{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:53:12Z","timestamp":1781106792682,"version":"3.54.1"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"13","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,6,19]]},"abstract":"<jats:p>\n                    Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and key regulator of both physiologic and pathologic (e.g., tumor) angiogenesis. In the course of studies designed to assess the ability of constitutive VEGF to block tumor regression in an inducible RAS melanoma model, mice implanted with VEGF-expressing tumors sustained high morbidity and mortality that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome characterized by massive sinusoidal dilation and endothelial cell proliferation and apoptosis. Systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-induced liver pathology and prolonged survival were achieved by surgical excision of VEGF-secreting tumor or by systemic administration of a potent VEGF antagonist (VEGF-TRAP\n                    <jats:sub>R1R2<\/jats:sub>\n                    ), thus defining a paraneoplastic syndrome caused by excessive VEGF activity. Moreover, this VEGF-induced syndrome resembles peliosis hepatis, a rare human condition that is encountered in the setting of advanced malignancies, high-dose androgen therapy, and\n                    <jats:italic>Bartonella henselae<\/jats:italic>\n                    infection. Thus, our findings in the mouse have suggested an etiologic role for VEGF in this disease and may lead to diagnostic and therapeutic options for this debilitating condition in humans.\n                  <\/jats:p>","DOI":"10.1073\/pnas.121192298","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:45:09Z","timestamp":1027680309000},"page":"7481-7486","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":56,"title":["Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome"],"prefix":"10.1073","volume":"98","author":[{"given":"Alex K.","family":"Wong","sequence":"first","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myra","family":"Alfert","sequence":"additional","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego H.","family":"Castrillon","sequence":"additional","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Holash","sequence":"additional","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George D.","family":"Yancopoulos","sequence":"additional","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynda","family":"Chin","sequence":"additional","affiliation":[{"name":"Department of Adult Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and Department of Dermatology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,6,12]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"265","volume":"24","author":"Nathanson L","year":"1997","unstructured":"L Nathanson, T C Hall Semin Oncol 24, 265\u2013268 (1997).","journal-title":"Semin Oncol"},{"key":"e_1_3_3_2_2","first-page":"299","volume":"24","author":"Odell W D","year":"1997","unstructured":"W D Odell Semin Oncol 24, 299\u2013317 (1997).","journal-title":"Semin Oncol"},{"key":"e_1_3_3_3_2","first-page":"1","volume":"237","author":"Ferrara N","year":"1999","unstructured":"N Ferrara Curr Top Microbiol Immunol 237, 1\u201330 (1999).","journal-title":"Curr Top Microbiol Immunol"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/22788"},{"key":"e_1_3_3_5_2","first-page":"4575","volume":"55","author":"Rak J","year":"1995","unstructured":"J Rak, Y Mitsuhashi, L Bayko, J Filmus, S Shirasawa, T Sasazuki, R S Kerbel Cancer Res 55, 4575\u20134580 (1995).","journal-title":"Cancer Res"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.3.861"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.7.3609"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0596-606"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80988-5"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/74725"},{"key":"e_1_3_3_11_2","first-page":"1195","volume-title":"Sleisenger and Fordtran's Gastrointestinal and Liver Disease","author":"Schafer D","year":"1998","unstructured":"D Schafer, M Sorrell Sleisenger and Fordtran's Gastrointestinal and Liver Disease, eds M Feldman, M Sleisenger (Saunders, Philadelphia), pp. 1195\u20131196 (1998)."},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199012063232301"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199012063232302"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1993.03500060070033"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/12.6.1280"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/5.12.1115"},{"key":"e_1_3_3_17_2","first-page":"392","volume":"58","author":"Hyder S M","year":"1998","unstructured":"S M Hyder, L Murthy, G M Stancel Cancer Res 58, 392\u2013395 (1998).","journal-title":"Cancer Res"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.25.14765"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8761"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.46.30336"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.23.16349"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.1.9"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)47116-5"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.18.1.0287"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.45.29979"},{"key":"e_1_3_3_26_2","first-page":"485","volume":"90","author":"Fine K D","year":"1995","unstructured":"K D Fine, M Solano, D E Polter, G W Tillery Am J Gastroenterol 90, 485\u2013488 (1995).","journal-title":"Am J Gastroenterol"},{"key":"e_1_3_3_27_2","first-page":"457","volume":"29","author":"Karasawa T","year":"1979","unstructured":"T Karasawa, T Shikata, R D Smith Acta Pathol Jpn 29, 457\u2013469 (1979).","journal-title":"Acta Pathol Jpn"},{"key":"e_1_3_3_28_2","first-page":"62","volume":"42","author":"Otani M","year":"1992","unstructured":"M Otani, Y Ohaki, Y Nakatani, E Ito, K Shimoyama, K Misugi Acta Pathol Jpn 42, 62\u201368 (1992).","journal-title":"Acta Pathol Jpn"},{"key":"e_1_3_3_29_2","first-page":"205","volume":"25","author":"Godoy P","year":"1979","unstructured":"P Godoy, E A Bambirra AMB Rev Assoc Med Bras 25, 205\u2013207 (1979).","journal-title":"AMB Rev Assoc Med Bras"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1177\/028418518502600515"},{"key":"e_1_3_3_31_2","first-page":"647","volume":"3","author":"Salven P","year":"1997","unstructured":"P Salven, H Manpaa, A Orpana, K Alitalo, H Joensuu Clin Cancer Res 3, 647\u2013651 (1997).","journal-title":"Clin Cancer Res"},{"key":"e_1_3_3_32_2","first-page":"1251","volume":"18","author":"Takigawa N","year":"1998","unstructured":"N Takigawa, Y Segawa, N Fujimoto, K Hotta, K Eguchi Anticancer Res 18, 1251\u20131254 (1998).","journal-title":"Anticancer Res"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19990101)85:1<178::AID-CNCR25>3.0.CO;2-7"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004059900208"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V90.8.3167"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(20000115)88:2<255::AID-CNCR2>3.0.CO;2-N"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1053\/ejso.2000.0977"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.121192298","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T21:56:39Z","timestamp":1649800599000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.121192298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,6,12]]},"references-count":37,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2001,6,19]]}},"alternative-id":["10.1073\/pnas.121192298"],"URL":"https:\/\/doi.org\/10.1073\/pnas.121192298","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,6,12]]},"assertion":[{"value":"2000-12-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-04-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}