Ewing sarcoma is an aggressive primary malignant bone tumor with high degree of tumor vascularization and is the second most common sarcoma of bone in children and young adults. Patients... Show more Ewing sarcoma is an aggressive primary malignant bone tumor with high degree of tumor vascularization and is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. To identify novel therapies and biomarkers for these patients we focused on the chemokines and chemokine receptors in Ewing sarcoma cells and their role its tumor microenvironment. CCL21 CXCL14, CXCR7 and the ratio between CXCR4-1 and CXCR4-2 have been identified as candidate prognostic markers, CCL21 immunotherapy as potential therapy and CXCR4 as potential therapeutic target in EWS. In addition, the presented peptide-based life cell imaging methods improve the ability to study CXCR4 cell membrane expression and dynamics qualitatively and quantitatively. This approach might be helpful for the measurement of anti-CXCR4 therapy efficacy. This work identified specific the chemokine signaling pathways that can be used to target Ewing sarcoma and its tumor microenvironment. Show less
Kovar, H.; Amatruda, J.; Brunet, E.; Burdach, S.; Cidre-Aranaz, F.; Alava, E. de; ... ; Delattre, O. 2016
Ewing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone... Show moreEwing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone cancer among adolescents and young adults. Contrary to the positive achievement in treatment of localized tumors, the long-term (5-years) survival for Ewing sarcoma patients with metastasis, however, remain below the 30% mark. In this thesis a report on experimental work aiming for a better understanding of the mechanisms underlying Ewing sarcoma metastasis is presented. Two distinct mechanisms are investigated: (1) a biochemical approach in which the initial steps in the CXCR4 signaling cascade are followed, and (2) a biophysical approach in which the guidance of Ewing sarcoma metastasis by the stiffness of their microenvironment is demonstrated. The results presented in this thesis provide deeper insights into the mechanisms controlling signaling of the chemokine receptor CXCR4 and into the role of the micro-environment in Ewing sarcoma cells behavior.Through various experimental approaches it was shown that both biochemical and biophysical guidance control how Ewing sarcoma develops into its distinct metastatic phenotype. Show less
Osteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic... Show moreOsteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic or chemotherapy-resistant disease have a poor outcome. Thus, novel targeted therapies are needed that combine potent and specific anti-cancer activity with limited toxicity toward normal tissues. The thesis is introduced by an outline of the biological properties of osteosarcoma and Ewing sarcoma, followed by an overview of cancer immunology and immunotherapy with the primary focus on innate immunity of human natural killer (NK) cells and macrophages. In the research chapters, cellular interactions of NK cells and macrophages with bone tumor cells are characterized in order to achieve favorable effects on anti-cancer immune cell functions. It is demonstrated that the anti-cancer potential of especially NK cells but also macrophages can be enhanced and directed to the bone tumor cells. It is discussed that the modulation of tumor__immune cell interactions may help to design novel immunotherapeutic approaches to harness anti-cancer functions of innate immune cells against osteosarcoma and Ewing sarcoma. Show less
In this thesis, we report on various aspects of tumor - host (immune) interactions in Ewing sarcoma patients with the aim to obtain leads for immunotherapeutic or targeted treatment strategies. We... Show moreIn this thesis, we report on various aspects of tumor - host (immune) interactions in Ewing sarcoma patients with the aim to obtain leads for immunotherapeutic or targeted treatment strategies. We demonstrate a key role for interferon gamma (IFNg) in enhancing both Ewing sarcoma immunogenicity and susceptibility to cytotoxicity. An (endogenous) pro-inflammatory tumor microenvironment consisting of cytotoxic T-lymphocytes and IFNg-inducible chemokines provides prognostic benefit. Moreover, despite evidence for immunologic pressure in selection of HLA class I loss variants, intact IFNg-inducibility of the HLA class I antigen processing machinery emphasizes the significance of a pro-inflammatory microenvironment for initiation/ execution of adaptive anti-tumor immunity. Pre-clinical support for the potential of adoptive cell transfer therapies, in particular combinatorial natural killer cell-based therapy, is provide d. Sensitization of Ewing sarcoma by conventional or targeted therapies, including histone deacetylase inhibitors, combined with cytokine activation of natural killer cells enhances anti-tumor responses and overcomes both intrinsic functional natural killer cell defects as well as cross-resistance of chemotherapy-resistant Ewing sarcoma to natural killer cells. Finally, due to a crucial role of the CXCR4-CXCL12 axis in Ewing sarcoma progression, disruption of this axis by a CXCR4-specific antagonist may represent a promising treatment option for patients with Ewing sarcoma. Show less
The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives... Show moreThe European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials. Show less
Mackintosh, C.; Ordonez, J.L.; Garcia-Dominguez, D.J.; Sevillano, V.; Llombart-Bosch, A.; Szuhai, K.; ... ; Alava, E. de 2012
Non-haematogenic tumours arising primarily in the bone are rare. They are classified based on their histomorphology. Within the osteofibrous group the spectrum ranges from benign, exclusively... Show moreNon-haematogenic tumours arising primarily in the bone are rare. They are classified based on their histomorphology. Within the osteofibrous group the spectrum ranges from benign, exclusively fibrous lesions to high-grade osteosarcoma. These osteofibrous tumours show histological variability in a given entity as well as similarities between entities. The purpose of this thesis was to reveal the meaning of the phenotypic spectrum of osteofibrous tumours. In retrospect, the histological subtype of osteosarcoma is a predictive factor for response to chemotherapy, late relapse and risk of a hereditary cancer syndrome, but not for survival. However, the poor histological response of chondroblastic osteosarcomas to neo-adjuvant chemotherapy did not translate in a lower survival rate. On the other hand, overlapping histological and/or clinical parameters between certain tumour entities such as for example adamantinoma and Ewing sarcoma, and desmoplastic fibroma of bone and desmoid type fibromatosis of soft tissue, does not justify to classify these tumours as part of one disease entity as was demonstrated in this thesis. Thus, the correct classification, reclassification of known entities on new insights and sub-classification on phenotypic differences, when related with biological behaviour, has implications for clinical practice and disease management, and contributes to optimal patient care. Show less
