Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis

Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered

Glutathione S-Transferases in Pediatric Cancer

The glutathione S-transferases (GSTs) are a family of ubiquitously expressed polymorphic enzymes important for detoxifying endogenous and exogenous compounds. In addition to their classic activity of detoxification by conjugation of compounds with glutathione, many other functions are now found to be associated with GSTs. The associations between GST polymorphisms/functions and human disease susceptibility or treatment outcome, mostly in adults, have been extensively studied and reviewed. This mini review focuses on studies related to GST epidemiology and functions related to pediatric cancer. Opportunities to exploit GST in pediatric cancer therapy are also discussed

Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma.

Ewing sarcoma is the second-most-common bone cancer in children. Driven by an oncogenic chromosomal translocation that results in the expression of an aberrant transcription factor, EWS/FLI, the disease is typically aggressive and micrometastatic upon presentation. Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion. Genes encoding focal adhesion, extracellular matrix, and actin regulatory proteins are dominant targets of EWS/FLI-mediated transcriptional repression. Reexpression of genes encoding just two of these proteins, zyxin and α5 integrin, is sufficient to restore cell adhesion and actin cytoskeletal integrity comparable to what is observed when the EWS/FLI oncogene expression is compromised. Using an orthotopic xenograft model, we show that EWS/FLI-induced repression of α5 integrin and zyxin expression promotes tumor progression by supporting anchorage-independent cell growth. This selective advantage is paired with a tradeoff in which metastatic lung colonization is compromised

Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas

One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL). The death-inducing signaling Ccmplex (DISC) and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor and in vitro data suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas

Increased risk for other cancers in individuals with Ewing sarcoma and their relatives.

BackgroundThere are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks.MethodsUsing a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives.ResultsCancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives.ConclusionsThis analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives

At-Risk Populations for Osteosarcoma: The Syndromes and Beyond

Osteosarcoma is the most common primary malignancy of bone. Most cases are sporadic without a known genetic or environmental cause. Heritable genetic predisposition syndromes are associated with a small percentage of osteosarcomas. Study of these rare disorders has provided insight into the molecular pathogenesis of osteosarcoma. Screening of at-risk families and surveillance of affected individuals for these syndromes may permit earlier diagnosis and more effective treatment of osteosarcoma in these populations. This paper reviews the genetic and clinical features of the known osteosarcoma predisposition syndromes

C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells.

CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPβ isoforms while re-expression of EWS-FLI1 rescued C/EBPβ expression. Overexpression of C/EBPβ-1, the largest of the three C/EBPβ isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPβ decreased colony formation, and re-expression of either C/EBPβ-1 or C/EBPβ-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPβ in Ewing sarcoma. Furthermore, increased expression of C/EBPβ led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPβ-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance