STAT3 is activated in a subset of the Ewing sarcoma family of tumours

Lai, Raymond; Navid, Fariba; Rodríguez‐Galindo, Carlos; Liu, T.; Fuller, Christine; Ganti, Ramapriya; Dien, Jennifer; Dalton, James; Billups, Catherine A.; Khoury, Joseph D.

doi:10.1002/path.1941

Cited by 44 publications

(48 citation statements)

References 47 publications

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“…In a group of Ewing sarcoma family tumors with confirmed EWS translocations, we have identified only 2/47 (4.2%) EGFR-positive tumors and 11/49 (22.4%) ErbB-2-positive tumors. 39,40 Likewise, neuroblastoma tumors predominantly lack EGFR expression (J Khoury, unpublished data), and in a published survey of a large group of neuroblastoma tumors only a small subset expressed ErbB-2. 41 These data seem to suggest that the prevalence of EGFR and ErbB-2 expression is distinctly higher among rhabdomyosarcoma tumors compared to the Ewing sarcoma family of tumors and neuroblastoma.…”

Section: Discussionmentioning

confidence: 98%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors. Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/ 66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P ¼ 0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, Po0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21. In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.

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Section: Discussionmentioning

confidence: 98%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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“…Tissue microarray slides from the Ewing sarcoma cases were analyzed by fluorescence in-situ hybridization (FISH) using a dual-color break-apart probe cocktail flanking the EWS-R1 breakpoint region (22q12) (Vysis, Downers Grove, IL, USA). 29 Tissue microarray blocks were constructed from 1 mm cores of formalin-fixed, paraffin-embedded tissue in triplicate. One tissue microarray block was produced for each tumor type, with each block containing a variety of normal and neoplastic tissue samples as internal controls.…”

Section: Methodsmentioning

confidence: 99%

Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma

2006

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As a result of overlapping morphologic and immunohistochemical features, it can be difficult to distinguish synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma/primitive neuroectodermal tumor in core biopsies. To analyze and compare immunohistochemical profiles, we stained tissue microarrays of 23 synovial sarcomas, 23 malignant peripheral nerve sheath tumors, and 27 Ewing sarcomas with 22 antibodies potentially useful in the differential diagnosis, and analyzed the data with cluster analysis. Stain intensity was scored as none, weak, or strong. For CD99, tumors with membranous accentuation were independently categorized. Cluster analysis sorted five groups, with like tumors clustering together. Synovial sarcoma clustered into two groups: one cytokeratin and EMA positive (n ¼ 11), the other mostly cytokeratin negative, EMA positive, bcl-2 positive and mostly CD56 positive (n ¼ 9). Malignant peripheral nerve sheath tumor clustered into two groups: one S100 positive, with nestin and NGFR positivity in most (n ¼ 10), the other mostly S100 negative, and variably but mostly weakly positive for nestin and NGFR (n ¼ 11). Ewing sarcomas clustered into a single group driven by membranous CD99 staining. Thirteen cases failed to cluster (outliers), while three Ewing sarcomas clustered into groups of other tumor types. Paired antibodies for each tumor type determined by visual assessment of cluster analysis data and statistical calculations of specificity, sensitivity, and predictive values showed that EMA/CK7 for synovial sarcoma, nestin/S100 for malignant peripheral nerve sheath tumor, and membranous CD99/Fli-1 for Ewing sarcoma yielded high specificity and positive predictive values. Cluster analysis also highlighted aberrant staining reactions and diagnostic pitfalls in these tumors. Hierarchical cluster analysis is an effective method for analyzing high-volume immunohistochemical data.

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“…It has been demonstrated that STAT3 is also constitutively activated in a number of human tumors, [25][26][27][28] including MCL cells, 29,30 and possesses tumorigenic potential 31 and antiapoptotic activities. 25,32 Inhibition of constitutively active STAT3 suppresses proliferation and induces apoptosis.…”

Section: Atiprimod Activated Jnk and Inhibited Nf-b And Stat3mentioning

confidence: 99%

Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways

Wang

Zhang

Han

et al. 2007

Blood

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Atiprimod is a novel cationic amphiphilic compound and has been shown to exert antimyeloma effects both in vitro and in mouse experiments. This study was undertaken to evaluate the therapeutic efficacy of atiprimod on mantle cell lymphoma (MCL) and elucidate the mechanism by which it induces cell apoptosis. IntroductionMantle cell lymphoma (MCL) represents approximately 8% of all non-Hodgkin lymphomas (NHLs). It has the worst prognosis among all B-cell-derived malignancies with median survival of 3 to 4 years. [1][2][3] Although MCL has been treated with chemotherapy, radiotherapy, hematopoietic stem cell transplantation, molecular targeted therapy, and combination therapy of these treatments, no standard treatment approach has been established thus far. Novel therapeutic agents are needed in clinical trials. [4][5][6][7][8]5] decane-2-propanamine), a novel cationic amphiphilic compound, has been studied for its anticancer properties in malignancies. [9][10][11] Recent reports have suggested that atiprimod exhibits antiproliferative and antiangiogenic activities, induces apoptosis via activation of caspases-3 and -8, and inhibits phosphorylation of Akt and STAT3 in multiple myeloma (MM). 10,12 In addition, atiprimod exhibits in vivo antimyeloma effects in xenograft severe combined immunodeficient (SCID) mouse models. 10,13 These results provide a framework for clinical trials of atiprimod in MM.MCL has distinct biologic, morphologic, and immunophenotypic features in NHL. 14 MCL responds to similar agents used effectively for MM. For example, the chemotherapy regimens CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and hyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) are effective in B-cell NHL, especially in MCL, 15 but their slight modifications are also effective in MM. [16][17][18][19] Bortezomib, a potent and specific proteasome inhibitor that was U. S. Food and Drug Administration-approved for relapsed MM, was also proven to be effective in MCL. 20 Thalidomide is active in MM, and thalidomide in combination with rituximab induces impressive antitumor activity in relapsed/ refractory MCL patients. 21 Revlimid, an immunomodulatory drug that produces durable clinical responses in patients with relapsed and refractory MM, 22 also is showing activity in clinical trials for treatment of NHL. Thus, we hypothesize that MCL and MM share certain biologic mechanisms in responding to various compound therapies. Atiprimod, which exhibits significant antitumor ability against MM cells by growth inhibition and apoptosis, 10 may also prove effective in MCL. In this study, we demonstrate that atiprimod not only inhibited growth and induced apoptosis of MCL cell lines SP53, MINO, Grant 519, Jeko-1, and freshly isolated patient-derived primary MCL cells in vitro, but it was also therapeutic against established human MCL in xenograft SCID mouse models. Of importance, atiprimod exhibited lower cytotoxicity against normal T cells. Furthermore, we attempted to eluc...

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STAT3 is activated in a subset of the Ewing sarcoma family of tumours

Cited by 44 publications

References 47 publications

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma

Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways

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