{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:04:27Z","timestamp":1792047867601,"version":"4.4.0"},"reference-count":33,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5528","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2001,7,13]]},"abstract":"<jats:p>Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberku\u0308hn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.<\/jats:p>","DOI":"10.1126\/science.1060191","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:39:52Z","timestamp":1027748392000},"page":"293-297","source":"Crossref","is-referenced-by-count":1121,"title":["Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice"],"prefix":"10.1126","volume":"293","author":[{"given":"Franc\u0327ois","family":"Paris","sequence":"first","affiliation":[{"name":"Laboratory of Signal Transduction and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zvi","family":"Fuks","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Kang","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Capodieci","sequence":"additional","affiliation":[{"name":"Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Juan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desiree","family":"Ehleiter","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Haimovitz-Friedman","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cordon-Cardo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Kolesnick","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1080\/09553009014552281","volume":"58","author":"Potten C. S.","year":"1990","unstructured":"Potten C. S., Int. J. Radiat. Biol. 58, 925 (1990).","journal-title":"Int. J. Radiat. Biol."},{"key":"e_1_3_1_3_2","doi-asserted-by":"crossref","unstructured":"C. S. Potten et al. Int. J. Exp. Pathol. 78 219 (1997).","DOI":"10.1016\/S0025-5610(97)00018-X"},{"key":"e_1_3_1_4_2","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1172\/JCI10229","volume":"105","author":"Booth C.","year":"2000","unstructured":"Booth C., Potten C. S., J. Clin. Invest. 105, 1493 (2000).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_1_5_2","first-page":"G249","volume":"276","author":"Houchen C. W.","year":"1999","unstructured":"Houchen C. W., et al., Am. J. Physiol. 276, G249 (1999).","journal-title":"Am. J. Physiol."},{"key":"e_1_3_1_6_2","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2307\/3579856","volume":"150","author":"Okunieff P.","year":"1998","unstructured":"Okunieff P., et al., Radiat. Res. 150, 204 (1998).","journal-title":"Radiat. Res."},{"key":"e_1_3_1_7_2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.2307\/3579609","volume":"148","author":"Khan W. B.","year":"1997","unstructured":"Khan W. B., et al., Radiat. Res. 148, 248 (1997).","journal-title":"Radiat. Res."},{"key":"e_1_3_1_8_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0092-8674(00)80091-4","volume":"86","author":"Santana P.","year":"1996","unstructured":"Santana P., et al., Cell 86, 189 (1996).","journal-title":"Cell"},{"key":"e_1_3_1_9_2","first-page":"321","volume":"60","author":"Pena L. A.","year":"2000","unstructured":"Pena L. A., et al., Cancer Res. 60, 321 (2000).","journal-title":"Cancer Res."},{"key":"e_1_3_1_10_2","first-page":"S105","volume":"27","author":"Okunieff P.","year":"1996","unstructured":"Okunieff P., et al., Br. J. Cancer Suppl. 27, S105 (1996).","journal-title":"Br. J. Cancer Suppl."},{"key":"e_1_3_1_11_2","unstructured":"F. Paris R. Kolesnick unpublished data."},{"key":"e_1_3_1_12_2","unstructured":"Late-stage and early-stage apoptosis were assessed by TUNEL (7) and by in situ labeling with annexin V ["},{"key":"e_1_3_1_12_3","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s004180000137","volume":"113","author":"Bronckers A. L.","year":"2000","unstructured":"Bronckers A. L., et al., Histochem. Cell Biol. 113, 293 (2000);","journal-title":"Histochem. Cell Biol."