Role of the CXCR4/CXCL12 axis in lymphangioleiomyomatosis and angiomyolipoma.
Lymphangioleiomyomatosis (LAM) is a progressive disease caused by accumulation of metastatic (LAM) cells in the lungs, lymphatics, and the tumor angiomyolipoma (AML). LAM cells have biallelic loss of either tuberous sclerosis complex gene (but predominantly TSC-2) and resultant dysregulation of the mammalian target of rapamycin (mTOR) pathway. Chemokines are associated with neoplastic cell growth, survival, and homing to specific organs and may play similar roles in LAM. Our objective was to study comprehensively the expression and function of chemokine receptors and how their function interacts with dysregulation of the mTOR pathway in LAM and AML. We used RT-PCR and FACS to study receptor expression in primary AML cells and immunohistochemistry to investigate expression in tissues. Chemokine receptor function was analyzed in AML cells by Western blotting of signaling proteins and cell proliferation and apoptosis assays. Primary AML cells, LAM, and AML tissues expressed CCR3, CXCR4, CXCR6, and CXC3CR1. In AML cells, their ligands CXCL12 CX3CL1, CCL11, CCL24, and CCL28 caused robust phosphorylation of p42/44 MAPK and Akt. CXCL12 was expressed in type II pneumocytes covering LAM nodules and caused AML cell growth and protection from apoptosis, which was blocked by AMD3100, a CXCR4 inhibitor. The mTOR inhibitor rapamycin, but not AMD3100, inhibited growth of AML tumor xenografts. We conclude that the CXCL12/CXCR4 axis promotes, but is not absolutely required for, AML/LAM cell growth and survival.
Clements
Debbie
D
Division of Therapeutics and Molecular Medicine and National Institute for Health Research Respiratory Biomedical Research Unit, University of Nottingham, University Hospital, Queens Medical Centre, Nottingham, United Kingdom. debbie.clements@nottingham.ac.uk
Markwick
Lee J
LJ
Puri
Nidhi
N
Johnson
Simon R
SR
D018207:Angiomyolipoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D000077004:Tuberous Sclerosis Complex 1 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D018836:Inflammation Mediators; D019718:Receptors, CXCR4; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins