The Microenvironmental Landscape of Brain Tumors

Cancer Cell

Volumn 31, Issue 3, 2017, Pages 326-341

  Quail, Daniela F ^a,b   Joyce, Johanna A ^c  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c UNIVERSITY OF LAUSANNE   (Switzerland)

Author keywords

blood brain barrier; brain metastasis; brain tumor microenvironment; glioma; immunotherapy; tumor associated macrophage

Indexed keywords

ASTROCYTE; BLOOD BRAIN BARRIER; BRAIN BLOOD VESSEL; BRAIN CANCER; BRAIN METASTASIS; BRAIN TUMOR; BREAST CANCER; CANCER GROWTH; CANCER RESISTANCE; CANCER THERAPY; DENDRITIC CELL; GLIOMA; GLIOSIS; HUMAN; IMMUNOREACTIVITY; IMMUNOSUPPRESSIVE TREATMENT; LYMPHOID CELL; MEDULLOBLASTOMA; MELANOMA; MICROGLIA; NERVE CELL; NEUTROPHIL; NON SMALL CELL LUNG CANCER; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; WOUND HEALING; ANGIOGENESIS; BRAIN NEOPLASMS; IMMUNOLOGY; MACROPHAGE; PHYSIOLOGY; T LYMPHOCYTE;

BLOOD-BRAIN BARRIER; BRAIN NEOPLASMS; DENDRITIC CELLS; HUMANS; MACROPHAGES; MICROGLIA; NEOVASCULARIZATION, PHYSIOLOGIC; NEUTROPHILS; T-LYMPHOCYTES; TUMOR MICROENVIRONMENT; WOUND HEALING;

EID: 85014999636     PISSN: 15356108     EISSN: 18783686     Source Type: Journal    
DOI: 10.1016/j.ccell.2017.02.009     Document Type: Review

References (179)

1. Abbott, N.J., Blood-brain barrier structure and function and the challenges for CNS drug delivery. J. Inherit. Metab. Dis. 36 (2013), 437–449.
2. Abbott, N.J., Ronnback, L., Hansson, E., Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7 (2006), 41–53.
3. Ahles, T.A., Saykin, A.J., Candidate mechanisms for chemotherapy-induced cognitive changes. Nat. Rev. Cancer 7 (2007), 192–201.
4. Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W., Rossi, F.M., Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10 (2007), 1538–1543.
5. Anguille, S., Smits, E.L., Lion, E., van Tendeloo, V.F., Berneman, Z.N., Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 15 (2014), e257–e267.
6. Aspelund, A., Antila, S., Proulx, S.T., Karlsen, T.V., Karaman, S., Detmar, M., Wiig, H., Alitalo, K., A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212 (2015), 991–999.
7. Bambury, R.M., Teo, M.Y., Power, D.G., Yusuf, A., Murray, S., Battley, J.E., Drake, C., O'Dea, P., Bermingham, N., Keohane, C., et al. The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme. J. Neurooncol. 114 (2013), 149–154.
8. Batchelor, T.T., Sorensen, A.G., di Tomaso, E., Zhang, W.T., Duda, D.G., Cohen, K.S., Kozak, K.R., Cahill, D.P., Chen, P.J., Zhu, M., et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11 (2007), 83–95.
9. Batchelor, T.T., Duda, D.G., di Tomaso, E., Ancukiewicz, M., Plotkin, S.R., Gerstner, E., Eichler, A.F., Drappatz, J., Hochberg, F.H., Benner, T., et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28 (2010), 2817–2823.
10. Bennett, M.L., Bennett, F.C., Liddelow, S.A., Ajami, B., Zamanian, J.L., Fernhoff, N.B., Mulinyawe, S.B., Bohlen, C.J., Adil, A., Tucker, A., et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA 113 (2016), E1738–E1746.
11. Bentolila, L.A., Prakash, R., Mihic-Probst, D., Wadehra, M., Kleinman, H.K., Carmichael, T.S., Peault, B., Barnhill, R.L., Lugassy, C., Imaging of angiotropism/vascular co-option in a murine model of brain melanoma: implications for melanoma progression along extravascular pathways. Sci. Rep., 6, 2016, 23834.
12. Berghoff, A.S., Venur, V.A., Preusser, M., Ahluwalia, M.S., Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am. Soc. Clin. Oncol. Educ. Book 35 (2016), e116–e122.
13. Bertaut, A., Truntzer, C., Madkouri, R., Kaderbhai, C.G., Derangere, V., Vincent, J., Chauffert, B., Aubriot-Lorton, M.H., Farah, W., Mourier, K.L., et al. Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma. Oncotarget 7 (2016), 70948–70958.
14. Bos, P.D., Zhang, X.H., Nadal, C., Shu, W., Gomis, R.R., Nguyen, D.X., Minn, A.J., van de Vijver, M.J., Gerald, W.L., Foekens, J.A., Massague, J., Genes that mediate breast cancer metastasis to the brain. Nature 459 (2009), 1005–1009.
15. Bouffet, E., Larouche, V., Campbell, B.B., Merico, D., de Borja, R., Aronson, M., Durno, C., Krueger, J., Cabric, V., Ramaswamy, V., et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34 (2016), 2206–2211.
16. Bowman, R.L., Joyce, J.A., Therapeutic targeting of tumor-associated macrophages and microglia in glioblastoma. Immunotherapy 6 (2014), 663–666.
17. Bowman, R.L., Klemm, F., Akkari, L., Pyonteck, S.M., Sevenich, L., Quail, D.F., Dhara, S., Simpson, K., Gardner, E.E., Iacobuzio-Donahue, C.A., et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 17 (2016), 2445–2459.
18. Brahmer, J., Reckamp, K.L., Baas, P., Crino, L., Eberhardt, W.E., Poddubskaya, E., Antonia, S., Pluzanski, A., Vokes, E.E., Holgado, E., et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373 (2015), 123–135.
19. Bresnick, A.R., Weber, D.J., Zimmer, D.B., S100 proteins in cancer. Nat. Rev. Cancer 15 (2015), 96–109.
20. Brosicke, N., Faissner, A., Role of tenascins in the ECM of gliomas. Cell Adh. Migr. 9 (2015), 131–140.
21. Brown, C.E., Alizadeh, D., Starr, R., Weng, L., Wagner, J.R., Naranjo, A., Ostberg, J.R., Blanchard, M.S., Kilpatrick, J., Simpson, J., et al. Regression of Glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375 (2016), 2561–2569.
22. Buckner, J.C., Shaw, E.G., Pugh, S.L., Chakravarti, A., Gilbert, M.R., Barger, G.R., Coons, S., Ricci, P., Bullard, D., Brown, P.D., et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N. Engl. J. Med. 374 (2016), 1344–1355.
23. Burda, J.E., Sofroniew, M.V., Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81 (2014), 229–248.
24. Butowski, N., Colman, H., De Groot, J.F., Omuro, A.M., Nayak, L., Wen, P.Y., Cloughesy, T.F., Marimuthu, A., Haidar, S., Perry, A., et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol. 18 (2015), 557–564.
25. Calabrese, C., Poppleton, H., Kocak, M., Hogg, T.L., Fuller, C., Hamner, B., Oh, E.Y., Gaber, M.W., Finklestein, D., Allen, M., et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11 (2007), 69–82.
26. Carmeliet, P., Jain, R.K., Molecular mechanisms and clinical applications of angiogenesis. Nature 473 (2011), 298–307.
27. Casbon, A.J., Reynaud, D., Park, C., Khuc, E., Gan, D.D., Schepers, K., Passegue, E., Werb, Z., Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. USA 112 (2015), E566–E575.
28. Charles, N., Holland, E.C., The perivascular niche microenvironment in brain tumor progression. Cell Cycle 9 (2010), 3012–3021.
29. Charles, N., Ozawa, T., Squatrito, M., Bleau, A.M., Brennan, C.W., Hambardzumyan, D., Holland, E.C., Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6 (2010), 141–152.
30. Chen, L., Flies, D.B., Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13 (2013), 227–242.
31. Chen, W., Wang, D., Du, X., He, Y., Chen, S., Shao, Q., Ma, C., Huang, B., Chen, A., Zhao, P., et al. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med. Oncol., 32, 2015, 43.
32. Chen, Q., Boire, A., Jin, X., Valiente, M., Er, E.E., Lopez-Soto, A., Jacob, L.S., Patwa, R., Shah, H., Xu, K., et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533 (2016), 493–498.
33. Chinot, O.L., Wick, W., Mason, W., Henriksson, R., Saran, F., Nishikawa, R., Carpentier, A.F., Hoang-Xuan, K., Kavan, P., Cernea, D., et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370 (2014), 709–722.
34. Coffelt, S.B., Kersten, K., Doornebal, C.W., Weiden, J., Vrijland, K., Hau, C.S., Verstegen, N.J., Ciampricotti, M., Hawinkels, L.J., Jonkers, J., et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522 (2015), 345–348.
35. Coffelt, S.B., Wellenstein, M.D., de Visser, K.E., Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16 (2016), 431–446.
36. Cohen, J.V., Kluger, H.M., Systemic immunotherapy for the treatment of brain metastases. Front. Oncol., 6, 2016, 49.
37. Cohen, M.H., Shen, Y.L., Keegan, P., Pazdur, R., FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14 (2009), 1131–1138.
38. Coniglio, S.J., Eugenin, E., Dobrenis, K., Stanley, E.R., West, B.L., Symons, M.H., Segall, J.E., Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol. Med. 18 (2012), 519–527.
39. Curtin, J.F., Liu, N., Candolfi, M., Xiong, W., Assi, H., Yagiz, K., Edwards, M.R., Michelsen, K.S., Kroeger, K.M., Liu, C., et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med., 6, 2009, e10.
40. da Fonseca, A.C., Matias, D., Garcia, C., Amaral, R., Geraldo, L.H., Freitas, C., Lima, F.R., The impact of microglial activation on blood-brain barrier in brain diseases. Front. Cell. Neurosci., 8, 2014, 362.
41. Davies, D.C., Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J. Anat. 200 (2002), 639–646.
42. De Palma, M., Venneri, M.A., Galli, R., Sergi Sergi, L., Politi, L.S., Sampaolesi, M., Naldini, L., Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8 (2005), 211–226.
43. Dudnik, E., Yust-Katz, S., Nechushtan, H., Goldstein, D.A., Zer, A., Flex, D., Siegal, T., Peled, N., Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer 98 (2016), 114–117.
44. Eichler, A.F., Chung, E., Kodack, D.P., Loeffler, J.S., Fukumura, D., Jain, R.K., The biology of brain metastases-translation to new therapies. Nat. Rev. Clin. Oncol. 8 (2011), 344–356.
45. Elmore, M.R., Najafi, A.R., Koike, M.A., Dagher, N.N., Spangenberg, E.E., Rice, R.A., Kitazawa, M., Matusow, B., Nguyen, H., West, B.L., Green, K.N., Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82 (2014), 380–397.
46. Engelhardt, B., Vajkoczy, P., Weller, R.O., The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18 (2017), 123–131.
47. Fecci, P.E., Mitchell, D.A., Whitesides, J.F., Xie, W., Friedman, A.H., Archer, G.E., Herndon, J.E. 2nd, Bigner, D.D., Dranoff, G., Sampson, J.H., Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 66 (2006), 3294–3302.
48. Fecci, P.E., Sweeney, A.E., Grossi, P.M., Nair, S.K., Learn, C.A., Mitchell, D.A., Cui, X., Cummings, T.J., Bigner, D.D., Gilboa, E., Sampson, J.H., Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells. Clin. Cancer Res. 12 (2006), 4294–4305.
49. Fecci, P.E., Ochiai, H., Mitchell, D.A., Grossi, P.M., Sweeney, A.E., Archer, G.E., Cummings, T., Allison, J.P., Bigner, D.D., Sampson, J.H., Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin. Cancer Res. 13 (2007), 2158–2167.
50. Fecci, P.E., Heimberger, A.B., Sampson, J.H., Immunotherapy for primary brain tumors: no longer a matter of privilege. Clin. Cancer Res. 20 (2014), 5620–5629.
51. Fine, H.A., Bevacizumab in glioblastoma – still much to learn. N. Engl. J. Med. 370 (2014), 764–765.
52. Fossati, G., Ricevuti, G., Edwards, S.W., Walker, C., Dalton, A., Rossi, M.L., Neutrophil infiltration into human gliomas. Acta Neuropathol. 98 (1999), 349–354.
53. Friedman, H.S., Prados, M.D., Wen, P.Y., Mikkelsen, T., Schiff, D., Abrey, L.E., Yung, W.K., Paleologos, N., Nicholas, M.K., Jensen, R., et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27 (2009), 4733–4740.
54. Gabrusiewicz, K., Rodriguez, B., Wei, J., Hashimoto, Y., Healy, L.M., Maiti, S.N., Thomas, G., Zhou, S., Wang, Q., Elakkad, A., et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight, 1, 2016, e85841.
55. Garg, A.D., Vandenberk, L., Koks, C., Verschuere, T., Boon, L., Van Gool, S.W., Agostinis, P., Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci. Transl. Med., 8, 2016, 328ra327.
56. Gautier, E.L., Shay, T., Miller, J., Greter, M., Jakubzick, C., Ivanov, S., Helft, J., Chow, A., Elpek, K.G., Gordonov, S., et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13 (2012), 1118–1128.
57. Gilbert, M.R., Dignam, J.J., Armstrong, T.S., Wefel, J.S., Blumenthal, D.T., Vogelbaum, M.A., Colman, H., Chakravarti, A., Pugh, S., Won, M., et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370 (2014), 699–708.
58. Gilbertson, R.J., Rich, J.N., Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nat. Rev. Cancer 7 (2007), 733–736.
59. Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F., Conway, S.J., Ng, L.G., Stanley, E.R., et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330 (2010), 841–845.
60. Ginhoux, F., Schultze, J.L., Murray, P.J., Ochando, J., Biswas, S.K., New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat. Immunol. 17 (2015), 34–40.
61. Goldberg, S.B., Gettinger, S.N., Mahajan, A., Chiang, A.C., Herbst, R.S., Sznol, M., Tsiouris, A.J., Cohen, J., Vortmeyer, A., Jilaveanu, L., et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 17 (2016), 976–983.
62. Goldmann, J., Kwidzinski, E., Brandt, C., Mahlo, J., Richter, D., Bechmann, I., T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J. Leukoc. Biol. 80 (2006), 797–801.
63. Goldmann, T., Wieghofer, P., Jordao, M.J., Prutek, F., Hagemeyer, N., Frenzel, K., Amann, L., Staszewski, O., Kierdorf, K., Krueger, M., et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17 (2016), 797–805.
64. Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., Garner, H., Trouillet, C., de Bruijn, M.F., Geissmann, F., Rodewald, H.R., Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518 (2015), 547–551.
65. Graeber, M.B., Scheithauer, B.W., Kreutzberg, G.W., Microglia in brain tumors. Glia 40 (2002), 252–259.
66. Hambardzumyan, D., Becher, O.J., Rosenblum, M.K., Pandolfi, P.P., Manova-Todorova, K., Holland, E.C., PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 22 (2008), 436–448.
67. Hambardzumyan, D., Gutmann, D.H., Kettenmann, H., The role of microglia and macrophages in glioma maintenance and progression. Nat. Neurosci. 19 (2016), 20–27.
68. Hart, D.N., Fabre, J.W., Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J. Exp. Med. 154 (1981), 347–361.
69. Hickey, W.F., Kimura, H., Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239 (1988), 290–292.
70. Hodi, F.S., O'Day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363 (2010), 711–723.
71. Hu, B., Wang, Q., Wang, Y.A., Hua, S., Sauve, C.G., Ong, D., Lan, Z.D., Chang, Q., Ho, Y.W., Monasterio, M.M., et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell 167 (2016), 1281–1295.e18.
72. Huang, J.Y., Cheng, Y.J., Lin, Y.P., Lin, H.C., Su, C.C., Juliano, R., Yang, B.C., Extracellular matrix of glioblastoma inhibits polarization and transmigration of T cells: the role of tenascin-C in immune suppression. J. Immunol. 185 (2010), 1450–1459.
73. Hussain, S.F., Yang, D., Suki, D., Aldape, K., Grimm, E., Heimberger, A.B., The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol. 8 (2006), 261–279.
74. Hutchinson, L., Immunotherapy: exploiting mismatch repair in GBM. Nat. Rev. Clin. Oncol., 13, 2016, 264.
75. Iliff, J.J., Goldman, S.A., Nedergaard, M., Implications of the discovery of brain lymphatic pathways. Lancet Neurol. 14 (2015), 977–979.
76. Jain, R.K., Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7 (2001), 987–989.
77. Jain, R.K., Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307 (2005), 58–62.
78. Jain, R.K., di Tomaso, E., Duda, D.G., Loeffler, J.S., Sorensen, A.G., Batchelor, T.T., Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8 (2007), 610–622.
79. Jilaveanu, L.B., Parisi, F., Barr, M.L., Zito, C.R., Cruz-Munoz, W., Kerbel, R.S., Rimm, D.L., Bosenberg, M.W., Halaban, R., Kluger, Y., Kluger, H.M., PLEKHA5 as a biomarker and potential mediator of melanoma brain metastasis. Clin. Cancer Res. 21 (2015), 2138–2147.
80. Joyce, J.A., Fearon, D.T., T cell exclusion, immune privilege, and the tumor microenvironment. Science 348 (2015), 74–80.
81. Kim, T.G., Kim, C.H., Park, J.S., Park, S.D., Kim, C.K., Chung, D.S., Hong, Y.K., Immunological factors relating to the antitumor effect of temozolomide chemoimmunotherapy in a murine glioma model. Clin. Vaccine Immunol. 17 (2010), 143–153.
82. Kim, S.J., Kim, J.S., Park, E.S., Lee, J.S., Lin, Q., Langley, R.R., Maya, M., He, J., Kim, S.W., Weihua, Z., et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13 (2011), 286–298.
83. Kim, S.J., Lee, H.J., Kim, M.S., Choi, H.J., He, J., Wu, Q., Aldape, K., Weinberg, J.S., Yung, W.K., Conrad, C.A., et al. Macitentan, a dual endothelin receptor antagonist, in combination with temozolomide leads to glioblastoma regression and long-term survival in mice. Clin. Cancer Res. 21 (2015), 4630–4641.
84. Koh, Y.W., Choi, J.H., Ahn, M.S., Choi, Y.W., Lee, H.W., Baseline neutrophil-lymphocyte ratio is associated with baseline and subsequent presence of brain metastases in advanced non-small-cell lung cancer. Sci. Rep., 6, 2016, 38585.
85. Komohara, Y., Ohnishi, K., Kuratsu, J., Takeya, M., Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J. Pathol. 216 (2008), 15–24.
86. Konstantinou, M.P., Dutriaux, C., Gaudy-Marqueste, C., Mortier, L., Bedane, C., Girard, C., Thellier, S., Jouary, T., Grob, J.J., Richard, M.A., et al. Ipilimumab in melanoma patients with brain metastasis: a retrospective multicentre evaluation of thirty-eight patients. Acta Derm. Venereol. 94 (2014), 45–49.
87. Kreisl, T.N., Kim, L., Moore, K., Duic, P., Royce, C., Stroud, I., Garren, N., Mackey, M., Butman, J.A., Camphausen, K., et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27 (2009), 740–745.
88. Kundu, S., Xiong, A., Spyrou, A., Wicher, G., Marinescu, V.D., Edqvist, P.D., Zhang, L., Essand, M., Dimberg, A., Smits, A., et al. Heparanase promotes glioma progression and is inversely correlated with patient survival. Mol. Cancer Res. 14 (2016), 1243–1253.
89. Lathia, J.D., Gallagher, J., Heddleston, J.M., Wang, J., Eyler, C.E., Macswords, J., Wu, Q., Vasanji, A., McLendon, R.E., Hjelmeland, A.B., Rich, J.N., Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6 (2010), 421–432.
90. Lathia, J.D., Mack, S.C., Mulkearns-Hubert, E.E., Valentim, C.L., Rich, J.N., Cancer stem cells in glioblastoma. Genes Dev. 29 (2015), 1203–1217.
91. Le, D.T., Uram, J.N., Wang, H., Bartlett, B.R., Kemberling, H., Eyring, A.D., Skora, A.D., Luber, B.S., Azad, N.S., Laheru, D., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372 (2015), 2509–2520.
92. Lee, H.J., Hanibuchi, M., Kim, S.J., Yu, H., Kim, M.S., He, J., Langley, R.R., Lehembre, F., Regenass, U., Fidler, I.J., Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel. Neuro Oncol. 18 (2016), 486–496.
93. Leenders, W.P., Kusters, B., Verrijp, K., Maass, C., Wesseling, P., Heerschap, A., Ruiter, D., Ryan, A., de Waal, R., Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin. Cancer Res. 10 (2004), 6222–6230.
94. Lemjabbar-Alaoui, H., McKinney, A., Yang, Y.W., Tran, V.M., Phillips, J.J., Glycosylation alterations in lung and brain cancer. Adv. Cancer Res. 126 (2015), 305–344.
95. Levy, C., Allouache, D., Lacroix, J., Dugue, A.E., Supiot, S., Campone, M., Mahe, M., Kichou, S., Leheurteur, M., Hanzen, C., et al. REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours. Ann. Oncol. 25 (2014), 2351–2356.
96. Li, B., Wang, C., Zhang, Y., Zhao, X.Y., Huang, B., Wu, P.F., Li, Q., Li, H., Liu, Y.S., Cao, L.Y., et al. Elevated PLGF contributes to small-cell lung cancer brain metastasis. Oncogene 32 (2013), 2952–2962.
97. Liang, J., Piao, Y., Holmes, L., Fuller, G.N., Henry, V., Tiao, N., de Groot, J.F., Neutrophils promote the malignant glioma phenotype through S100A4. Clin. Cancer Res. 20 (2014), 187–198.
98. Lin, Q., Balasubramanian, K., Fan, D., Kim, S.J., Guo, L., Wang, H., Bar-Eli, M., Aldape, K.D., Fidler, I.J., Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia 12 (2010), 748–754.
99. Liu, C., Sage, J.C., Miller, M.R., Verhaak, R.G., Hippenmeyer, S., Vogel, H., Foreman, O., Bronson, R.T., Nishiyama, A., Luo, L., Zong, H., Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146 (2011), 209–221.
100. Liu, Y., Kosaka, A., Ikeura, M., Kohanbash, G., Fellows-Mayle, W., Snyder, L.A., Okada, H., Premetastatic soil and prevention of breast cancer brain metastasis. Neuro Oncol. 15 (2013), 891–903.
101. Liu, Y., Gu, Y., Han, Y., Zhang, Q., Jiang, Z., Zhang, X., Huang, B., Xu, X., Zheng, J., Cao, X., Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30 (2016), 243–256.
102. Lockman, P.R., Mittapalli, R.K., Taskar, K.S., Rudraraju, V., Gril, B., Bohn, K.A., Adkins, C.E., Roberts, A., Thorsheim, H.R., Gaasch, J.A., et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res. 16 (2010), 5664–5678.
103. Lou, N., Takano, T., Pei, Y., Xavier, A.L., Goldman, S.A., Nedergaard, M., Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proc. Natl. Acad. Sci. USA 113 (2016), 1074–1079.
104. Louveau, A., Harris, T.H., Kipnis, J., Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36 (2015), 569–577.
105. Louveau, A., Smirnov, I., Keyes, T.J., Eccles, J.D., Rouhani, S.J., Peske, J.D., Derecki, N.C., Castle, D., Mandell, J.W., Lee, K.S., et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523 (2015), 337–341.
106. Lowe, J., MacLennan, K.A., Powe, D.G., Pound, J.D., Palmer, J.B., Microglial cells in human brain have phenotypic characteristics related to possible function as dendritic antigen presenting cells. J. Pathol. 159 (1989), 143–149.
107. Lu-Emerson, C., Snuderl, M., Kirkpatrick, N.D., Goveia, J., Davidson, C., Huang, Y., Riedemann, L., Taylor, J., Ivy, P., Duda, D.G., et al. Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. Neuro Oncol. 15 (2013), 1079–1087.
108. Lyle, L.T., Lockman, P.R., Adkins, C.E., Mohammad, A.S., Sechrest, E., Hua, E., Palmieri, D., Liewehr, D.J., Steinberg, S.M., Kloc, W., et al. Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. Clin. Cancer Res. 22 (2016), 5287–5299.
