, Audrey Mohr, Nathalie Gaspar, Bojana Stefanovska and Olivia Fromigué

Cancers 2021, 13(22), 5869; https://doi.org/10.3390/cancers13225869 - 22 Nov 2021

Cited by 12 | Viewed by 2783

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 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

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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10 pages, 7151 KiB

Open AccessArticle

Co-Treatment with the Epigenetic Drug, 3-Deazaneplanocin A (DZNep) and Cisplatin after DZNep Priming Enhances the Response to Platinum-Based Therapy in Chondrosarcomas

by Eva Lhuissier, Juliette Aury-Landas, Marion Lenté, Karim Boumediene and Catherine Baugé

Cancers 2021, 13(18), 4648; https://doi.org/10.3390/cancers13184648 - 16 Sep 2021

Cited by 2 | Viewed by 2112

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 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

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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Review

Jump to: Research

12 pages, 1758 KiB

Open AccessReview

CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers

by Caterina Mancarella, Marianna Carrabotta, Lisa Toracchio and Katia Scotlandi

Cancers 2022, 14(21), 5411; https://doi.org/10.3390/cancers14215411 - 2 Nov 2022

Cited by 5 | Viewed by 4361

Abstract

Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between CIC and, in most of the cases, DUX4. CIC-DUX4 imposes a CIC-specific transcriptional signature, which drives cell transformation, proliferation, and migration. While the discovery of the fusion represented the first evidence of a role of CIC in cancer, a complete comprehension of CIC-rearranged activity is still required before providing new potential avenues for therapy. To date, a specific and effective treatment for CIC sarcoma has yet to be defined. In this review, we initially highlight the clinical features and pathogenesis of CIC-rearranged sarcomas along with current therapeutic approaches and then focus on the specific oncogenic mechanisms driven by the CIC-rearrangement. We discuss novel therapeutic options evoked by the aberrant relations of CIC-DUX4 with the IGF system, DUSP6, P300/CBP, and CCNE1. We also discuss how different mutations involving CIC might converge on a common upregulation of CIC-target genes across human cancers. A deeper understanding of the oncogenic mechanisms driven by the chimera CIC-DUX4 might provide novel therapeutic opportunities with a general impact in cancer. Full article

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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Graphical abstract

16 pages, 1457 KiB

Open AccessReview

Metastatic Progression of Osteosarcomas: A Review of Current Knowledge of Environmental versus Oncogenic Drivers

by Guillaume Anthony Odri, Joëlle Tchicaya-Bouanga, Diane Ji Yun Yoon and Dominique Modrowski

Cancers 2022, 14(2), 360; https://doi.org/10.3390/cancers14020360 - 12 Jan 2022

Cited by 31 | Viewed by 6333

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 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

(This article belongs to the Special Issue Primary Bone Tumors: Microenvironment, Signaling and Therapeutic Targeting)

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