Skip to main content

Advertisement

SpringerLink
Log in

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies.

Conclusions

The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. R. Siegel, E. Ward, O. Brawley, A. Jemal, Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J. Clin. 61, 212–236 (2011)

    Article  PubMed  Google Scholar 

  2. SEER. Stat fact sheets: lung and bronchus cancer 2016 [cited 2016 September 2016] Available from: http://seer.cancer.gov/statfacts/html/lungb.html

  3. R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016)

    Article  PubMed  Google Scholar 

  4. SEER. Cancer statistics review 1975-2013 2013 [cited 2016 September 2016] Available from: http://seer.cancer.gov/csr/1975_2013/browse_csr.php

  5. Centers for Disease Control and Prevention. Smoking & tobacco use. [cited 2016 September 2016]. Available from: http://www.cdc.gov/tobacco/data_statistics/tables/trends/cig_smoking/

  6. K. Sawada. [Lung cancer: classification by cell types]. Nihon rinsho Japanese journal of clinical medicine 38, 2574–80 (1980)

  7. W.C. Dempke, T. Suto, M. Reck, Targeted therapies for non-small cell lung cancer. Lung Cancer 67, 257–274 (2010)

    Article  PubMed  Google Scholar 

  8. M. Dragoj, Z. Milosevic, J. Bankovic, N. Tanic, M. Pesic, T. Stankovic, Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma. Cell. Oncol. 40, 47–62 (2017)

    Article  CAS  Google Scholar 

  9. I.T. Gavrilovic, J.B. Posner, Brain metastases: Epidemiology and pathophysiology. J. Neuro-Oncol. 75, 5–14 (2005)

    Article  Google Scholar 

  10. J.B. Sorensen, H.H. Hansen, M. Hansen, P. Dombernowsky, Brain metastases in adenocarcinoma of the lung: Frequency, risk groups, and prognosis. J. Clin. Oncol. 6, 1474–1480 (1988)

    Article  CAS  PubMed  Google Scholar 

  11. A. Mujoomdar, J.H. Austin, R. Malhotra, C.A. Powell, G.D. Pearson, M.C. Shiau, H. Raftopoulos, Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: Primary tumor size, cell type, and lymph node metastases. Radiology 242, 882–888 (2007)

    Article  PubMed  Google Scholar 

  12. J. Budczies, M. von Winterfeld, F. Klauschen, M. Bockmayr, J.K. Lennerz, C. Denkert, T. Wolf, A. Warth, M. Dietel, I. Anagnostopoulos, W. Weichert, D. Wittschieber, A. Stenzinger, The landscape of metastatic progression patterns across major human cancers. Oncotarget 6, 570–583 (2015)

    Article  PubMed  Google Scholar 

  13. B.D. Fox, V.J. Cheung, A.J. Patel, D. Suki, G. Rao. Epidemiology of metastatic brain tumors. Neurosurg. Clin. N. Am. 22, 1–6 (2011)

  14. J.D. Cox, R.A. Yesner, Adenocarcinoma of the lung: Recent results from the veterans administration lung group. Am. Rev. Respir. Dis. 120, 1025–1029 (1979)

    CAS  PubMed  Google Scholar 

  15. J.S. Barnholtz-Sloan, A.E. Sloan, F.G. Davis, F.D. Vigneau, P. Lai, R.E. Sawaya, Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit cancer surveillance system. J. Clin. Oncol. 22, 2865–2872 (2004)

    Article  PubMed  Google Scholar 

  16. F.G. Davis, T.A. Dolecek, B.J. McCarthy, J.L. Villano, Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data. Neuro-Oncology 14, 1171–1177 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  17. Z. Ji, N. Bi, J. Wang, Z. Hui, Z. Xiao, Q. Feng, Z. Zhou, D. Chen, J. Lv, J. Liang, C. Fan, L. Liu, L. Wang, Risk factors for brain metastases in locally advanced non-small cell lung cancer with definitive chest radiation. Int. J. Radiat. Oncol. Biol. Phys. 89, 330–337 (2014)

    Article  PubMed  Google Scholar 

  18. G.L. Ceresoli, M. Reni, G. Chiesa, A. Carretta, S. Schipani, P. Passoni, A. Bolognesi, P. Zannini, E. Villa, Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment: Risk factors analysis. Cancer 95, 605–612 (2002)

    Article  PubMed  Google Scholar 

  19. L. Gaspar, C. Scott, M. Rotman, S. Asbell, T. Phillips, T. Wasserman, W.G. McKenna, R. Byhardt, Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int. J. Radiat. Oncol. Biol. Phys. 37, 745–751 (1997)

