The role of chemokines in migration of metastatic-like lymphangioleiomyomatosis cells.
Lymphangioleiomyomatosis (LAM), a rare cystic lung disease with multi-organ involvement, occurs primarily in women of childbearing age. LAM can present sporadically or in association with tuberous sclerosis complex (TSC). Loss of lung function in patients with LAM can be attributed to the dysregulated growth of LAM cells, with dysfunctional TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively, leading to hyperactivation of the mammalian target of rapamycin (mTOR). LAM cells are smooth muscle-like cells that express melanoma antigens such as gp100, a splice variant of the Pmel17 gene. Tuberin and hamartin form heterodimers that act as negative regulators of mTOR. Lack of TSC2 function, as occurs in LAM cells, leads to the production of the chemokine CCL2/monocyte chemotactic protein 1 (MCP-1), which increases LAM cell mobility. Although many chemokines and their receptors could influence LAM cell mobilization, we propose that a positive-feedback loop is generated when dysfunctional TSC2 is present in LAM cells. We identified a group of chemokine receptors that is expressed in LAM cells and differs from those on smooth muscle and melanoma cells (Malme-3M). Chemokines have been implicated in tumor metastasis, and our data suggest a role for chemokines in LAM cell mobilization and thereby in the pathogenesis of LAM.
Pacheco-Rodriguez
Gustavo
G
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
Moss
Joel
J
D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000276:immunology* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000276:immunology; D019707:Receptors, Chemokine / Q000276:immunology
D018925:Chemokines; D019707:Receptors, Chemokine