Characteristics of human Ewing/PNET sarcoma models

Abstract

Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global collaborations and many years. In vivo models that as accurately as possible reflect the clinical disease are helpful in selecting therapeutics with the most promise of positive clinical impact. Human Ewing/PNET sarcoma cell lines developed over the past 45 years are described. Several of these have undergone genetic analysis and have been confirmed to be those of Ewing/PNET sarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in understanding the biology of this disease in the mouse. The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma. Cell lines that express this genetic profile are confirmed to be those of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a xenograft in immunodeficient mice. The A673 model has been used to study Ewing sarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma clinical specimens express the cell surface protein endosialin. Several Ewing sarcoma cell lines, including the A673 line, also express cell surface endosialin when grown as subcutaneous tumor nodules and as disseminated disease; thus the A673 is a useful model for the study of endosialin biology and endosialin-directed therapies. With the advent of tools that allow characterization of clinical disease to facilitate optimal treatment, it becomes imperative, especially for rare tumors, to develop preclinical models reflecting disease subsets. Ewing PNET sarcomas are a rare disease where models are available.

The Biology of Ewing Sarcoma

“…In contrast to localized cases of ES, advances in standard treatment approaches have not been encouraging with regard to improving the survival rates for metastatic and recurrent cases, as 5-year survival rates have recently been described as less than 25% [8, 62, 63]. It has been suggested that chemotherapy and radiation treatments are reaching their efficacy and toxicity limits [83].…”

“…All three forms of treatments have shown efficacy in some cases [52]. Most current therapies call for multidrug chemotherapy, consisting of cycles of varied combinations of vincristine, doxorubicin, cyclophosphamide, etoposide, ifosfamide, actinomycin D, and topotecan, followed by local therapies (radiation and/or surgery) [8, 53]. …”

“…While these tumors are rare, accounting for less than 10% of all human malignancies, they are of the most aggressive and often occur in the long bones and pelvis where they can quickly metastasize to the bone marrow, lung, and other tissues [3, 4]. ES is the second most common bone cancer, most often occurring in Caucasian children, adolescents, and young adults, and is considered a high-grade malignancy [5–8]. Originally, it was thought that ES was derived from primitive neuroectodermal cells; however, there is much debate over the origin of ES.…”

Primary primitive neuroectodermal tumor of the cervix

“…Occasionally, epithelial markers and desmin might show focal positivity, whereas the expression of neural markers such as NSE, S-100, neurofilaments, glial fibrillary acid protein, and CgA is uncertain. A characteristic chromosomal translocation t(11;22)(q24;q12), resulting in EWS–FLI1 fusion, is observed in 85% of PNET cases;14,15 most of the remaining cases (10%–15%) show fusion of the EWS gene to a second member of the ETS family of genes, namely ERG. EWS–ERG fusion occurs as a result of the chromosomal translocation t(21;22)(q22;q12) 12…”

Bridge-Induced Chromosome Translocation in Yeast Relies upon a Rad54/Rdh54-Dependent, Pol32-Independent Pathway

“…Chromosomal translocations characterize many types of cancers [1], [2] and also can become useful markers in the diagnosis of liquid and solid tumors [3], [4]. However, the molecular factors that elicit this gross chromosomal rearrangement (GCR) are still object of investigation [5], [6].…”