    Article  CAS  PubMed  Google Scholar 

  20. M. Hanibuchi, S.J. Kim, I.J. Fidler, Y. Nishioka, The molecular biology of lung cancer brain metastasis: An overview of current comprehensions and future perspectives. J. Med. Investig. 61, 241–253 (2014)

    Article  Google Scholar 

  21. L. Ding, G. Getz, D.A. Wheeler, E.R. Mardis, M.D. McLellan, K. Cibulskis, C. Sougnez, H. Greulich, D.M. Muzny, M.B. Morgan, L. Fulton, R.S. Fulton, Q. Zhang, M.C. Wendl, M.S. Lawrence, D.E. Larson, K. Chen, D.J. Dooling, A. Sabo, A.C. Hawes, H. Shen, S.N. Jhangiani, L.R. Lewis, O. Hall, Y. Zhu, T. Mathew, Y. Ren, J. Yao, S.E. Scherer, K. Clerc, G.A. Metcalf, B. Ng, A. Milosavljevic, M.L. Gonzalez-Garay, J.R. Osborne, R. Meyer, X. Shi, Y. Tang, D.C. Koboldt, L. Lin, R. Abbott, T.L. Miner, C. Pohl, G. Fewell, C. Haipek, H. Schmidt, B.H. Dunford-Shore, A. Kraja, S.D. Crosby, C.S. Sawyer, T. Vickery, S. Sander, J. Robinson, W. Winckler, J. Baldwin, L.R. Chirieac, A. Dutt, T. Fennell, M. Hanna, B.E. Johnson, R.C. Onofrio, R.K. Thomas, G. Tonon, B.A. Weir, X. Zhao, L. Ziaugra, M.C. Zody, T. Giordano, M.B. Orringer, J.A. Roth, M.R. Spitz, I.I. Wistuba, B. Ozenberger, P.J. Good, A.C. Chang, D.G. Beer, M.A. Watson, M. Ladanyi, S. Broderick, A. Yoshizawa, W.D. Travis, W. Pao, M.A. Province, G.M. Weinstock, H.E. Varmus, S.B. Gabriel, E.S. Lander, R.A. Gibbs, M. Meyerson, R.K. Wilson, Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. S. Matsumoto, R. Iwakawa, K. Takahashi, T. Kohno, Y. Nakanishi, Y. Matsuno, K. Suzuki, M. Nakamoto, E. Shimizu, J.D. Minna, J. Yokota, Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene 26, 5911–5918 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. M. Ji, Y. Liu, Q. Li, X.D. Li, W.Q. Zhao, H. Zhang, X. Zhang, J.T. Jiang, C.P. Wu, PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. J. Transl. Med. 13 (2015)

  24. W. Shi, A.P. Dicker, CNS metastases in patients with non-small-cell lung cancer and ALK gene rearrangement. J. Clin. Oncol. 34, 107–109 (2016)

    Article  CAS  PubMed  Google Scholar 

  25. R.C. Doebele, X. Lu, C. Sumey, D.A. Maxson, A.J. Weickhardt, A.B. Oton, P.A. Bunn Jr., A.E. Baron, W.A. Franklin, D.L. Aisner, M. Varella-Garcia, D.R. Camidge, Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118, 4502–4511 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. D.Y. Shin, I.I. Na, C.H. Kim, S. Park, H. Baek, S.H. Yang, EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J. Thorac. Oncol. 9, 195–199 (2014)

    Article  CAS  PubMed  Google Scholar 

  27. C. Villalva, V. Duranton-Tanneur, K. Guilloteau, F. Burel-Vandenbos, M. Wager, J. Doyen, P.M. Levillain, D. Fontaine, H. Blons, F. Pedeutour, L. Karayan-Tapon, EGFR, KRAS, BRAF, and HER-2 molecular status in brain metastases from 77 NSCLC patients. Cancer Med. 2, 296–304 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. A.B. Cortot, A. Italiano, F. Burel-Vandenbos, G. Martel-Planche, P. Hainaut, KRAS mutation status in primary nonsmall cell lung cancer and matched metastases. Cancer 116, 2682–2687 (2010)

    Article  PubMed  Google Scholar 

  29. L. Daniele, P. Cassoni, E. Bacillo, S. Cappia, L. Righi, M. Volante, F. Tondat, G. Inghirami, A. Sapino, G.V. Scagliotti, M. Papotti, S. Novello, Epidermal growth factor receptor gene in primary tumor and metastatic sites from non-small cell lung cancer. J. Thorac. Oncol. 4, 684–688 (2009)

