title: Chemokine-enhanced chemotaxis of lymphangioleiomyomatosis cells with mutations in the tumor suppressor TSC2 gene.
abstract: 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.
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pacheco-Rodriguez
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Kumaki
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Steagall
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Lin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Billings
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002460:Cell Line; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000502:physiology; D054425:Chemokine CCL27 / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019742:Chemokines, CC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic / Q000276:immunology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: C111835:CCL2 protein, human; C492276:CCL27 protein, human; C414047:CCL28 protein, human; D018932:Chemokine CCL2; D054425:Chemokine CCL27; D018925:Chemokines; D019742:Chemokines, CC; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins