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Chemokine-Enhanced Chemotaxis of Lymphangioleiomyomatosis Cells with Mutations in the Tumor Suppressor TSC2 Gene¹

Gustavo Pacheco-Rodriguez^2,*, Fumiyuki Kumaki^2,*, Wendy K. Steagall^*, Yi Zhang^*, Yoshihiko Ikeda^*, Jing-Ping Lin, Eric M. Billings and Joel Moss^3,*

^* Translational Medicine Branch, Office of Biostatistics Research, and Integrative Computational Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. Y.I. was contracted through a Senior Fellowship from the Oak Ridge Institute for Science and Education.

² G.P.-R. and F.K. contributed equally to this paper.

³ Address correspondence and reprint requests to Dr. Joel Moss, Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590. E-mail address: mossj{at}nhlbi.nih.gov

⁴ Abbreviations used in this paper: LAM, lymphangioleiomyomatosis; BALF, bronchoalveolar lavage fluid; DL_CO, diffusion capacity of carbon monoxide; FEV₁, forced expiratory volume in 1 s; LCM, laser capture microdissection; LOH, loss of heterozygosity; PASM, pulmonary artery smooth muscle cells; TSC, tuberous sclerosis complex.

⁵ The online version of this article contains supplemental material.