Brain infiltration by cancer cells: different roads to the same target?

Abstract

Brain infiltration by cancer cells is a complex process in which metastatic cells detached from the primary tumor must firstly survive in the blood flow, cross the blood brain barrier (BBB) and finally colonize a foreign microenvironment. The cells that successfully bypass the cellular barriers surrounding capillaries, proliferate to form micrometastasis and trigger the angiogenetic process. Different molecular mechanisms have been proposed to explain the metastatic behaviour of solid tumors that infiltrate brain tissue; in this review the most recent findings concerning mechanisms and genes potentially involved in brain metastasis, that differ according to primary tumor types, will be discussed. The three tumors that more frequently develop brain metastasis, lung cancer, breast cancer and melanoma, will be considered and, in addition, the role of BBB and the process of endothelial to mesenchymal transition in cancer metastasis will be briefly described.

Keywords

Brain metastasis / breast / epithelial-mesenchymal transition / lung / melanoma / micro-RNA

References

[1] Gavrilovic IT.Brain metastases: epidemiology and pathophysiology..J Neurooncol2005;75:5-14

[2] Kondziolka D,Brunswick A,Silverman JS.The biology of radiosurgery and its clinical applications for brain tumors..Neuro Oncol2015;17:29-44 PMCID:PMC4483054

[3] Nayak L,Wen PY.Epidemiology of brain metastases..Curr Oncol Rep2012;14:48-54

[4] Ba JL,Nesbit A,Chen M.Current and emerging treatments for brain metastases..Oncology2015;29:250-7

[5] Friedl P.Cancer invasion and the microenvironment: plasticity and reciprocity..Cell2011;147:992-1009

[6] Langley RR.The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs..Int J Cancer2011;128:2527-35 PMCID:PMC3075088

[7] Saitoh M.Epithelial-mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-β signaling during tumor progression..Cancer Sci2015;106:481-8 PMCID:PMC4452147

[8] Lindsey S.Crosstalk of Oncogenic Signaling Pathways during Epithelial Mesenchymal Transition..Front Oncol2014;4:358 PMCID:PMC4263086

[9] Pasquier J,Al Thani H.Epithelial to Mesenchymal Transition in a Clinical Perspective..J Oncol2015;2015:792182 PMCID:PMC4575734

[10] Mori S,Ito A,Kawaguchi N,Takada Y.Enhanced expression of integrin αvβ3 induced by TGF-β is equired for the enhancing effect of Fibroblast Growth Factor 1 (FGF1) in TGF-β-induced Epithelial-Mesenchymal Transition (EMT) in mammary epithelial cells..PLoS One2015;10:e0137486

[11] Li W,Li H,Zhong Y,Lv S.TGF β1 mediates epithelial mesenchymal transition via β6 integrin signaling pathway in breast cancer..Cancer Invest2014;32:409-15

[12] Parvani JG,Schiemann BJ.Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β..Mol Biol Cell2013;24:3449-59 PMCID:PMC3814150

[13] Panzeri S,Arosio D,Dal Corso A,Paolillo M,Belvisi L,Piarulli U.Cyclic isoDGR and RGD peptidomimetics containing bifunctional diketopiperazine scaffolds are integrin antagonists..Chemistry2015;21:6265-71

[14] Hugo H,Blick T,Clements JA,Thompson EW.Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression..J Cell Physiol2007;213:374-83

[15] Labelle M,Hynes RO.Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis..Cancer Cell2011;20:576-90 PMCID:PMC3487108

[16] Tang YN,Guo XJ,Wang DM.Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis..Nat Commun2015;10:6:8230

[17] Zhang L,Ma Y,Dong B,Wang X,Fang F.Testicular orphan receptor 4 (TR4) is a marker for metastasis and poor prognosis in non-small cell lung cancer that drives the EMT phenotype..Lung Cancer2015;89:320-8

[18] Kong FF,Yuan HH,Zhao M,Shi J,Zhu YL,Zhang WY.Overexpression of FOXM1 is associated with EMT and is a predictor of poor prognosis in non-small cell lung cancer..Oncol Rep2014;31:2660-8

[19] Okabe H,Saito S,Imai K,Hashimoto D,Ishiko T,Baba H.Epithelial-mesenchymal transition in gastroenterological cancer..J Canc Met Treat2015;1:183-9

[20] Meng F.The rejuvenated scenario of epithelial-mesenchymal transition (EMT) and cancer metastasis..Cancer Metastasis Rev2012;31:455-67

[21] Berezikov E,van de Belt J,Plasterk RHA.Phylogenetic shadowing and computational identification of human microRNA genes..Cell2005;120:21-4

[22] Garzon R,Cimmino A,Croce CM.MicroRNA expression and function in cancer..Trends Mol Med2006;12:580-7

[23] Leung AK.The Whereabouts of microRNA Actions Cytoplasm and Beyond..Trends Cell Biol2015;25:601-10 PMCID:PMC4610250

[24] Zhang B,Cobb GP.microRNAs as oncogenes and tumor suppressors..Dev Biol2007;302:1-12

[25] Calin GA,Dumitru CD,Noch E,Shimizu M,Bullrich F,Croce CM.Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers..Proc Natl Acad Sci USA2004;101:2999-3004 PMCID:PMC365734

[26] Sevignani C,Nnadi SC,Davuluri RV,Demant P,Siracusa LD.MicroRNA genes are frequently located near mouse cancer susceptibility loci..Proc Natl Acad Sci USA2007;104:8017-22 PMCID:PMC1876564

[27] Joyce JA.Microenvironmental regulation of metastasis..Nat Rev Cancer2009;9:239-52 PMCID:PMC3251309

[28] Korpal M,Hu G.The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2..J Biol Chem2008;283:14910-4 PMCID:PMC3258899

[29] Zhao C,Zhang Y,Xue J,Zhang Y,Hu X.Downregulation of miR-145 contributes to lung adenocarcinoma cell growth to form brain metastases..Oncol Rep2013;30:2027-34 PMCID:PMC3820619

[30] Sachdeva M.MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1..Cancer Res2010;70:378-87 PMCID:PMC2805032

[31] Götte M,Koo CY,Vaske AK,Ibrahim SA,Teng YH,Ebnet K,Yip GW.miR-145-dependent targeting of junctional adhesion molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness..Oncogene2010;29:6569-80

[32] Hanniford D,Koetz L,Lackaye DJ,Pavlick A,Berman R,Shao Y,Hernando E.A miRNA-Based Signature Detected in Primary Melanoma Tissue Predicts Development of Brain Metastasis..Clin Cancer Res2015;21:4903-12 PMCID:PMC4631639

[33] He L.MicroRNAs: small RNAs with a big role in gene regulation..Nat Rev Genet2004;5:522-31

[34] Cortez MA,Ferdin J,Sood A K,GA.MicroRNAs in body fluids - the mix of hormones and biomarkers..Nat Rev Clin Oncol2011;8:467-77 PMCID:PMC3423224

[35] Corrado C,Chiesi,Ciccia F,Alessandro R.Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications..Int J Mol Sci2013;14:5338-66 PMCID:PMC3634447

[36] Azmi AS,Sarkar FH.Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review..Cancer Metastasis Rev2013;32:623-42 PMCID:PMC3843988

[37] Zhou W,Min Y,Liu L,Yu Y,O'Connor ST,Yen Y,Marcusson EG,Wu J,Li AX,Gao H,Boldin MP,Wang SE.Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis..Cancer Cell2014;25:501-15 PMCID:PMC4016197

[38] Tominaga N,Ono M,Yoshioka Y,Lötvall J,Ochiya T.Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier..Nat Commun2015;6:6716 PMCID:PMC4396394

[39] Hoshino A,Shen TL,Hashimoto A,Molina H,Di Giannatale A,Singh S,Soplop N,Pharmer L,Bojmar L,Ararso Y,Zhang H,Weiss JM,Kramer K,Narendran A,Healey JH,Jørgen Labori K,Grandgenett PM,de Sousa M,Jain M,Batra SK,Brady MS,Muller V,Minn AJ,Garcia BA,Rajasekhar VK,Matei I,Bromberg J.Tumour exosome integrins determine organotropic metastasis..Nature2015;

[40] Abbott NJ,Dolman DE,Begley DJ.Structure and function of the blood-brain barrier..Neurobiol Dis2010;37:13-25

[41] Klemke M,Konstandin MH.High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers..J Cell Physiol2007;212:368-74

[42] Wu K,Xing F,Sharma S,Chan MD,Qasem SA,Mo YY.Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer..J Biol Chem2015;290:9842-54 PMCID:PMC4392281

[43] Rolland Y,Fenart L.Inhibition of melanoma brain metastasis by targeting melanotransferrin at the cell surface..Pigment Cell Melanoma Res2009;22:86-98

[44] Perides G,Lin T,Bronson RT.The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis..BMC Cancer2006;6:56 PMCID:PMC1421425

[45] Fazakas C,Nagyoszi P,Haskó J,Bauer H,Ayaydin F,Siklós L.Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases..PLoS One2001;6:e20758

[46] Lorger M.Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis..Am J Pathol2010;176:2958-71 PMCID:PMC2877856

[47] Kienast Y,Fuhrmann M,Goldbrunner R,Winkler F.Real-time imaging reveals the single steps of brain metastasis formation..Nat Med2010;16:116-22

[48] Blecharz KG,Rohde V.Control of the blood-brain barrier function in cancer cell metastasis..Biol Cell2015;107:342-71

[49] Louveau A,Keyes TJ,Rouhani SJ,Derecki NC,Mandell JW,Harris TH.Structural and functional features of central nervous system lymphatic vessels..Nature2015;523:337-41 PMCID:PMC4506234

[50] Aspelund A,Proulx ST,Karaman S,Wiig H.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules..J Exp Med2015;212:991-9 PMCID:PMC4493418

[51] Sperduto PW,Roberge D,Shanley R,Sneed PK,Weil RJ,Bhatt A,Brown PD,Kirkpatrick J,Fiveash JB,Knisely JP,Lin N.Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases..J Clin Oncol2012;30:419-25 PMCID:PMC3269967

[52] Oser MG,Sequist LV.Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin..Lancet Oncol2015;16:165-72

[53] Ramakrishna R.Seed, soil, and beyond: the basic biology ofbrain metastasis..Surg Neurol Int2013;4:S256-64

[54] St Hill CA.Interactions between endothelial selectins and cancer cellsregulate metastasis..Front Biosci2011;16:3233-51

[55] Li B,Tan ZM.Zhu L, Chen YH. Involvement ofRho/ROCK signalling in small cell lung cancer migration through human brainmicrovascular endothelial cells..FEBS Lett2006;580:4252-60

[56] Liu Y,Wu PF,Dai WM,Xu ZH,Miao ZW,Chen YH.Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis..Int J Biochem Cell Biol2015;66:11-9

[57] Biaoxue R,Shuanying Y,Xiguang C,Min Z.Upregulation of Hsp90-beta and annexin A1 correlates with poor survival andlymphatic metastasis in lung cancer patients..J Exp Clin Cancer Res2012;31:70 PMCID:PMC3444906

[58] van Meerbeeck JP1,De Ruysscher DK.Small-cell lung cancer..Lancet2011;12:378:1741-55

[59] Hodkinson PS,Wong WS,Mackinnon AC,Sethi T.ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through beta1 integrin-dependent activation of PI3-kinase..Cell Death Differ2006;13:1776-88

[60] Ali A1,Arnold A.Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases..Curr Oncol2013;20:300-6 PMCID:PMC3728058

[61] Goldstraw P,Jett JR,Lim E,Shepherd FA.Non-small-cell lung cancer..Lancet2011;378:1727-40

[62] Ceresoli GL,Gregorc V,Crinò L.Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial..Ann Oncol2004;15:1042-7

[63] Lai CS,Falzon M.Complete response to erlotinib treatment in brain metastases from recurrent NSCLC..Thorax2006;61:91 PMCID:PMC2080696

[64] Prudkin L,Ozburn NC,Behrens C,Moran C.Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung..Mod Pathol2009;22:668-78 PMCID:PMC2675657

[65] Seike M,Okano T,Schetter AJ,Mathe EA,Yang P,Gemma A,Croce CM.MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers..Proc Natl Acad Sci USA2009;106:12085-90 PMCID:PMC2715493

[66] Chin LJ,Leng S,Nallur S,Muller RU,Su L,Crowell RE,Kulkarni T,Zelterman D,Zhu Y,Belinsky SA,Weidhaas JB.A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk..Cancer Res2008;68:8535-40 PMCID:PMC2672193

[67] Zhao C1,Zhang Y,Xue J,Zhang Y,Hu X.Downregulation of miR-145 contributes to lung adenocarcinoma cell growth to form brain metastases..Oncol Rep2013;30:2027-34

[68] Zhang Y.MicroRNA-145 inhibits migration and invasion by down-regulating FSCN1 in lung cancer..Int J Clin Exp Med2015;8:8794-802

[69] Donzelli S,Bellissimo T,Casini B,Roscilli G,Facciolo F,Carosi MA,Segatto O,Muti P,Strano S,Blandino G.Epigenetic silencing of miR-145-5p contributes to brain metastasis..Oncotarget2015;6:35183-201 PMCID:PMC4742098

[70] Arora S,Tran NL,Sridhar S,Ross JT,Foss KM,Ryken T,Kim S.MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration..Int J Cancer2011;129:2621-31 PMCID:PMC3154499

[71] Tano K.Long noncoding RNAs in cancer progression..Front genet2012;3:219 PMCID:PMC3479403

[72] Shen L,Wang Y,Xia H.Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer..J Neurooncol2015;121:101-8

[73] Mittelbronn M,Meyermann R,Weller M.Expression of integrins alphavbeta3 and alphavbeta5 and their ligands in primary and secondary central nervous system neoplasms..Histol Histopathol2012;33:405-12

[74] Vogetseder A,Ingold B,Weller M,Goodman SL.Alphav-Integrin isoform expression in primary human tumors and brain metastases..Int J Cancer2013;133:2362-71

[75] Lorger M,O'Neal M,Felding-Habermann B.Activation of tumor cell integrin αvβ3 controls angiogenesis and metastatic growth in the brain..Proc Natl Acad Sci USA2009;106:10666-71 PMCID:PMC2697113

[76] Berghoff AS,Melchardt T,Hainfellner JA,Schittenhelm J,Widhalm G,Weller M,Birner P.αvβ3, αvβ5 and αvβ6 integrins in brain metastases of lung cancer..Clin Exp Metastasis2014;31:841-51

[77] Deryugina EI.Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature..Matrix Biol2015;44-46:94-112

[78] Rojiani MV,Esposito N.Expression of MMP-2 correlates with increased angiogenesis in CNS metastasis of lung carcinoma..Int J Clin Exp Pathol2010;3:775-81

[79] Preusser M,Berger W,Dinhof C,Dieckmann K,Hackl M,Streubel B.High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer..Lung Cancer2014;8:83-9

[80] Lee HW,Choi YL,Joo KM,Lee JI.Genomic copy number alterations associated with the early brain metastasis of non-small cell lung cancer..Int J Oncol2012;4:2013-20

[81] Prat A.Deconstructing the molecular portraits of breast cancer..Mol Oncol2011;5:5-23

[82] Niikura N,Tokuda Y.Brain metastases in breast cancer..Jpn J Clin Oncol2014;44:1133-40

[83] Hung MH,Shiau CY,Tsai YF,Tai LC,Chao TC,Su CH,Tzeng CH,Tseng LM.Effect of age and biological subtype on the risk and timing of brain metastasis in breast cancer patients..PLoS One2014;9:e89389

[84] Venkitaraman R,Dhadda A,Upadhyay S.Prognosis of patients with triple-negative breast cancer and brain metastasis..Clin Oncol2009;21:729-30

[85] Niikura N,Hayashi N,Gong Y,Tokuda Y,Hortobagyi GN.Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors..J Clin Oncol2012;30:593-9 PMCID:PMC3295557

[86] Bos PD,Nadal C,Gomis RR,Minn AJ,Gerald WL,Massagué J.Genes that mediate breast cancer metastasis to the brain..Nature2009;459:1005-9 PMCID:PMC2698953

[87] Gupta GP,Chiang AC,Kim JY,Gomis RR,Massagué J.Mediators of vascular remodelling co-opted for sequential steps in lung metastasis..Nature2007;446:765-70

[88] Fan C,Wessels L,Nuyten DS,van't Veer LJ.Concordance among gene-expression-based predictors for breast cancer..N Engl J Med2006;355:560-9

[89] Egeblad M.New functions for the matrix metalloproteinases in cancer progression..Nature Rev Cancer2002;2:161-74

[90] Padua D,Wang Q,Gerald WL,Massagué J.TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4..Cell2008;133:66-77 PMCID:PMC2390892

[91] Adams JC.Roles of fascin in cell adhesion and motility..Curr Opin Cell Biol2004;16:590-6

[92] Dall'Olio F.Sialyltransferases in cancer..Glycoconj J2001;18:841-50

[93] Palmieri D,Shreeve SM,Bronder JL,Davis S,Merino MJ,Mehdorn HM,Steinberg SM,Aldape K.Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis..Mol Cancer Res2009;7:1438-45 PMCID:PMC2746883

[94] Smith TA.Mammalian hexokinases and their abnormal expression in cancer..Br J Biomed Sci2000;57:170-8

[95] Brastianos PK,Santagata S,Taylor-Weiner A,Van Allen EM,Horowitz PM,Ligon KL,Seoane J,Curry WT,Paek SH,McKenna A,Rosenberg M,Gill CM,Thorner AR,Hoang MP,Signoretti S,Rabin MS,Winer EP,Meyerson M,Gabriel S,Beroukhim R,Baselga J,Getz G.Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets..Cancer Discov2015;5:1164-77 PMCID:PMC4916970

[96] Ray PS,Qu Y,Shamonki J,Ye X,Elashoff D,Walter MA,Richardson AL,Cui X.FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer..Cancer Res2010;70:3870-6

[97] Sizemore ST.The forkhead box transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression..J Biol Chem2012;287:24631-40 PMCID:PMC3397891

[98] Yu M,Wittner BS,Smas ME,Isakoff SJ,Wells MN,Concannon KF,Sequist LV,Sgroi D,Ramaswamy S,Haber DA.Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition..Science2013;339:580-4 PMCID:PMC3760262

[99] Miller AJ.Melanoma..N Engl J Med2006;355:51-65

[100] Damsky WE,Bosenberg M.Melanoma metastasis: new concepts and evolving paradigms..Oncogene2014;33:2413-22

[101] The International Agency for Research on Cancer..Pathology and Genetics of Skin Tumours (IARC WHO Classification of Tumours)..Lyon: IARC Press2006;

[102] Fidler IJ.The Biology of brain metastasis: challenges for therapy..Cancer J2015;21:284-93

[103] Berghoff AS.BRAF alterations in brain tumours: molecular pathology and therapeutic opportunities..Curr Opin Neurol2014;27:689-96

[104] Mu-oz-Couselo E,Pérez-García JM,Castán JC.Recent advances in the treatment of melanoma with BRAF and MEK inhibitors..Ann Transl Med2015;3:207

[105] Cancer Genome Atlas Network..Genomic Classification of Cutaneous Melanoma..Cell2015;161:1681-96 PMCID:PMC4580370

[106] Thompson EW,Tarin D.Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?.Cancer Res2005;65:5991-5

[107] Caramel J,Hill L,Richard G,Saldanha G,Hutchinson P,Lachuer J,Pringle JH,Tulchinsky E.A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma..Cancer Cell2013;24:466-80

[108] Van Roy F.Beyond E-cadherin: roles of other cadherin superfamily members in cancer..Nat Rev Cancer2014;14:121-34

[109] Wilmott JS,Menzies AM,Hyman J,Hersey P,Scolyer RA.Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment..J Immunol2014;192:2505-13

[110] Robertson GP.Functional and therapeutic significance of Akt deregulation in malignant melanoma..Cancer Metastasis Rev2005;24:273-85

[111] Stahl JM,Sharma A,Shanmugam S.Loss of PTEN promotes tumor development in malignant melanoma..Cancer Res2003;63:2881-90

[112] Mumford BS.Circulating melanoma cells in the diagnosis and monitoring of melanoma: an appraisal of clinical potential..Mol Diagn Ther2014;18:175-83 PMCID:PMC4379044

[113] Lin Q,Fan D,Guo L,Bar-Eli M,Fidler IJ.Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels..Neoplasia2010;12:748-54 PMCID:PMC2933695

[114] Wilhelm I.In vitro models of the blood-brain barrier for the study of drug delivery to the brain..Mol Pharm2014;11:1949-63

[115] Hopkins AM,Chwalek K.3D in vitro modeling of the central nervous system..Prog Neurobiol2015;125:1-25 PMCID:PMC4324093