109. Malkki, H., Neuro-oncology: bevacizumab prolongs progression-free survival but not overall survival in newly diagnosed glioblastoma. Nat. Rev. Neurol., 10, 2014, 179.
110. Margolin, K., Ernstoff, M.S., Hamid, O., Lawrence, D., McDermott, D., Puzanov, I., Wolchok, J.D., Clark, J.I., Sznol, M., Logan, T.F., et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13 (2012), 459–465.
111. Massague, J., Obenauf, A.C., Metastatic colonization by circulating tumour cells. Nature 529 (2016), 298–306.
112. Masson, F., Calzascia, T., Di Berardino-Besson, W., de Tribolet, N., Dietrich, P.Y., Walker, P.R., Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells. J. Immunol. 179 (2007), 845–853.
113. Mathios, D., Kim, J.E., Mangraviti, A., Phallen, J., Park, C.K., Jackson, C.M., Garzon-Muvdi, T., Kim, E., Theodros, D., Polanczyk, M., et al. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci. Transl. Med., 8, 2016, 370ra180.
114. McNamara, M.G., Lwin, Z., Jiang, H., Templeton, A.J., Zadeh, G., Bernstein, M., Chung, C., Millar, B.A., Laperriere, N., Mason, W.P., Factors impacting survival following second surgery in patients with glioblastoma in the temozolomide treatment era, incorporating neutrophil/lymphocyte ratio and time to first progression. J. Neurooncol. 117 (2014), 147–152.
115. Medawar, P.B., Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29 (1948), 58–69.
116. Miroshnikova, Y.A., Mouw, J.K., Barnes, J.M., Pickup, M.W., Lakins, J.N., Kim, Y., Lobo, K., Persson, A.I., Reis, G.F., McKnight, T.R., et al. Tissue mechanics promote IDH1-dependent HIF1alpha-tenascin C feedback to regulate glioblastoma aggression. Nat. Cell Biol. 18 (2016), 1336–1345.
117. Mitchell, D.A., Batich, K.A., Gunn, M.D., Huang, M.N., Sanchez-Perez, L., Nair, S.K., Congdon, K.L., Reap, E.A., Archer, G.E., Desjardins, A., et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519 (2015), 366–369.
118. Mitsuya, K., Nakasu, Y., Kurakane, T., Hayashi, N., Harada, H., Nozaki, K., Elevated preoperative neutrophil-to-lymphocyte ratio as a predictor of worse survival after resection in patients with brain metastasis. J. Neurosurg., 2016, 10.3171/2016.8.JNS16899.
119. Mondin, V., Ferlito, A., Devaney, K.O., Woolgar, J.A., Rinaldo, A., A survey of metastatic central nervous system tumors to cervical lymph nodes. Eur. Arch. Otorhinolaryngol. 267 (2010), 1657–1666.
120. Morikawa, A., Peereboom, D.M., Thorsheim, H.R., Samala, R., Balyan, R., Murphy, C.G., Lockman, P.R., Simmons, A., Weil, R.J., Tabar, V., et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro Oncol. 17 (2015), 289–295.
121. Mulvenna, P., Nankivell, M., Barton, R., Faivre-Finn, C., Wilson, P., McColl, E., Moore, B., Brisbane, I., Ardron, D., Holt, T., et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 388 (2016), 2004–2014.
122. Murphy, K.A., Lechner, M.G., Popescu, F.E., Bedi, J., Decker, S.A., Hu, P., Erickson, J.R., O'Sullivan, M.G., Swier, L., Salazar, A.M., et al. An in vivo immunotherapy screen of costimulatory molecules identifies Fc-OX40L as a potent reagent for the treatment of established murine gliomas. Clin. Cancer Res. 18 (2012), 4657–4668.
123. Mustafa, D.A., Dekker, L.J., Stingl, C., Kremer, A., Stoop, M., Sillevis Smitt, P.A., Kros, J.M., Luider, T.M., A proteome comparison between physiological angiogenesis and angiogenesis in glioblastoma. Mol. Cell. Proteomics, 11, 2012 M111.008466.
124. Neman, J., Termini, J., Wilczynski, S., Vaidehi, N., Choy, C., Kowolik, C.M., Li, H., Hambrecht, A.C., Roberts, E., Jandial, R., Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc. Natl. Acad. Sci. USA 111 (2014), 984–989.
125. Nicolas-Avila, J.A., Adrover, J.M., Hidalgo, A., Neutrophils in homeostasis, immunity, and cancer. Immunity 46 (2017), 15–28.
126. O'Keeffe, E., Campbell, M., Modulating the paracellular pathway at the blood-brain barrier: current and future approaches for drug delivery to the CNS. Drug Discov. Today Technol. 20 (2016), 35–39.
127. Oskarsson, T., Batlle, E., Massague, J., Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14 (2014), 306–321.
128. Osswald, M., Jung, E., Sahm, F., Solecki, G., Venkataramani, V., Blaes, J., Weil, S., Horstmann, H., Wiestler, B., Syed, M., et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528 (2015), 93–98.
