Ewing's Family Research Articles

Inhibition of the transcriptional function of p53 by EWS–Fli1 chimeric protein in Ewing Family Tumors

The chromosomal translocation t(11;22)(q24;q12) generates the EWS–Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Although p53 mutations are found only in 5–20% of EFTs, the p53 pathway is thought to be abrogated in EFTs. The role of EWS–Fli1 in the p53 pathway in the tumor is still poorly understood. In this study, using immunoprecipitation and co-localization, we show that EWS–Fli1 interacts with p53 within the nucleus in vivo. The introduction of EWS–Fli1 resulted in significant reduction of promoter activities and mRNA levels of p21 and mdm2, meanwhile it canceled p53-dependent growth suppression. In contrast, knockdown of EWS–Fli1 expression mediated by small interfering RNAs (siRNA) also augmented the induction of p21 and mdm2 in response to DNA damage. Furthermore, using serial deletion constructs of the EWS–Fli1 fusion protein, we determined that EWS–Fli1 binding to p53 as well as inhibition of p21 and mdm2 promoter activities was mediated by its N-terminal domain (amino acid residues 65–109). These observations suggest that the N-terminal region of EWS–Fli1 might associate with p53 and impair its transcriptional activity, subsequently inhibiting the expression of its downstream genes. These results might provide new insight into the oncogenesis of EFTs by EWS–Fli1 via the inhibition of p53 function.

Outcomes With High Dose Chemotherapy And Autologous Stem Cell Transplantation (ASCT) In Comparison To Conventional Chemotherapy In Pediatric Patients With High Risk Ewing's Family Tumors

Outcomes With High Dose Chemotherapy And Autologous Stem Cell Transplantation (ASCT) In Comparison To Conventional Chemotherapy In Pediatric Patients With High Risk Ewing's Family Tumors

The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes β-catenin/TCF-mediated transcription

Tumours of the Ewing family, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumours, are highly aggressive and mostly affect children and adolescents. They are characterized by chromosomal translocations leading to the generation of fusion proteins between EWS (or very rarely FUS) and members of the E-twenty-six (ETS) family of transcription factors that are capable of transforming cells. EWS/FLI1, the most frequent fusion, is thought to cause transformation through activation or repression of specific target genes. We present evidence demonstrating that the Wnt inhibitor and beta-catenin/T-cell factor (TCF)-responsive gene DICKKOPF-1 (DKK-1) is a transcriptional target of EWS/FLI1, which can inhibit both basal and beta-catenin-induced transactivation of the DKK-1 promoter. Moreover, our data indicate that EWS/FLI1 has a more general effect on beta-catenin/TCF-mediated transcription since it can block transactivation of a consensus beta-catenin/TCF reporter construct. Consistently, Ewing tumour cells expressing different EWS/ETS translocations cannot engage beta-catenin/TCF-dependent transcription, whereas silencing of EWS/FLI1 restores beta-catenin responsiveness in A673 and RD-ES Ewing tumour cells. Accordingly, gene set enrichment analysis shows that beta-catenin/TCF target genes are significantly enriched among genes downregulated by EWS/FLI1 in the Ewing cell line A673. Mechanistically, the inhibitory effect of EWS/FLI1 can be overcome by a constitutively active TCF4 protein (TCF4-VP16). Moreover, EWS/FLI1 binds lymphoid enhancer factor 1, a TCF family member, and interferes with its binding to beta-catenin, which could explain its negative effect on beta-catenin/TCF-mediated transcription. Our results show that EWS/FLI1 inhibits both DKK-1 expression as well as beta-catenin/TCF-dependent transcription, which could contribute to progression of tumours of the Ewing family.

Molecular Diagnosis of Ewing Sarcoma Family of Tumors

To compare the sensitivity and specificity of fluorescence in situ hybridization (FISH) with reverse transcription polymerase chain reaction (RT-PCR) in the diagnosis of Ewing sarcoma family of tumors (ESFTs) and other small round-cell tumors (SRCTs) in formalin-fixed paraffin-embedded tissue assembled in tissue microarrays (TMAs). The second objective is to confirm the value of molecular methods and immunohistochemical (IHC) assays, to perform a differential diagnosis between ESFTs and SRCTs with similar or overlapping morphology. A total of 560 cases were selected for the present study out the 806 cases collected from the PROgnosis and THerapeutic Targets in the Ewing's Family of TumorS project. Case selection bias included only the cases with enough material to enable the TMA construction, as FISH analysis and the majority of IHC studies were performed in TMAs. Histopathologic, IHC, and molecular assays were carried out. Of the 560 total cases, 411 (73.4%) were considered informative (with results by FISH and/or RT-PCR assays). From the informative cases, 382 (92.9%) were diagnosed as ESFT, 23 cases (5.6%) as non-ESFT but with specific diagnosis for another established entity, and 6 cases (1.5%) as small round cell tumors not otherwise specified. Sensitivity and specificity for the FISH assays was 96.3% and 95.2%, respectively, whereas RT-PCR presented a sensitivity of 97.5% and specificity of 92.9%. In concordant cases, both methods showed a sensitivity and specificity of 99.2% and 100%, respectively. Twenty-nine cases (7.1%) initially interpreted at morphologic level as atypical ESFTs were finally reclassified, with the support of molecular methods and IHC, as either non-ESFT with another specific histologic type or as small round cell tumors not otherwise specified. FISH and RT-PCR are ancillary techniques possessing high sensitivity in the diagnosis of ESFT; nevertheless, FISH is more specific than RT-PCR in the diagnosis of formalin-fixed paraffin-embedded tissue. Both methods in combination displayed the highest sensitivity and specificity. The combination of histopathologic, IHC, and molecular findings is the method of choice for the diagnosis of ESFT, as well as for the differential diagnosis with other SRCTs.

High expression of the evolutionarily conserved α/β hydrolase domain containing 6 (ABHD6) in Ewing tumors

Despite improvements in the treatment of patients with Ewing family tumors (EFT), the prognosis for patients with advanced disease is still unsatisfactory. Recently, we identified lipase I as an EFT-associated gene that might be interesting for the development of new immunological or pharmacological treatment strategies. Lipase I is a member of the large protein superfamilies of alpha/beta hydrolases and serine hydrolases. In the present paper we describe high expression of another member of these superfamilies in EFT. By DNA microarray data base mining we found exceptional high expression of alpha/beta hydrolase domain containing 6 (ABHD6) in EFT but not in other sarcomas. Expression of ABHD6 in EFT correlated with expression of another EFT-associated gene, aristaless. Analysis of ABHD6-associated GGAA microsatellites revealed shorter microsatellites in EFT with lack of ABHD6 expression. ABHD6 homologues were found in varying chordata but not in other animal species. Based on homology modeling we predicted the 3D-structure of ABHD6, which shows high similarity with bacterial homoserine transacetylases. High expression of ABHD6 in EFT in comparison to normal tissues and other tumors suggests that ABHD6 might be an interesting new diagnostic or therapeutic target for EFT. However, knock down of ABHD6 in EFT cells did not inhibit tumor cell growth.

Ewing sarcoma–peripheral neuroectodermal tumor of the kidney with a FUS–ERG fusion transcript

The Ewing family of tumors (EFTs) represents a neoplastic entity characterized by specific chromosomal rearrangements. The most commonly detected translocation involves fusion of EWSR1 to one of the genes encoding ETS family of transcription factors, usually FLI1 or ERG. In rare cases, FUS or FEV has been shown to substitute for EWSR1. The detection of specific translocations by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), or both has become a diagnostic hallmark for the EFTs. We report here a case of small round blue cell tumor detected in the kidney of a 3-year-old girl. The use of FISH in combination with RT-PCR led to identification of a novel FUS–ERG fusion transcript in the tumor, with FUS exons 1–5 fused in-frame to ERG exons 6–9. The results from the molecular analyses were critical for reaching a final diagnostic conclusion of Ewing tumor–peripheral neuroectodermal tumor and hence had important therapeutic implications for the patient.

9407 Ewing's family (EFT) tumours: biomolecular characterization on paraffine-embedded samples

Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative.200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS, EWSR1/WT1, PAX3/7-FOX01 or SYT/SSX transcripts, and the negative tumors were subsequently analyzed for CIC/DUX4, BCOR/CCNB3 and CIC/FOX04 transcripts.133 (66.5%) ESFT displayed one of the above EWSR1-ETS translocations. Three cases (1.5%) revealed the SYT-SSX transcript for Synovial sarcoma, and one (0.5%) a EWSR1-WT1 transcript for Desmoplastic Small Round Cell tumor. The CIC-DUX4 translocation was found in six Ewing-like tumors (3%) with CD99 positivity. The BCOR-CCNB3 gene fusion was observed in 5 tumors (2.5%) displaying round or spindle cells with strong CCNB3 IHC expression in 3 tumors. Moreover, RT-PCR failed to detect any gene fusion transcripts in 19 tumors (9.5%) and were considered “undifferentiated small round cell sarcoma” (SRCS). Molecular biology results were non-informative in 33 SRCTs (16.5%) due to RNA degradation through inadequate fixation and/or decalcification.Our analysis of 200 SRCTs confirms the molecular heterogeneity of neoplasms with ESFT morphology and highlight that molecular studies with RT-PCR including new emerging gene fusion transcripts are mandatory for the diagnosis when EWSR1 FISH is negative or non-informative. The incidence of CIC-DUX4, BCOR-CCNB3 and CIC-FOX04 transcripts was relatively low. A small group of Ewing-like sarcomas or undifferentiated SRCS remains unclassified. Adopting appropriate tissue fixation and processing protocols is important to avoid degradation of fixed/embedded tissue when no frozen tumor is available.

Devazepide, a nonpeptide antagonist of CCK receptors, induces apoptosis and inhibits Ewing tumor growth

The Ewing family of tumors is a group of highly malignant tumors that mainly arise in bone and most often affect children and young adults in the first two decades of life. Despite the use of multimodal therapy, the long-term disease-free survival rate of patients with Ewing tumors is still disappointingly low, making the discovery of innovative therapeutic strategies all the more necessary. We have recently shown that cholecystokinin (CCK), a neuroendocrine peptide, involved in many biological functions, including cell growth and proliferation, is a relevant target of the EWS/FLI1 oncoprotein characteristic of Ewing tumors. CCK silencing inhibits cell proliferation and tumor growth in vivo, suggesting that CCK acts as an autocrine growth factor for Ewing cells. Here, we analyzed the impact of two CCK receptor antagonists, devazepide (a CCK1-R antagonist) and L365 260 (a CCK2-R antagonist), on the growth of Ewing tumor cells. Devazepide (10 micromol/l) inhibited cell growth of four different Ewing tumor cells in vitro (range 85-88%), whereas the effect of the CCK2-R antagonist on cell growth was negligible. In a mouse tumor xenograft model, devazepide reduced tumor growth by 40%. Flow cytometry experiments showed that devazepide, but not L365 260, induced apoptosis of Ewing tumor cells. In summary, devazepide induces cell death of Ewing tumor cells, suggesting that it could represent a new therapeutic approach in the management of Ewing's tumor patients.

Local and systemic control of Ewing's bone sarcoma family tumors of the ribs

A retrospective analysis of the results and relapse pattern was evaluated in 34 patients with Ewing's family bone tumors (EFBT) treated at Rizzoli Institute with neoadjuvant chemotherapy between 1983 and 2003. The aim of the study was to evaluate treatment strategy and compare our results with those obtained in other studies. Local treatment in these patients was radiotherapy alone in 4 cases, surgery alone in 13 and surgery followed by radiotherapy in 17. Five-year event-free survival (EFS) was 44%, no different from that observed in another 558 patients with EFBT located in other sites treated in the same period with neoadjuvant chemotherapy protocols. Eighteen patients had a systemic relapse, followed by local relapse in two and one patient had a local relapse alone. EFS was significantly correlated to the time interval between onset symptoms and beginning of treatment and, in operated patients to histologic response to preoperative treatment. We conclude that EFBT of the ribs, when treated with neoadjuvant chemotherapy, have an outcome similar to that of patients with EFBT located in other sites.