    Article  PubMed  Google Scholar 

  30. C. Han, H. Zou, J. Ma, Y. Zhou, J. Zhao. [Comparison of EGFR and KRAS status between primary non-small cell lung cancer and corresponding metastases: a systematic review and meta-analysis]. Zhongguo Fei Ai Za Zhi 13, 882–891 (2010)

  31. S.E. Monaco, M.N. Nikiforova, K. Cieply, L.A. Teot, W.E. Khalbuss, S. Dacic, A comparison of EGFR and KRAS status in primary lung carcinoma and matched metastases. Hum. Pathol. 41, 94–102 (2010)

    Article  CAS  PubMed  Google Scholar 

  32. D. Munfus-McCray, S. Harada, C. Adams, F. Askin, D. Clark, E. Gabrielson, Q.K. Li, EGFR and KRAS mutations in metastatic lung adenocarcinomas. Hum. Pathol. 42, 1447–1453 (2011)

    Article  CAS  PubMed  Google Scholar 

  33. N. Zhao, M.D. Wilkerson, U. Shah, X. Yin, A. Wang, M.C. Hayward, P. Roberts, C.B. Lee, A.M. Parsons, L.B. Thorne, B.E. Haithcock, J.E. Grilley-Olson, T.E. Stinchcombe, W.K. Funkhouser, K.K. Wong, N.E. Sharpless, D.N. Hayes, Alterations of LKB1 and KRAS and risk of brain metastasis: Comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer 86, 255–261 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  34. X. Ding, H. Dai, Z. Hui, W. Ji, J. Liang, J. Lv, Z. Zhou, W. Yin, J. He, L. Wang, Risk factors of brain metastases in completely resected pathological stage IIIA-N2 non-small cell lung cancer. Radiat. Oncol. 7, 119 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  35. E.A. Maher, J. Mietz, C.L. Arteaga, R.A. DePinho, S. Mohla, Brain metastasis: Opportunities in basic and translational research. Cancer Res. 69, 6015–6020 (2009)

    Article  CAS  PubMed  Google Scholar 

  36. I.J. Fidler, K. Balasubramanian, Q. Lin, S.W. Kim, S.J. Kim, The brain microenvironment and cancer metastasis. Mol. Cell 30, 93–98 (2010)

    Article  CAS  Google Scholar 

  37. B. Tayyeb, M. Parvin, Pathogenesis of breast cancer metastasis to brain: A comprehensive approach to the signaling network. Mol. Neurobiol. 53, 446–454 (2016)

    Article  CAS  PubMed  Google Scholar 

  38. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: The next generation. Cell 144, 646–674 (2011)

    Article  CAS  PubMed  Google Scholar 

  39. R. Paduch, The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell. Oncol. 39, 397–410 (2016)

    Article  CAS  Google Scholar 

  40. M. S. Wicha, S. Liu, G. Dontu. Cancer stem cells: an old idea--a paradigm shift. Cancer Res 66, 1883–90; discussion 95–6 (2006)

  41. J.P. Thiery, H. Acloque, R.Y. Huang, M.A. Nieto, Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009)

    Article  CAS  PubMed  Google Scholar 

  42. S.A. Mani, W. Guo, M.J. Liao, E.N. Eaton, A. Ayyanan, A.Y. Zhou, M. Brooks, F. Reinhard, C.C. Zhang, M. Shipitsin, L.L. Campbell, K. Polyak, C. Brisken, J. Yang, R.A. Weinberg, The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. T. Reya, S.J. Morrison, M.F. Clarke, I.L. Weissman, Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)

    Article  CAS  PubMed  Google Scholar 

  44. S. Gottschling, P.A. Schnabel, F.J.F. Herth, E. Herpel, Are we missing the target? – Cancer stem cells and drug resistance in non-small cell lung cancer. Cancer Genomics Proteomics 9, 275–286 (2012)

    CAS  PubMed  Google Scholar 

  45. J. Fuxe, T. Vincent, A. Garcia de Herreros, Transcriptional crosstalk between TGF-beta and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes. Cell Cycle 9, 2363–2374 (2010)

    Article  CAS  PubMed  Google Scholar 

  46. S.Y. Shin, O. Rath, A. Zebisch, S.M. Choo, W. Kolch, K.H. Cho, Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res. 70, 6715–6724 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. A. Eger, A. Stockinger, J. Park, E. Langkopf, M. Mikula, J. Gotzmann, W. Mikulits, H. Beug, R. Foisner, beta-Catenin and TGFbeta signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 23, 2672–2680 (2004)