129. Osswald, M., Blaes, J., Liao, Y., Solecki, G., Gommel, M., Berghoff, A.S., Salphati, L., Wallin, J.J., Phillips, H.S., Wick, W., Winkler, F., Impact of blood-brain barrier integrity on tumor growth and therapy response in brain metastases. Clin. Cancer Res. 22 (2016), 6078–6087.
130. Palucka, K., Banchereau, J., Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer 12 (2012), 265–277.
131. Papadopoulos, M.C., Saadoun, S., Davies, D.C., Bell, B.A., Emerging molecular mechanisms of brain tumour oedema. Br. J. Neurosurg. 15 (2001), 101–108.
132. Pham, C.D., Flores, C., Yang, C., Pinheiro, E.M., Yearley, J.H., Sayour, E.J., Pei, Y., Moore, C., McLendon, R.E., Huang, J., et al. Differential immune microenvironments and response to immune checkpoint blockade among molecular subtypes of murine medulloblastoma. Clin. Cancer Res. 22 (2016), 582–595.
133. Phoenix, T.N., Patmore, D.M., Boop, S., Boulos, N., Jacus, M.O., Patel, Y.T., Roussel, M.F., Finkelstein, D., Goumnerova, L., Perreault, S., et al. Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer Cell 29 (2016), 508–522.
134. Piao, Y., Liang, J., Holmes, L., Zurita, A.J., Henry, V., Heymach, J.V., de Groot, J.F., Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro Oncol. 14 (2012), 1379–1392.
135. Pietras, A., Katz, A.M., Ekstrom, E.J., Wee, B., Halliday, J.J., Pitter, K.L., Werbeck, J.L., Amankulor, N.M., Huse, J.T., Holland, E.C., Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14 (2014), 357–369.
136. Preusser, M., Lim, M., Hafler, D.A., Reardon, D.A., Sampson, J.H., Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat. Rev. Neurol. 11 (2015), 504–514.
137. Prins, R.M., Soto, H., Konkankit, V., Odesa, S.K., Eskin, A., Yong, W.H., Nelson, S.F., Liau, L.M., Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 17 (2011), 1603–1615.
138. Pukrop, T., Dehghani, F., Chuang, H.N., Lohaus, R., Bayanga, K., Heermann, S., Regen, T., Van Rossum, D., Klemm, F., Schulz, M., et al. Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 58 (2010), 1477–1489.
139. Pyonteck, S.M., Akkari, L., Schuhmacher, A.J., Bowman, R.L., Sevenich, L., Quail, D.F., Olson, O.C., Quick, M.L., Huse, J.T., Teijeiro, V., et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19 (2013), 1264–1272.
140. Qian, B.Z., Pollard, J.W., Macrophage diversity enhances tumor progression and metastasis. Cell 141 (2010), 39–51.
141. Quail, D.F., Joyce, J.A., Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19 (2013), 1423–1437.
142. Quail, D.F., Bowman, R.L., Akkari, L., Quick, M.L., Schuhmacher, A.J., Huse, J.T., Holland, E.C., Sutton, J.C., Joyce, J.A., The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science, 352, 2016, aad3018.
143. Queirolo, P., Spagnolo, F., Ascierto, P.A., Simeone, E., Marchetti, P., Scoppola, A., Del Vecchio, M., Di Guardo, L., Maio, M., Di Giacomo, A.M., et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J. Neurooncol. 118 (2014), 109–116.
144. Ramirez-Castillejo, C., Sanchez-Sanchez, F., Andreu-Agullo, C., Ferron, S.R., Aroca-Aguilar, J.D., Sanchez, P., Mira, H., Escribano, J., Farinas, I., Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat. Neurosci. 9 (2006), 331–339.
145. Ransohoff, R.M., Engelhardt, B., The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12 (2012), 623–635.
146. Reinhard, J., Brosicke, N., Theocharidis, U., Faissner, A., The extracellular matrix niche microenvironment of neural and cancer stem cells in the brain. Int. J. Biochem. Cell Biol. 81 (2016), 174–183.
147. Restifo, N.P., Smyth, M.J., Snyder, A., Acquired resistance to immunotherapy and future challenges. Nat. Rev. Cancer 16 (2016), 121–126.
148. Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T., Maira, G., Parati, E.A., Stassi, G., Larocca, L.M., De Maria, R., Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468 (2010), 824–828.
149. Robel, S., Berninger, B., Gotz, M., The stem cell potential of glia: lessons from reactive gliosis. Nat. Rev. Neurosci. 12 (2011), 88–104.
150. Rosano, L., Spinella, F., Bagnato, A., Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 13 (2013), 637–651.
151. Sarkar, S., Doring, A., Zemp, F.J., Silva, C., Lun, X., Wang, X., Kelly, J., Hader, W., Hamilton, M., Mercier, P., et al. Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Nat. Neurosci. 17 (2014), 46–55.
152. Serdarevic, M., Kukulj, S., Nikolic, I., Taradi, I., Romic, Z., Samarzija, M., 203P: could neutrophil-to-lymphocyte ratio be predictor of brain metastases in non small cell lung cancer?. J. Thorac. Oncol., 11, 2016, S145.