Diagnosis and prognosis for the Ewing family of tumors

Ewing's sarcoma was first described by James Ewing in 1921. It is the second most common bone sarcoma seen in children, adolescents and young adults after osteosarcoma and belongs to the group of 'small round blue cell tumors', showing an aggressive natural history. Once almost invariably fatal and treated only with palliative radiation, thanks to a multidisciplinary approach, the probability of survival at 5 years is now ∼ 65 - 75% for patients with localized disease. This percentage is no more than 20 - 25% for patients with metastatic disease at presentation. To review epidemiology, diagnosis and prognosis of Ewing's sarcoma family tumors (EFT) of bone. This entity includes a wide spectrum of tumors, from the less differentiated or classic Ewing's sarcoma to the more differentiated peripheral neuroectodermal tumor. A translocation involving the EWS gene on the chromosome 22 band q12 is characteristic of EFTs. A complete clinical and radiological assessment is essential for initial patient evaluation. Owing to the rarity of this entity, whenever an EFT is suspected patients should be referred to a bone tumor treatment center before a diagnostic biopsy is performed. The molecular characterization of chromosomal translocations has an important role in the diagnosis of EFT.

Unusual histological variant of Ewing's sarcoma of mandible

Ewing family of tumors (EFTs) comprise highly malignant, nearly undifferentiated neoplasms including Ewing's sarcoma (ES), primitive neuroectodermal tumor (PNET) and a spectrum of other unusual variants. In general, EFTs are included among small blue cell tumors. Establishing histological diagnosis can be difficult; CD99 and FLI1 immunohistochemical staining has improved diagnosis, but these markers are not specific for EFTs. The diagnosis of EFTs is confirmed by molecular diagnostic testing showing the presence of established rearrangements of the EWS gene. The use of this molecular signature in EFTs revealed rare variants in the histomorphologic spectrum of these tumors. The authors report an unusual variant of EFT in the mandible of a 17-year-old patient, which was confirmed by translocation rearrangement in EWR1 gene at 22q12 by fluorescence in situ hybridization. The unusual histologic features, with prominent spindling of tumor cells and deviation from the classic features of Ewing's sarcoma posed a diagnostic challenge for the medical centers involved in the diagnosis and treatment of this patient. This highlights the importance of the genetic study of undifferentiated sarcomas to identify rare morphologic variants of ES, in view of the chemosensitivity of EFTs and how this affects patient management.

PAX Immunoreactivity Identifies Alveolar Rhabdomyosarcoma

PAX5 is a member of the paired box transcription factors involved in development and its expression has been well characterized among hematopoietic malignancies of B-cell lineage. Its expression has also been reported in a subset of neuroendocrine carcinomas, urothelial tumors, Merkel cell carcinoma, glioblastoma, and neuroblastoma cell lines. As such, we sought to assess it as a diagnostic marker in the evaluation of pediatric small round blue cell tumors. Tumors selected for evaluation included embryonal rhabdomyosarcoma (55 cases), alveolar rhabdomyosarcoma (ARMS) (51 cases), neuroblastoma (22 cases), Wilms tumor (18 cases), Ewing Family of Tumors (11 cases), lymphoblastic lymphoma (8 cases), hepatoblastoma (6 cases), and granulocytic sarcoma (3 cases) as either cores in a tissue microarray or whole mount sections. All cases were immunostained using an antibody directed toward PAX5 and immunoreactivity was scored semiquantitatively according to percentage of nuclear staining. As expected, all B-cell lymphoblastic lymphomas were strongly immunoreactive against PAX5. Additionally, all Wilms tumors showed staining of variable intensity, most intensely in the epithelial component. Of the rhabdomyosarcoma cases, 34 of 51 (67%) ARMS were immunoreactive whereas none of the 55 embryonal rhabdomyosarcoma cases stained. No other tumor type on the array was immunoreactive toward PAX5. Genetic information was available on 7 ARMS, 5 of which had characteristic translocations involving PAX genes, either t(2:13) or t(1;13). Of the translocation-positive cases, all showed nuclear reactivity toward PAX5, and both the translocation-negative cases did not. Possible explanations of PAX5 staining include aberrant expression of the PAX5 transcription factor, PAX5 expression in normal tissue at the time the tumors most closely recapitulates in development or crossreactivity with another member of the PAX family. PAX3 and PAX7 fusion genes characterize the majority of ARMS making crossreactivity with these proteins an attractive theory, and suggest that PAX5 immunoreactivity may be specific for translocation-positive ARMS. Further study in a larger series of rhabdomyosarcomas is warranted to assess the sensitivity and specificity of PAX5 immunoreactivity for the ARMS variant.

A potential role for ajulemic acid in treatment of the Ewing family of tumors

Ewing's Sarcoma is a bone cancer that primarily affects children and teenagers. With a five‐year survival rate of approximately 30%, improved treatment options are needed. Our research has focused on the ability of the synthetic cannabinoid, ajulemic acid, to induce death in Ewing's sarcoma cells in vitro. We find ajulemic acid induces apoptosis in Ewing's sarcoma cells and several other tumor types in the Ewing family of tumors. In order to test the efficacy of ajulemic acid in vivo, we developed Ewing's sarcoma cells that express a firefly luciferase expression system as a handle by which to monitor tumor growth and drug response in living mice. SK‐ES Ewing's sarcoma cells were transiently transfected with firefly luciferase and then injected into the tibiae of nude mice. Tumors were allowed to develop and the growth of the bioluminescent tumors tracked using in vivo imaging techniques. The effect of different doses of ajulemic acid (and other potential therapies) can be used in these mice and tumor responses in individual mice can be monitored and measured. We hypothesize that these experiments provide the rationale for the development of improved therapies for this devastating cancer. The project described was supported by NIH Grant Number P20 RR‐16460 from the IDeA Networks of Biomedical Research Excellence (INBRE) Program of the National Center for Research Resources.

In Vitro Activity of the EWS Oncogene Transcriptional Activation Domain

Aberrant chromosomal fusion of the Ewings sarcoma oncogene (EWS) to several different cellular partners gives rise to the Ewing's family of oncogenic proteins [EWS fusion proteins (EFPs)] and associated tumors (EFTs). EFPs are potent transcriptional activators dependent on the N-terminal region of EWS [the EWS activation domain (EAD)], and this function is thought to be central to EFT oncogenesis and maintenance. Thus, EFPs are promising therapeutic targets, and detailed molecular studies of the EAD will be pivotal for exploring this potential. For many reasons, the molecular mechanism of EAD action is poorly understood and one major obstacle to progress is the lack of an in vitro transcription assay. Using well-characterized EAD-dependent activators and soluble nuclear extracts, we have attempted to recapitulate EAD transcriptional activity in vitro. We report that while the EAD activates transcription strongly in vitro, the effect of EAD mutations is strikingly different from that observed in vivo. Our results therefore suggest that crude soluble extracts do not support bona fide EAD activity in vitro, and we discuss our findings in relation to future assay development and potential mechanisms of EAD action.

A Rational Approach to Genetic Testing for Sarcoma

Diagnosis of sarcoma increasingly relies on identifying genetic defects using modern molecular technologies. Each analytic method has unique advantages and specimen requirements that should be considered when allocating tissue for downstream testing. Karyotype on fresh tissue represents a genome-wide screen of gross chromosomal alterations, whereas fluorescence in situ hybridization and polymerase chain reaction detect specific defects that are characteristic of a given tumor type such as t(11;22) EWSR1-FLI1 in Ewing family tumors, t(X;18) SS18-SSX1 in synovial sarcoma, t(2;13) PAX3-FOXO1A in alveolar rhabdomyosarcoma, and MYCN gene amplification in neuroblastoma. Identifying a clonal genetic defect also provides a tumor marker that could help stage the extent of spread of the neoplasm or monitor the efficacy of therapy. In research laboratories, array-based methods identify genes and biochemical pathways contributing to tumor growth and maintenance, opening avenues for pharmacogenetic tests that predict which therapy is likely to overcome the biochemical defects with minimal toxicity. Array-based discoveries are also spurring validation of smaller test panels that rely on conventional technologies such as immunohistochemistry and reverse transcription polymerase chain reaction. The pathologist's expertise is critical in: (1) consulting with clinicians about specimen collection and handling; (2) preserving tissue for immediate testing and for any downstream testing that is indicated once morphology and immunophenotype are known; (3) performing tests that maximize outcome on the basis of the strengths and limitations of each assay in each available specimen type; and (4) conveying results to the rest of the healthcare team using proper gene nomenclature and interpreting the findings in a way that facilitates optimal clinical management.

EWS/ETS Regulates the Expression of the Dickkopf Family in Ewing Family Tumor Cells

BackgroundThe Dickkopf (DKK) family comprises a set of proteins that function as regulators of Wnt/β–catenin signaling and has a crucial role in development. Recent studies have revealed the involvement of this family in tumorigenesis, however their role in tumorigenesis is still remained unclear.Methodology/Principal FindingsWe found increased expression of DKK2 but decreased expression of DKK1 in Ewing family tumor (EFT) cells. We showed that EFT-specific EWS/ETS fusion proteins enhance the DKK2 promoter activity, but not DKK1 promoter activity, via ets binding sites (EBSs) in the 5′ upstream region. EWS/ETS-mediated transactivation of the promoter was suppressed by the deletion and mutation of EBSs located upstream of the DKK2 gene. Interestingly, the inducible expression of EWS/ETS resulted in the strong induction of DKK2 expression and inhibition of DKK1 expression in human primary mesenchymal progenitor cells that are thought to be a candidate of cell origin of EFT. In addition, using an EFT cell line SK-ES1 cells, we also demonstrated that the expression of DKK1 and DKK2 is mutually exclusive, and the ectopic expression of DKK1, but not DKK2, resulted in the suppression of tumor growth in immuno-deficient mice.Conclusions/SignificanceOur results suggested that DKK2 could not functionally substitute for DKK1 tumor-suppressive effect in EFT. Given the mutually exclusive expression of DKK1 and DKK2, EWS/ETS regulates the transcription of the DKK family, and the EWS/ETS-mediated DKK2 up-regulation could affect the tumorigenicity of EFT in an indirect manner.

Cooperative Trial CWS-91 for Localized Soft Tissue Sarcoma in Children, Adolescents, and Young Adults

To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% +/- 4% and 73% +/- 4%, respectively (all survival rates in this abstract are calculated and displayed with +/-95% CI). EFS/OS rates by histology were 60% +/- 5%/72% +/- 5% in rhabdomyosarcoma, 62% +/- 10%/69% +/- 10% for Ewing tumors of soft tissues, 84% +/- 12%/90% +/- 10% for synovial sarcoma, and 67% +/- 38%/83% +/- 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% +/- 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% +/- 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

PDGF-C Mediates the Angiogenic and Tumorigenic Properties of Fibroblasts Associated with Tumors Refractory to Anti-VEGF Treatment

Tumor- or cancer-associated fibroblasts (TAFs or CAFs) from different tumors exhibit distinct angiogenic and tumorigenic properties. Unlike normal skin fibroblasts or TAFs from TIB6 tumors that are sensitive to anti-VEGF treatment (TAF-TIB6), TAFs from resistant EL4 tumors (TAF-EL4) can stimulate TIB6 tumor growth even when VEGF is inhibited. We show that platelet-derived growth factor C (PDGF-C) is upregulated in TAFs from resistant tumors. PDGF-C-neutralizing antibodies blocked the angiogenesis induced by such TAFs in vivo, slowed the growth of EL4 and admixture (TAF-EL4 + TIB6) tumors, and exhibited additive effects with anti-VEGF-A antibodies. Hence, our data reveal an additional mechanism for TAF-mediated tumorigenesis and suggest that some tumors may overcome inhibition of VEGF-mediated angiogenesis through upregulation of PDGF-C.

Genetics and Epigenetics of the TET-ETS Translocation Network

In the present paper we review the translocation network involving TET and ETS family members with special focus on the Ewing family of tumors. FUS (fusion, involved in t(12;16) in malignant liposarcoma = TLS, Translocated in liposarcoma), EWSR1 (Ewing sarcoma breakpoint region 1) and TAF15 (TATA box-binding protein-associated factor, 68-KD) are the three human members of the TET family of RNA binding proteins. In addition, two EWSR1 pseudogenes are present in the human genome. TET family members are involved in several oncogenic gene fusions. Five of the 18 known fusion partners belong to the E26 (E twenty-six, ETS) family of transcription factors. Gene fusions between TET or ETS family members and other fusion partners link these gene fusions to a large network of oncogenic gene rearrangements.

Radiation treatment for Ewing family of tumors in adults: The University of Florida experience

Radiation treatment for Ewing family of tumors in adults: The University of Florida experience