    Article  CAS  PubMed  Google Scholar 

  48. L.A. Timmerman, J. Grego-Bessa, A. Raya, E. Bertran, J.M. Perez-Pomares, J. Diez, S. Aranda, S. Palomo, F. McCormick, J.C. Izpisua-Belmonte, J.L. de la Pompa, Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99–115 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. D. Xiao, J. He, Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2, 154–159 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. B. De Craene, G. Berx, Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97–110 (2013)

    Article  PubMed  CAS  Google Scholar 

  51. U. Valcourt, M. Kowanetz, H. Niimi, C.H. Heldin, A. Moustakas, TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol. Biol. Cell 16, 1987–2002 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. P. Chunhacha, V. Sriuranpong, P. Chanvorachote, Epithelial-mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells. Oncol. Lett. 5, 1043–1047 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. G. Berx, F. van Roy, Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb. Perspect. Biol. 1, a003129 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  54. J.Y. Yoo, S.H. Yang, J.E. Lee, D.G. Cho, H.K. Kim, S.H. Kim, I.S. Kim, J.T. Hong, J.H. Sung, B.C. Son, S.W. Lee, E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model. J. Neuro-Oncol. 109, 219–227 (2012)

    Article  CAS  Google Scholar 

  55. U. Cavallaro, G. Christofori, Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat. Rev. Cancer 4, 118–132 (2004)

    Article  CAS  PubMed  Google Scholar 

  56. H. Grinberg-Rashi, E. Ofek, M. Perelman, J. Skarda, P. Yaron, M. Hajduch, J. Jacob-Hirsch, N. Amariglio, M. Krupsky, D.A. Simansky, Z. Ram, R. Pfeffer, I. Galernter, D.M. Steinberg, I. Ben-Dov, G. Rechavi, S. Izraeli, The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin. Cancer Res. 15, 1755–1761 (2009)

    Article  CAS  PubMed  Google Scholar 

  57. M. Dauphin, C. Barbe, S. Lemaire, B. Nawrocki-Raby, E. Lagonotte, G. Delepine, P. Birembaut, C. Gilles, M. Polette, Vimentin expression predicts the occurrence of metastases in non small cell lung carcinomas. Lung Cancer 81, 117–122 (2013)

    Article  PubMed  Google Scholar 

  58. M. Polette, C. Gilles, S. de Bentzmann, D. Gruenert, J.M. Tournier, P. Birembaut, Association of fibroblastoid features with the invasive phenotype in human bronchial cancer cell lines. Clin. Exp. Metastasis 16, 105–112 (1998)

    Article  CAS  PubMed  Google Scholar 

  59. R.L. Yauch, T. Januario, D.A. Eberhard, G. Cavet, W. Zhu, L. Fu, T.Q. Pham, R. Soriano, J. Stinson, S. Seshagiri, Z. Modrusan, C.Y. Lin, V. O'Neill, L.C. Amler, Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin. Cancer Res. 11, 8686–8698 (2005)

    Article  CAS  PubMed  Google Scholar 

  60. S. Thomson, E. Buck, F. Petti, G. Griffin, E. Brown, N. Ramnarine, K.K. Iwata, N. Gibson, J.D. Haley, Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 65, 9455–9462 (2005)

    Article  CAS  PubMed  Google Scholar 

  61. X. Sun, P. Fa, Z. Cui, Y. Xia, L. Sun, Z. Li, A. Tang, Y. Gui, Z. Cai, The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin alpha9beta1-mediated activation of PI3-K/AKT and Erk1/2. Carcinogenesis 35, 184–191 (2014)

    Article  CAS  PubMed  Google Scholar 

  62. S. Singh, S. Chellappan, Lung cancer stem cells: Molecular features and therapeutic targets. Mol. Asp. Med. 39, 50–60 (2014)

    Article  CAS  Google Scholar 

  63. L.S. Orlichenko, D.C. Radisky, Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin. Exp. Metastasis 25, 593–600 (2008)

    Article  CAS  PubMed  Google Scholar 

  64. J.P. Thiery, J.P. Sleeman, Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7, 131–142 (2006)

    Article  CAS  PubMed  Google Scholar 

  65. B. De Craene, B. Gilbert, C. Stove, E. Bruyneel, F. van Roy, G. Berx, The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 65, 6237–6244 (2005)