153. Sevenich, L., Bowman, R.L., Mason, S.D., Quail, D.F., Rapaport, F., Elie, B.T., Brogi, E., Brastianos, P.K., Hahn, W.C., Holsinger, L.J., et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16 (2014), 876–888.
154. Shechter, R., London, A., Schwartz, M., Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13 (2013), 206–218.
155. Shen, Q., Goderie, S.K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., Temple, S., Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304 (2004), 1338–1340.
156. Shi, C., Pamer, E.G., Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11 (2011), 762–774.
157. Silver, J., Miller, J.H., Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5 (2004), 146–156.
158. Sofroniew, M.V., Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16 (2015), 249–263.
159. Sorensen, A.G., Batchelor, T.T., Zhang, W.T., Chen, P.J., Yeo, P., Wang, M., Jennings, D., Wen, P.Y., Lahdenranta, J., Ancukiewicz, M., et al. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res. 69 (2009), 5296–5300.
160. Steeg, P.S., Camphausen, K.A., Smith, Q.R., Brain metastases as preventive and therapeutic targets. Nat. Rev. Cancer 11 (2011), 352–363.
161. Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Brandes, A.A., Marosi, C., Bogdahn, U., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352 (2005), 987–996.
162. Tavazoie, M., Van der Veken, L., Silva-Vargas, V., Louissaint, M., Colonna, L., Zaidi, B., Garcia-Verdugo, J.M., Doetsch, F., A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3 (2008), 279–288.
163. Tong, R.T., Boucher, Y., Kozin, S.V., Winkler, F., Hicklin, D.J., Jain, R.K., Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64 (2004), 3731–3736.
164. Ulvestad, E., Williams, K., Bjerkvig, R., Tiekotter, K., Antel, J., Matre, R., Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells. J. Leukoc. Biol. 56 (1994), 732–740.
165. Unruh, D., Schwarze, S.R., Khoury, L., Thomas, C., Wu, M., Chen, L., Chen, R., Liu, Y., Schwartz, M.A., Amidei, C., et al. Mutant IDH1 and thrombosis in gliomas. Acta Neuropathol. 132 (2016), 917–930.
166. Valiente, M., Obenauf, A.C., Jin, X., Chen, Q., Zhang, X.H., Lee, D.J., Chaft, J.E., Kris, M.G., Huse, J.T., Brogi, E., Massague, J., Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156 (2014), 1002–1016.
167. Venkatesh, H.S., Johung, T.B., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E.M., Mount, C.W., Polepalli, J., Mitra, S.S., et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161 (2015), 803–816.
168. Wade, A., Robinson, A.E., Engler, J.R., Petritsch, C., James, C.D., Phillips, J.J., Proteoglycans and their roles in brain cancer. FEBS J. 280 (2013), 2399–2417.
169. Wang, Y., Yang, J., Zheng, H., Tomasek, G.J., Zhang, P., McKeever, P.E., Lee, E.Y., Zhu, Y., Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15 (2009), 514–526.
170. Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K.E., Geber, A., Fligelman, B., Leversha, M., Brennan, C., Tabar, V., Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468 (2010), 829–833.
171. Wculek, S.K., Malanchi, I., Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528 (2015), 413–417.
172. Weiss, N., Miller, F., Cazaubon, S., Couraud, P.O., The blood-brain barrier in brain homeostasis and neurological diseases. Biochim. Biophys. Acta 1788 (2009), 842–857.
173. Weiss, T., Weller, M., Roth, P., Immunological effects of chemotherapy and radiotherapy against brain tumors. Expert Rev. Anticancer Ther. 16 (2016), 1087–1094.
174. Winkler, F., Kozin, S.V., Tong, R.T., Chae, S.S., Booth, M.F., Garkavtsev, I., Xu, L., Hicklin, D.J., Fukumura, D., di Tomaso, E., et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6 (2004), 553–563.
175. Wu, A., Wei, J., Kong, L.Y., Wang, Y., Priebe, W., Qiao, W., Sawaya, R., Heimberger, A.B., Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 12 (2010), 1113–1125.
176. Wurmser, A.E., Nakashima, K., Summers, R.G., Toni, N., D'Amour, K.A., Lie, D.C., Gage, F.H., Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430 (2004), 350–356.
177. Zamanian, J.L., Xu, L., Foo, L.C., Nouri, N., Zhou, L., Giffard, R.G., Barres, B.A., Genomic analysis of reactive astrogliosis. J. Neurosci. 32 (2012), 6391–6410.
178. Zhang, L., Zhang, S., Yao, J., Lowery, F.J., Zhang, Q., Huang, W.C., Li, P., Li, M., Wang, X., Zhang, C., et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527 (2015), 100–104.
179. Zhou, W., Ke, S.Q., Huang, Z., Flavahan, W., Fang, X., Paul, J., Wu, L., Sloan, A.E., McLendon, R.E., Li, X., et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat. Cell Biol. 17 (2015), 170–182.