Abstract
Brain metastasis (BM) is a major cause of mortality in small-cell lung cancer (SCLC) patients; however, the molecular pathway of SCLC BM remains largely unknown because of a lack of investigation. Here we screen the levels of some candidate-soluble factors in the serum of SCLC patients and find that SCLC patients with high levels of placental growth factor (PLGF) are prone to BM. Using in vitro blood–brain barrier model, we show that PLGF derived from SCLC cells triggers vascular endothelial growth factor receptor-1-Rho-extracellular regulated protein kinase 1/2 signaling axis activation, results in disassembly of tight junction in brain endothelial cells and promotes SCLC cell transendothelial migration. Furthermore, the downregulation of PLGF suppresses SCLC cell metastasis to the brain in an experimental BM model. These data suggest that PLGF is a potential signature of SCLC BM and a prospective therapeutic target for SCLC BM.
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References
Castrucci WA, Knisely JP . An update on the treatment of CNS metastases in small cell lung cancer. Cancer J 2008; 14: 138–146.
Dowell JE . Small cell lung cancer: are we making progress? Am J Med Sci 2010; 339: 68–76.
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ . Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37: 13–25.
Langley RR, Fidler IJ . The seed and soil hypothesis revisited—the role of tumorstroma interactions in metastasis to different organs. Int J Cancer 2011; 128: 2527–2535.
Li B, Zhao WD, Tan ZM, Fang WG, Zhu L, Chen YH . Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett 2006; 580: 4252–4260.
Ribatti D . The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis 2008; 11: 215–221.
Casalou C, Fragoso R, Nunes JF, Dias S . VEGF/PLGF induces leukemia cell migration via P38/ERK1/2 kinase pathway, resulting in Rho GTPases activation and caveolae formation. Leukemia 2007; 21: 1590–1594.
Taylor AP, Leon E, Goldenberg DM . Placental growth factor (PLGF) enhances breast cancer cell motility by mobilizing ERK1/2 phosphorylation and cytoskeletal rearrangement. Br J Cancer 2010; 103: 82–89.
Chen J, Ye L, Zhang L, Jiang WG . Placenta growth factor, PLGF, influences the motility of lung cancer cells, the role of Rho associated kinase, Rock1. J Cell Biochem 2008; 105: 313–320.
Wei SC, Tsao PN, Yu SC, Shun CT, Tsai-Wu JJ, Wu CH et al. Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 2005; 54: 666–672.
Parr C, Watkins G, Boulton M, Cai J, Jiang WG . Placenta growth factor is over-expressed and has prognostic value in human breast cancer. Eur J Cancer 2005; 41: 2819–2827.
Chen CN, Hsieh FJ, Cheng YM, Cheng WF, Su YN, Chang KJ et al. The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett 2004; 213: 73–82.
Eichler AF, Chung E, Kodack DP, Loeffler JS, Fukumura D, Jain RK . The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 2011; 8: 344–356.
Phelps RM, Johnson BE, Ihde DC, Gazdar AF, Carbone DP, McClintock PR et al. NCI-Navy Medical Oncology Branch cell line data base. J Cell Biochem Suppl 1996; 24: 32–91.
Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 1985; 45: 2913–2923.
Pedram A, Razandi M, Levin ER . Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. J Biol Chem 2002; 277: 44385–44398.
Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV . Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 2006; 281: 8379–8388.
Murakami T, Felinski EA, Antonetti DA . Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J Biol Chem 2009; 284: 21036–21046.
Khan NA, Siddiqui R . Acanthamoeba affects the integrity of human brain microvascular endothelial cells and degrades the tight junction proteins. Int J Parasitol 2009; 39: 1611–1616.
Wang X, Li B, Zhao WD, Liu YJ, Shang DS, Fang WG et al. Perfluorooctane sulfonate triggers tight junction ‘opening’ in brain endothelial cells via phosphatidylinositol 3-kinase. Biochem Biophys Res Commun 2011; 410: 258–263.
Willis CL, Meske DS, Davis TP . Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. J Cereb Blood Flow Metab 2010; 30: 1847–1859.
Miyamoto N, de Kozak Y, Jeanny JC, Glotin A, Mascarelli F, Massin P et al. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia 2007; 50: 461–470.
Meyer TN, Hunt J, Schwesinger C, Denker BM . Galpha12 regulates epithelial cell junctions through Src tyrosine kinases. Am J Physiol Cell Physiol 2003; 285: C1281–C1293.
Fujisawa K, Fujita A, Ishizaki T, Saito Y, Narumiya S . Identification of the Rho-binding domain of p160ROCK, a Rho-associated coiled-coil containing protein kinase. J Biol Chem 1996; 27: 23022–23028.