},{"key":"e_1_3_1_12_4","unstructured":"]. To identify endothelial cells we immunostained tissue with a rat monoclonal antibody against CD31 as in (16) except that we used a biotinylated rabbit antibody directed against a rat secondary antibody (1:100 dilution) and omitted the counterstaining. For annexin V staining we injected mice iv with 0.5 mg of annexin V\u2013FITC (Sigma St Louis MO) and killed mice 30 min later by hypercapnia asphyxiation. Tissue sections were counterstained with propidium iodide and scored by fluorescence microscopy."},{"key":"e_1_3_1_13_2","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/bjc.1998.618","volume":"78","author":"Potten C. S.","year":"1998","unstructured":"Potten C. S., Grant H. K., Br. J. Cancer 78, 993 (1998).","journal-title":"Br. J. Cancer"},{"key":"e_1_3_1_14_2","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.1038\/sj.onc.1201126","volume":"14","author":"Merritt A. J.","year":"1997","unstructured":"Merritt A. J., et al., Oncogene 14, 2759 (1997).","journal-title":"Oncogene"},{"key":"e_1_3_1_15_2","unstructured":"A. J. Merritt L. S. Jones C. S. Potten in Techniques in Apoptosis T. G. Cotter S. J. Martin Eds. (Portland Press London 1996) pp. 269\u2013299."},{"key":"e_1_3_1_16_2","unstructured":"Supplementary material is available on Science Online at www.sciencemag.org\/cgi\/content\/full\/293\/5528\/293\/DC1"},{"key":"e_1_3_1_17_2","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1084\/jem.186.11.1831","volume":"186","author":"Haimovitz-Friedman A.","year":"1997","unstructured":"Haimovitz-Friedman A., et al., J. Exp. Med. 186, 1831 (1997).","journal-title":"J. Exp. Med."},{"key":"e_1_3_1_18_2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/0360-3016(89)90108-9","volume":"17","author":"Terry N. H.","year":"1989","unstructured":"Terry N. H., Travis E. L., Int. J. Radiat. Oncol. Biol. Phys. 17, 569 (1989).","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"e_1_3_1_19_2","unstructured":"Mouse FGFR cDNA sequences were incorporated into pBluescript SK 50 plasmids and included FGFR 1b 1c 2b 2c 3b 3c and FGFR-4 [D.M.Ornitz et al. J. Biol. Chem. 271 15292 (1996)]. FGFR-1 and FGFR-3 probes were generated by polymerase chain reaction using specific primers to produce T3 promoter-tailed DNA fragments. These were subsequently used as templates to transcribe the sense and antisense riboprobe with T3 polymerase. FGFR-2 and FGFR-4 probes were transcribed from the pBluescript SK 50 plasmids. Recombinant plasmid (1 \u03bcg) was linearized by Bgl II and Nhe I or Nco I and Not I respectively to generate sense and antisense transcripts. Riboprobes were generated with T7 and T3 polymerases for 2 hours at 37\u00b0C in 1\u00d7 transcription buffer (Boehringer Mannheim Indianapolis) containing 20 U of RNase inhibitor; 1 mmol\/liter each of ATP GTP and CTP; 6.5 mmol\/liter of UTP; and 3.5 mmol\/liter of digoxigenin-UTP. In situ hybridization was carried out by using deparaffinized tissue sections rinsed in water and phosphate-buffered saline for 10 min. Slides were digested in prewarmed citrate buffer for 5 min in a microwave. Prehybridization was performed for 30 min at 45\u00b0C in 50% deionized formamide and 2\u00d7 SSC. For hybridization 10 pmol\/liter of digoxigenin-labeled riboprobe was added to 50 \u03bcl hybridization buffer [50% deionized formamide (v\/v) 10% dextran sulfate 2\u00d7 SSC 1% SDS and 0.25 mg\/ml of herring sperm DNA]. After overnight incubation at 45\u00b0C slides were washed twice for 20 min in prewarmed 2\u00d7 SSC at 42\u00b0C followed by two washes in prewarmed 1\u00d7 SSC at 42\u00b0C for 20 min. Slides were then incubated in normal sheep serum diluted in buffer 1 (2 M Tris HCl 5 M NaCl pH 7.5). In some experiments slides were incubated in the same buffer with antibody against digoxigenin-AP (Boehringer Mannheim Indianapolis IN) at a dilution of 1:500 for 1 hour at room temperature. Visualization of hybridized transcripts was accomplished by nitroblue tetrazolium 5-bromo-4-chloro-3-indolylphosphate. Slides were counterstained with methyl green and mounted. In other experiments hybridization was at 42\u00b0C and slides were incubated with antibody against digoxigenin-rhodamine (Boehringer Mannheim) at a dilution of 1:200 for 1 hour at 37\u00b0C in the dark. Slides were counterstained in 4 6-diamino-2-phenylindole (DAPI) mounted and examined by using a fluorescent microscope (Olympus VX40) with blue and red filters."},{"key":"e_1_3_1_20_2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/00019606-199804000-00002","volume":"7","author":"Capodieci P.","year":"1998","unstructured":"Capodieci P., et al., Diagn. Mol. Pathol. 7, 69 (1998).","journal-title":"Diagn. Mol. Pathol."},{"key":"e_1_3_1_21_2","first-page":"37","volume":"76","author":"Magi-Galluzzi C.","year":"1997","unstructured":"Magi-Galluzzi C., et al., Lab. Invest. 76, 37 (1997).","journal-title":"Lab. Invest."},{"key":"e_1_3_1_22_2","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1177\/002215549904701001","volume":"47","author":"Fahimi H.","year":"1999","unstructured":"Fahimi H., Baumgart E., J. Histochem. Cytochem. 47, 1219 (1999).","journal-title":"J. Histochem. Cytochem."},{"key":"e_1_3_1_23_2","doi-asserted-by":"crossref","first-page":"4081","DOI":"10.1074\/jbc.273.7.4081","volume":"273","author":"Marathe S.","year":"1998","unstructured":"Marathe S., et al., J. Biol. Chem. 273, 4081 (1998).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_24_2","doi-asserted-by":"crossref","first-page":"18250","DOI":"10.1074\/jbc.273.29.18250","volume":"273","author":"Schissel S. L.","year":"1998","unstructured":"Schissel S. L., et al., J. Biol. Chem. 273, 18250 (1998).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_25_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S0076-6879(00)11080-8","volume":"311","author":"Dobrowsky R. T.","year":"2000","unstructured":"Dobrowsky R. T., Gazula V. R., Methods Enzymol. 311, 184 (2000).","journal-title":"Methods Enzymol."},{"key":"e_1_3_1_26_2","first-page":"832","volume":"63","author":"Cordon-Cardo C.","year":"1990","unstructured":"Cordon-Cardo C., et al., Lab. Invest. 63, 832 (1990).","journal-title":"Lab. Invest."},{"key":"e_1_3_1_27_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/B978-0-12-035414-6.50011-0","volume":"14","author":"Reinhold H. S.","year":"1990","unstructured":"Reinhold H. S., Fajardo L. F., Hopewell J. W., Adv. Radiat. Biol. 14, 177 (1990).","journal-title":"Adv. Radiat. Biol."},{"key":"e_1_3_1_28_2","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/0959-8049(92)90104-A","volume":"28","author":"Fuks Z.","year":"1992","unstructured":"Fuks Z., et al., Eur. J. Cancer 28A, 725 (1992).","journal-title":"Eur. J. Cancer"},{"key":"e_1_3_1_29_2","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1080\/01621459.1958.10501452","volume":"53","author":"Kaplan E. L.","year":"1958","unstructured":"Kaplan E. L., Meyer P., J. Am. Stat. Assoc. 53, 447 (1958).","journal-title":"J. Am. Stat. Assoc."},{"key":"e_1_3_1_30_2","first-page":"163","volume":"50","author":"Mantel N.","year":"1966","unstructured":"Mantel N., Cancer Chemother. Rep. 50, 163 (1966).","journal-title":"Cancer Chemother. Rep."},{"key":"e_1_3_1_31_2","unstructured":"C. Cordon-Cardo P. Capodieci unpublished data."},{"key":"e_1_3_1_32_2","unstructured":"We thank S. Jio for outstanding technical support and M. Goldfarb for the FGFR cDNAs. These studies were supported by grants CA85704 (R.K.) and CA52462 (Z.F.) and a Fellowship from the Association pour la Recherche sur le Cancer (F.P.)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1060191","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T17:14:14Z","timestamp":1704820454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1060191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,7,13]]},"references-count":33,"journal-issue":{"issue":"5528","published-print":{"date-parts":[[2001,7,13]]}},"alternative-id":["10.1126\/science.1060191"],"URL":"https:\/\/doi.org\/10.1126\/science.1060191","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,7,13]]}}}