{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:06:22Z","timestamp":1791201982184,"version":"4.2.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2009,2,1]],"date-time":"2009-02-01T00:00:00Z","timestamp":1233446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction caused by LAM cells (smooth-muscle-like cells) that have mutations in the tumor suppressor genes tuberous sclerosis complex (TSC) 1 or 2 and have the capacity to metastasize. Since chemokines and their receptors function in chemotaxis of metastatic cells, we hypothesized that LAM cells may be recruited by chemokine(s) in the lung. Quantification of 25 chemokines in bronchoalveolar lavage fluid from LAM patients and healthy volunteers revealed that concentrations of CCL2, CXCL1, and CXCL5 were significantly higher in samples from LAM patients than those from healthy volunteers. In vitro, CCL2 or MCP-1 induced selective migration of cells, showing loss of heterozygosity of TSC2 from a heterogeneous population of cells grown from explanted LAM lungs. Additionally, the frequencies of single-nucleotide polymorphisms in the CCL2 gene promoter region differed significantly in LAM patients and healthy volunteers (p = 0.018), and one polymorphism was associated significantly more frequently with the decline of lung function. The presence (i.e., potential functionality) of chemokine receptors was evaluated using immunohistochemistry in lung sections from 30 LAM patients. Expression of chemokines and these receptors varied among LAM patients and differed from that seen in some cancers (e.g., breast cancer and melanoma cells). These observations are consistent with the notion that chemokines such as CCL2 may serve to determine mobility and specify the site of metastasis of the LAM cell.<\/jats:p>","DOI":"10.4049\/jimmunol.182.3.1270","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:01:40Z","timestamp":1397847700000},"page":"1270-1277","source":"Crossref","is-referenced-by-count":54,"title":["Chemokine-Enhanced Chemotaxis of Lymphangioleiomyomatosis Cells with Mutations in the Tumor Suppressor\n                    <i>TSC2<\/i>\n                    Gene"],"prefix":"10.1093","volume":"182","author":[{"given":"Gustavo","family":"Pacheco-Rodriguez","sequence":"first","affiliation":[{"name":"Translational Medicine Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiyuki","family":"Kumaki","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K","family":"Steagall","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Ping","family":"Lin","sequence":"additional","affiliation":[{"name":"Office of Biostatistics Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M","family":"Billings","sequence":"additional","affiliation":[{"name":"Integrative Computational Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Moss","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,2,1]]},"reference":[{"key":"2026012806223442400_R1","first-page":"563","article-title":"Dissemination and growth of cancer cells in metastatic sites.","volume-title":"Nat. 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Diffuse Lung Dis.","year":"2005"},{"key":"2026012806223442400_R10","first-page":"6085","article-title":"Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2000"},{"key":"2026012806223442400_R11","first-page":"1345","article-title":"The tuberous sclerosis complex.","volume-title":"N. Engl. J. Med.","year":"2006"},{"key":"2026012806223442400_R12","first-page":"253","article-title":"The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2001"},{"key":"2026012806223442400_R13","first-page":"166","article-title":"A patient with TSC1 germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosis.","volume-title":"J. Intern. Med.","year":"2004"},{"key":"2026012806223442400_R14","first-page":"95","article-title":"Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis.","volume-title":"Hum. Pathol.","year":"2003"},{"key":"2026012806223442400_R15","first-page":"976","article-title":"Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2003"},{"key":"2026012806223442400_R16","first-page":"17462","article-title":"Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"},{"key":"2026012806223442400_R17","first-page":"727","article-title":"Cellular heterogeneity in lymphangiomyomatosis of the lung.","volume-title":"Hum. Pathol.","year":"1991"},{"key":"2026012806223442400_R18","first-page":"732","article-title":"HMB-45 reactivity in renal angiomyolipoma and lymphangioleiomyomatosis.","volume-title":"Arch. Pathol. Lab. Med.","year":"1994"},{"key":"2026012806223442400_R19","first-page":"846","article-title":"Pulmonary lymphangioleiomyomatosis: diagnosis based on results of transbronchial biopsy and immunohistochemical studies and correlation with high-resolution computed tomography findings.","volume-title":"Arch. Pathol. Lab. Med.","year":"1994"},{"key":"2026012806223442400_R20","first-page":"20126","article-title":"Molecular characterization of the melanocyte lineage-specific antigen gp100.","volume-title":"J. Biol. Chem.","year":"1994"},{"key":"2026012806223442400_R21","first-page":"327","article-title":"Markers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis.","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"1999"},{"key":"2026012806223442400_R22","first-page":"30958","article-title":"Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM).","volume-title":"J. Biol. Chem.","year":"2002"},{"key":"2026012806223442400_R23","first-page":"10573","article-title":"TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis.","volume-title":"Cancer Res.","year":"2007"},{"key":"2026012806223442400_R24","first-page":"121","article-title":"Chemokines: a new classification system and their role in immunity.","volume-title":"Immunity","year":"2000"},{"key":"2026012806223442400_R25","first-page":"1067","article-title":"Chemokine\/chemokine receptor nomenclature.","volume-title":"J. 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Dermatol. Sci.","year":"2004"},{"key":"2026012806223442400_R57","first-page":"5466","article-title":"Human vascular smooth muscle cells possess functional CCR5.","volume-title":"J. Biol. Chem.","year":"2000"},{"key":"2026012806223442400_R58","first-page":"10142","article-title":"HIV envelope gp120 activates human arterial smooth muscle cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2001"},{"key":"2026012806223442400_R59","first-page":"2498","article-title":"Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1).","volume-title":"Circulation","year":"2003"},{"key":"2026012806223442400_R60","first-page":"579","article-title":"Role of chemokines in severe asthma.","volume-title":"Curr. Drug Targets","year":"2006"},{"key":"2026012806223442400_R61","first-page":"643","article-title":"Genetic instabilities in human cancers.","volume-title":"Nature","year":"1998"},{"key":"2026012806223442400_R62","first-page":"569","article-title":"Ever since Knudson.","volume-title":"Trends Genet.","year":"2001"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/3\/1270\/62681233\/8455.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/3\/1270\/62681233\/8455.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T11:22:57Z","timestamp":1769599377000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/182\/3\/1270\/8004463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,1]]},"references-count":62,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2009,2,1]]},"published-print":{"date-parts":[[2009,2,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.182.3.1270","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,2]]},"published":{"date-parts":[[2009,2,1]]}}}