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The Ewing Tumor Family of Peripheral Primitive Neuroectodermal Tumors Expresses Human Gastrin-releasing Peptide¹

Department of Pathology, British Columbia's Children's Hospital, Vancouver, British Columbia, V6H 4H4 Canada [E. R. L., J. F. L., W. T., C. P., C. J. C., I. V. K., P. H. B. S.]; Children's Cancer Research Institute, St. Anna Kinderspitel, A-1090 Vienna, Austria [H. K.]; and the Department of Medicine, University of Western Ontario, London, Ontario, N6A 5A5 Canada [T. J. M.]

The Ewing tumor family of peripheral primitive neuroectodermal tumors (pPNETs) are characterized by chromosomal translocations leading to EWS-ETS gene fusions. These hybrid genes express chimeric proteins that are thought to act as aberrant transcription factors. We therefore used differential display-PCR to compare gene expression patterns in pPNET cell lines with those of other small round cell tumors (SRCTs) of childhood. This technique detected differential expression of sequences corresponding to human gastrin-releasing peptide (GRP) in pPNET cell lines but not in other SRCT cell lines. Subsequent Northern and reverse transcription-PCR analysis of SRCT cell lines confirmed GRP positivity in all pPNET lines tested. Of primary tumors tested by reverse transcription-PCR, GRP expression was found in 7 (44%) of 16 pPNETs but in no other primary SRCTs examined. Expression of the GRP receptor gene was demonstrable in 55% of pPNET cell lines and 25% of primary pPNET tumors but also in several other SRCTs. Radioimmunoassays and immunohistochemistry confirmed expression of bioactive GRP peptide in pPNET cell lines and primary tumors, respectively. Moreover, in vitro growth of a pPNET cell line was slowed by treatment with a GRP receptor antagonist and accelerated by a GRP receptor agonist. GRP is a known autocrine growth factor in small cell lung cancer and other neuroendocrine tumors. Its expression in pPNETs provides further evidence for a neuroectodermal histogenesis of these tumors and suggests that autocrine growth of this family of tumors may be at least partially regulated by GRP.

¹ This research was supported by the British Columbia Research Institute for Child and Family Health Mining for Miracles Post-Doctoral Fellowship (to E. R. L.) and the National Cancer Institute of Canada with funds from the Terry Fox Run (to P. H. B. S.).

² To whom requests for reprints should be addressed, at Department of Pathology, British Columbia's Children's Hospital, Room L200, 4480 Oak Street, Vancouver, British Columbia, V6H 3V4 Canada.

Received 9/ 2/97. Accepted 3/30/98.

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