Valerie Fock

Ewing sarcoma (ES) is a rare aggressive cancer of bone and soft tissue that is mainly characterized by a reciprocal chromosomal translocation. As a result, about 90% of cases express the EWS-FLI1 fusion protein that has been shown to function as an aberrant transcription factor driving sarcomagenesis. ES is the second most common malignant bone tumor in children and young adults. Current treatment modalities include dose-intensified chemo- and radiotherapy, as well as surgery. Despite these strategies, patients who present with metastasis or relapse still have dismal prognosis, warranting a better understanding of treatment resistant-disease biology in order to generate better prognostic and therapeutic tools. Since the genomes of ES tumors are relatively quiet and stable, exploring the contributions of epigenetic mechanisms in the initiation and progression of the disease becomes inevitable. The search for novel biomarkers and potential therapeutic targets of cancer metastasis and chemotherapeutic drug resistance is increasingly focusing on long non-coding RNAs (lncRNAs). Recent advances in genome analysis by high throughput sequencing have immensely expanded and advanced our knowledge of lncRNAs. They are non-protein coding RNA species with multiple biological functions that have been shown to be dysregulated in many diseases and are emerging as crucial players in cancer development. Understanding the various roles of lncRNAs in tumorigenesis and metastasis would determine eclectic avenues to establish therapeutic and diagnostic targets. In ES, some lncRNAs have been implicated in cell proliferation, migration and invasion, features that make them suitable as relevant biomarkers and therapeutic targets. In this review, we comprehensively discuss known lncRNAs implicated in ES that could serve as potential biomarkers and therapeutic targets of the disease. Though some current reviews have discussed non-coding RNAs in ES, to our knowledge, this is the first review focusing exclusively on ES-associated lncRNAs.

Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.