    Article  PubMed  Google Scholar 

  66. J.P. Thiery, Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002)

    Article  CAS  PubMed  Google Scholar 

  67. K.R. Fischer, A. Durrans, S. Lee, J. Sheng, F. Li, S.T. Wong, H. Choi, T. El Rayes, S. Ryu, J. Troeger, R.F. Schwabe, L.T. Vahdat, N.K. Altorki, V. Mittal, D. Gao, Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. X. Zheng, J.L. Carstens, J. Kim, M. Scheible, J. Kaye, H. Sugimoto, C.C. Wu, V.S. LeBleu, R. Kalluri, Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. J.E. Chu, A.L. Allan, The role of cancer stem cells in the organ tropism of breast cancer metastasis: A mechanistic balance between the "seed" and the "soil"? Intl. J. Breast Cancer 2012, 209748 (2012)

    Google Scholar 

  70. L.F. Brown, B. Berse, L. Van de Water, A. Papadopoulos-Sergiou, C.A. Perruzzi, E.J. Manseau, H.F. Dvorak, D.R. Senger, Expression and distribution of osteopontin in human tissues: Widespread association with luminal epithelial surfaces. Mol. Biol. Cell 3, 1169–1180 (1992)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. J.E. Draffin, S. McFarlane, A. Hill, P.G. Johnston, D.J. Waugh, CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res. 64, 5702–5711 (2004)

    Article  CAS  PubMed  Google Scholar 

  72. M.Z. Dewan, S. Ahmed, Y. Iwasaki, K. Ohba, M. Toi, N. Yamamoto. Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed. Pharmacother. 60, 273–276 (2006)

  73. B. Furusato, A. Mohamed, M. Uhlen, J.S. Rhim, CXCR4 and cancer. Pathol. Int. 60, 497–505 (2010)

    Article  CAS  PubMed  Google Scholar 

  74. H.A. Kargi, M.F. Kuyucuoglu, M. Alakavuklar, O. Akpinar, S. Erk, CD44 expression in metastatic and non-metastatic non-small cell lung cancers. Cancer Lett. 119, 27–30 (1997)

    Article  CAS  PubMed  Google Scholar 

  75. A. Salmaggi, E. Maderna, C. Calatozzolo, P. Gaviani, A. Canazza, I. Milanesi, A. Silvani, F. DiMeco, A. Carbone, B. Pollo, CXCL12, CXCR4 and CXCR7 expression in brain metastases. Cancer Biol Ther 8, 1608–1614 (2009)

    Article  CAS  PubMed  Google Scholar 

  76. K.R. Hess, G.R. Varadhachary, S.H. Taylor, W. Wei, M.N. Raber, R. Lenzi, J.L. Abbruzzese, Metastatic patterns in adenocarcinoma. Cancer 106, 1624–1633 (2006)

    Article  PubMed  Google Scholar 

  77. A.C. Obenauf, J. Massague, Surviving at a distance: Organ specific metastasis. Trends Cancer 1, 76–91 (2015)

    Article  PubMed Central  Google Scholar 

  78. R.R. Langley, I.J. Fidler, The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs. Int. J. Cancer 128, 2527–2535 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. H. Sugiura, K. Yamada, T. Sugiura, T. Hida, T. Mitsudomi, Predictors of survival in patients with bone metastasis of lung cancer. Clin. Orthop. Relat. Res. 466, 729–736 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  80. L.E. Gaspar, Brain metastases in lung cancer. Expert. Rev. Anticancer. Ther. 4, 259–270 (2004)

    Article  CAS  PubMed  Google Scholar 

  81. N.J. Abbott, L. Ronnback, E. Hansson, Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006)

    Article  CAS  PubMed  Google Scholar 

  82. B. Li, W.D. Zhao, Z.M. Tan, W.G. Fang, L. Zhu, Y.H. Chen, Involvement of rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett. 580, 4252–4260 (2006)

    Article  CAS  PubMed  Google Scholar 

  83. B. Wojciak-Stothard, A.J. Ridley, Rho GTPases and the regulation of endothelial permeability. Vasc. Pharmacol. 39, 187–199 (2002)

    Article  CAS  Google Scholar 

  84. J. JuanYin, K. Tracy, L. Zhang, J. Munasinghe, E. Shapiro, A. Koretsky, K. Kelly, Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model. Clin. Exp. Metastasis 26, 403–414 (2009)

    Article  CAS  PubMed  Google Scholar 

  85. M. Lorger, B. Felding-Habermann, Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am. J. Pathol. 176, 2958–2971 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  86. L. Sevenich, R.L. Bowman, S.D. Mason, D.F. Quail, F. Rapaport, B.T. Elie, E. Brogi, P.K. Brastianos, W.C. Hahn, L.J. Holsinger, J. Massague, C.S. Leslie, J.A. Joyce, Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876–888 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. P.D. Bos, X.H. Zhang, C. Nadal, W. Shu, R.R. Gomis, D.X. Nguyen, A.J. Minn, M.J. van de Vijver, W.L. Gerald, J.A. Foekens, J. Massague, Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. W. Zhou, M.Y. Fong, Y. Min, G. Somlo, L. Liu, M.R. Palomares, Y. Yu, A. Chow, S.T. O'Connor, A.R. Chin, Y. Yen, Y. Wang, E.G. Marcusson, P. Chu, J. Wu, X. Wu, A.X. Li, Z. Li, H. Gao, X. Ren, M.P. Boldin, P.C. Lin, S.E. Wang, Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. N. Tominaga, N. Kosaka, M. Ono, T. Katsuda, Y. Yoshioka, K. Tamura, J. Lotvall, H. Nakagama, T. Ochiya, Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat. Commun. 6, 6716 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. J.F. Deeken, W. Loscher, The blood-brain barrier and cancer: Transporters, treatment, and Trojan horses. Clin. Cancer Res. 13, 1663–1674 (2007)

    Article  CAS  PubMed  Google Scholar 

  91. A. Regina, M. Demeule, A. Laplante, J. Jodoin, C. Dagenais, F. Berthelet, A. Moghrabi, R. Beliveau, Multidrug resistance in brain tumors: Roles of the blood-brain barrier. Cancer Metastasis Rev. 20, 13–25 (2001)

    Article  CAS  PubMed  Google Scholar 

  92. Y. Kienast, L. von Baumgarten, M. Fuhrmann, W.E. Klinkert, R. Goldbrunner, J. Herms, F. Winkler, Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010)

    Article  CAS  PubMed  Google Scholar 

  93. J. Massague, A.C. Obenauf, Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. D. Spano, M. Zollo, Tumor microenvironment: A main actor in the metastasis process. Clin. Exp. Metastasis 29, 381–395 (2012)

    Article  CAS  PubMed  Google Scholar 

  95. H. Fazilaty, M. Gardaneh, T. Bahrami, A. Salmaninejad, B. Behnam, Crosstalk between breast cancer stem cells and metastatic niche: Emerging molecular metastasis pathway? Tumour Biol. 34, 2019–2030 (2013)

    Article  CAS  PubMed  Google Scholar 

  96. S.J. Morrison, A.C. Spradling, Stem cells and niches: Mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Y.C. Hsu, L. Li, E. Fuchs, Emerging interactions between skin stem cells and their niches. Nat. Med. 20, 847–856 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. T. Oskarsson, E. Batlle, J. Massague, Metastatic stem cells: Sources, niches, and vital pathways. Cell Stem Cell 14, 306–321 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. W.S. Carbonell, O. Ansorge, N. Sibson, R. Muschel, The vascular basement membrane as "soil" in brain metastasis. PLoS One 4, e5857 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. M. Valiente, A.C. Obenauf, X. Jin, Q. Chen, X.H. Zhang, D.J. Lee, J.E. Chaft, M.G. Kris, J.T. Huse, E. Brogi, J. Massague, Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. S.W. Kim, H.J. Choi, H.J. Lee, J. He, Q. Wu, R.R. Langley, I.J. Fidler, S.J. Kim, Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells. Neuro-Oncology 16, 1585–1598 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Q. Chen, A. Boire, X. Jin, M. Valiente, E.E. Er, A. Lopez-Soto, L.S. Jacob, R. Patwa, H. Shah, K. Xu, J.R. Cross, J. Massague, Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. S.S. McAllister, R.A. Weinberg, The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 16, 717–727 (2014)

    Article  CAS  PubMed  Google Scholar 

  104. D.R. Edwards, M.M. Handsley, C.J. Pennington, The ADAM metalloproteinases. Mol. Asp. Med. 29, 258–289 (2008)

    Article  CAS  Google Scholar 

  105. N. Rocks, G. Paulissen, M. El Hour, F. Quesada, C. Crahay, M. Gueders, J.M. Foidart, A. Noel, D. Cataldo, Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie 90, 369–379 (2008)

    Article  CAS  PubMed  Google Scholar 

  106. Y. Shintani, S. Higashiyama, M. Ohta, H. Hirabayashi, S. Yamamoto, T. Yoshimasu, H. Matsuda, N. Matsuura, Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 64, 4190–4196 (2004)

    Article  CAS  PubMed  Google Scholar 

  107. M. Noda, T. Seike, K. Fujita, Y. Yamakawa, M. Kido, H. Iguchi, The role of immune cells in brain metastasis of lung cancer cells and neuron-tumor cell interaction. Ross. Fiziol. Zh. Im. I M Sechenova 95, 1386–1396 (2009)

    CAS  PubMed  Google Scholar 

  108. S. Feng, J. Cen, Y. Huang, H. Shen, L. Yao, Y. Wang, Z. Chen, Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS One 6, e20599 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. L. Hu, J. Zhang, H. Zhu, J. Min, Y. Feng, H. Zhang, Biological characteristics of a specific brain metastatic cell line derived from human lung adenocarcinoma. Med. Oncol. 27, 708–714 (2010)

    Article  PubMed  CAS  Google Scholar 

  110. E.C. Keeley, B. Mehrad, R.M. Strieter, CXC chemokines in cancer angiogenesis and metastases. Adv. Cancer Res. 106, 91–111 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. S. Paratore, G.L. Banna, M. D'Arrigo, S. Saita, R. Iemmolo, L. Lucenti, D. Bellia, H. Lipari, C. Buscarino, R. Cunsolo, S. Cavallaro, CXCR4 and CXCL12 immunoreactivities differentiate primary non-small-cell lung cancer with or without brain metastases. Cancer Biomark 10, 79–89 (2011)

    Article  CAS  PubMed  Google Scholar 

  112. G. Chen, Z. Wang, X.Y. Liu, F.Y. Liu, High-level CXCR4 expression correlates with brain-specific metastasis of non-small cell lung cancer. World J. Surg. 35, 56–61 (2011)

    Article  PubMed  Google Scholar 

  113. T.N. Hartmann, J.A. Burger, A. Glodek, N. Fujii, M. Burger, CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 24, 4462–4471 (2005)

    Article  CAS  PubMed  Google Scholar 

  114. F.A. Mauri, D.J. Pinato, P. Trivedi, R. Sharma, R.J. Shiner, Isogeneic comparison of primary and metastatic lung cancer identifies CX3CR1 as a molecular determinant of site-specific metastatic diffusion. Oncol. Rep. 28, 647–653 (2012)

    Article  PubMed  Google Scholar 

  115. H. Mir, R. Singh, G.H. Kloecker, J.W. Lillard Jr., S. Singh, CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases. Oncotarget 6, 9985–9998 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  116. T. Seike, K. Fujita, Y. Yamakawa, M.A. Kido, S. Takiguchi, N. Teramoto, H. Iguchi, M. Noda, Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin. Exp. Metastasis 28, 13–25 (2011)

    Article  CAS  PubMed  Google Scholar 

  117. H. Peinado, M. Aleckovic, S. Lavotshkin, I. Matei, B. Costa-Silva, G. Moreno-Bueno, M. Hergueta-Redondo, C. Williams, G. Garcia-Santos, C. Ghajar, A. Nitadori-Hoshino, C. Hoffman, K. Badal, B.A. Garcia, M.K. Callahan, J. Yuan, V.R. Martins, J. Skog, R.N. Kaplan, M.S. Brady, J.D. Wolchok, P.B. Chapman, Y. Kang, J. Bromberg, D. Lyden, Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. A. Caivano, F. La Rocca, V. Simeon, M. Girasole, S. Dinarelli, I. Laurenzana, A. De Stradis, L. De Luca, S. Trino, A. Traficante, G. D'Arena, G. Mansueto, O. Villani, G. Pietrantuono, L. Laurenti, L. Del Vecchio, P. Musto, MicroRNA-155 in serum-derived extracellular vesicles as a potential biomarker for hematologic malignancies - a short report. Cell. Oncol. 40, 97–103 (2017)

    Article  CAS  Google Scholar 

  119. B. Costa-Silva, N.M. Aiello, A.J. Ocean, S. Singh, H. Zhang, B.K. Thakur, A. Becker, A. Hoshino, M.T. Mark, H. Molina, J. Xiang, T. Zhang, T.M. Theilen, G. Garcia-Santos, C. Williams, Y. Ararso, Y. Huang, G. Rodrigues, T.L. Shen, K.J. Labori, I.M. Lothe, E.H. Kure, J. Hernandez, A. Doussot, S.H. Ebbesen, P.M. Grandgenett, M.A. Hollingsworth, M. Jain, K. Mallya, S.K. Batra, W.R. Jarnagin, R.E. Schwartz, I. Matei, H. Peinado, B.Z. Stanger, J. Bromberg, D. Lyden, Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015)