Dimitri CA, Dowdle W, MacKeigan JP, Blenis J, Murphy LO . Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo. Curr Biol 2005; 15: 1319–1324.
Lee TH, Avraham HK, Jiang S, Avraham S . Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem 2003; 278: 5277–5284.
Lee BC, Lee TH, Avraham S, Avraham HK . Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2004; 2: 327–338.
Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX et al. Genes that mediate breast cancer metastasis to the brain. Nature 2009; 459: 1005–1009.
Zhang C, Zhang F, Tsan R, Fidler IJ . Transforming growth factor-beta2 is a molecular determinant for site-specific melanoma metastasis in the brain. Cancer Res 2009; 69: 828–835.
Clarke H, Soler AP, Mullin JM . Protein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheets. J Cell Sci 2000; 113: 3187–3196.
Cipolla MJ, Crete R, Vitullo L, Rix RD . Transcellular transport as a mechanism of blood-brain barrier disruption during stroke. Front Biosci 2004; 9: 777–785.
Denker BM, Nigam SK . Molecular structure and assembly of the tight junction. Am J Physiol 1998; 274: F1–F9.
Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW . Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999; 274: 23463–23467.
Tsukamoto T, Nigam SK . Role of tyrosine phosphorylation in the reassembly of occludin and other tight junction proteins. Am J Physiol 1999; 276: F737–F750.
Carbonell WS, Ansorge O, Sibson N, Muschel R . The vascular basement membrane as ‘soil’ in brain metastasis. PLoS One 2009; 4: e5857.
Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 2010; 16: 116–122.
Lorger M, Felding-Habermann B . Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 2010; 176: 2958–2971.
Fischer C, Mazzone M, Jonckx B, Carmeliet P . FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 2008; 8: 942–956.
Schreurs MP, Houston EM, May V, Cipolla MJ . The adaptation of the blood-brain barrier to vascular endothelial growth factor and placental growth factor during pregnancy. FASEB J 2012; 26: 355–362.
Rottbauer W, Just S, Wessels G, Trano N, Most P, Katus HA et al. VEGF-PLCgamma1 pathway controls cardiac contractility in the embryonic heart. Genes Dev 2005; 19: 1624–1634.
Vogel C, Bauer A, Wiesnet M, Preissner KT, Schaper W, Marti HH et al. Flt-1, but not Flk-1 mediates hyperpermeability through activation of the PI3-K/Akt pathway. J Cell Physiol 2007; 212: 236–243.
Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M, Autocrine VEGF . Signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 2010; 140: 268–279.
Kevil CG, Oshima T, Alexander B, Coe LL, Alexander JS . H(2)O(2)-mediated permeability: role of MAPK and occludin. Am J Physiol Cell Physiol 2000; 279: C21–C30.
Zhao WD, Liu W, Fang WG, Kim KS, Chen YH . Vascular endothelial growth factor receptor 1 contributes to Escherichia coli K1 invasion of human brain microvascular endothelial cells through the phosphatidylinositol 3-kinase/Akt signaling pathway. Infect Immun 2010; 78: 4809–4816.
Li M, Shang DS, Zhao WD, Tian L, Li B, Fang WG et al. Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier. J Immunol 2009; 182: 5778–5788.
Fujimaki T, Fan D, Staroselsky A, Gohji K, Bucana C, Fidler I . Critical factors regulating site-specific brain metastasis of murine melanomas. Int J Oncol 1993; 3: 789–799.
Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS . Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer 2011; 11: 135–141.
Acknowledgements
We are grateful to Drs Monique Stins and Kwang Sik Kim (Department of Pediatrics, John Hopkins University School of Medicine) for providing HBMEC and Dr Shuh Narumiya (Kyoto University Faculty of Medicine, Kyoto, Japan) for providing pCAG-myc, pCAG-myc-ROCK-WT and pCAG-myc-ROCK-KDIA. This work was supported by the Trans-Century Training Program Foundation for Talents, Ministry of Education of China (JJH2002–48), the Innovation Team Program Foundation of Liaoning Province (2006T131, LT2011011), the National Natural Science Foundation of China (30600270) and the Science and Technology Foundation of Liaoning Province (20102291).
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Li, B., Wang, C., Zhang, Y. et al. Elevated PLGF contributes to small-cell lung cancer brain metastasis. Oncogene 32, 2952–2962 (2013). https://doi.org/10.1038/onc.2012.313
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DOI: https://doi.org/10.1038/onc.2012.313
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