    Article  CAS  PubMed  Google Scholar 

  120. A. Hoshino, B. Costa-Silva, T.L. Shen, G. Rodrigues, A. Hashimoto, M. Tesic Mark, H. Molina, S. Kohsaka, A. Di Giannatale, S. Ceder, S. Singh, C. Williams, N. Soplop, K. Uryu, L. Pharmer, T. King, L. Bojmar, A.E. Davies, Y. Ararso, T. Zhang, H. Zhang, J. Hernandez, J.M. Weiss, V.D. Dumont-Cole, K. Kramer, L.H. Wexler, A. Narendran, G.K. Schwartz, J.H. Healey, P. Sandstrom, K.J. Labori, E.H. Kure, P.M. Grandgenett, M.A. Hollingsworth, M. de Sousa, S. Kaur, M. Jain, K. Mallya, S.K. Batra, W.R. Jarnagin, M.S. Brady, O. Fodstad, V. Muller, K. Pantel, A.J. Minn, M.J. Bissell, B.A. Garcia, Y. Kang, V.K. Rajasekhar, C.M. Ghajar, I. Matei, H. Peinado, J. Bromberg, D. Lyden, Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Y. Liu, X. Cao, Organotropic metastasis: Role of tumor exosomes. Cell Res. 26, 149–150 (2016)

    Article  CAS  PubMed  Google Scholar 

  122. L. Zhang, S. Zhang, J. Yao, F.J. Lowery, Q. Zhang, W.C. Huang, P. Li, M. Li, X. Wang, C. Zhang, H. Wang, K. Ellis, M. Cheerathodi, J.H. McCarty, D. Palmieri, J. Saunus, S. Lakhani, S. Huang, A.A. Sahin, K.D. Aldape, P.S. Steeg, D. Yu, Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. G. Improta, A. Zupa, H. Fillmore, J. Deng, M. Aieta, P. Musto, L.A. Liotta, W. Broaddus, E.F. Petricoin 3rd, J.D. Wulfkuhle, Protein pathway activation mapping of brain metastasis from lung and breast cancers reveals organ type specific drug target activation. J. Proteome Res. 10, 3089–3097 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. M. Sun, C. Behrens, L. Feng, N. Ozburn, X. Tang, G. Yin, R. Komaki, M. Varella-Garcia, W. K. Hong, K. D. Aldape, Wistuba, II. HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors Clin. Cancer Res. 15, 4829–37 (2009)

  125. G.M. Stella, S. Benvenuti, P.M. Comoglio, Targeting the MET oncogene in cancer and metastases. Expert Opin. Investig. Drugs 19, 1381–1394 (2010)

    Article  CAS  PubMed  Google Scholar 

  126. K. Tsuta, Y. Kozu, T. Mimae, A. Yoshida, T. Kohno, I. Sekine, T. Tamura, H. Asamura, K. Furuta, H. Tsuda. c-MET/phospho-MET protein expression and MET gene copy number in non-small cell lung carcinomas. J Thorac Oncol 7, 331–9 (2012)

  127. J.A. Engelman, K. Zejnullahu, T. Mitsudomi, Y. Song, C. Hyland, J.O. Park, N. Lindeman, C.M. Gale, X. Zhao, J. Christensen, T. Kosaka, A.J. Holmes, A.M. Rogers, F. Cappuzzo, T. Mok, C. Lee, B.E. Johnson, L.C. Cantley, P.A. Janne, MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007)

    Article  CAS  PubMed  Google Scholar 

  128. J. Bean, C. Brennan, J.Y. Shih, G. Riely, A. Viale, L. Wang, D. Chitale, N. Motoi, J. Szoke, S. Broderick, M. Balak, W.C. Chang, C.J. Yu, A. Gazdar, H. Pass, V. Rusch, W. Gerald, S.F. Huang, P.C. Yang, V. Miller, M. Ladanyi, C.H. Yang, W. Pao, MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. U. S. A. 104, 20932–20937 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. S. Yano, W. Wang, Q. Li, K. Matsumoto, H. Sakurama, T. Nakamura, H. Ogino, S. Kakiuchi, M. Hanibuchi, Y. Nishioka, H. Uehara, T. Mitsudomi, Y. Yatabe, T. Nakamura, S. Sone, Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479–9487 (2008)

    Article  CAS  PubMed  Google Scholar 

  130. E. Benedettini, L.M. Sholl, M. Peyton, J. Reilly, C. Ware, L. Davis, N. Vena, D. Bailey, B.Y. Yeap, M. Fiorentino, A.H. Ligon, B.S. Pan, V. Richon, J.D. Minna, A.F. Gazdar, G. Draetta, S. Bosari, L.R. Chirieac, B. Lutterbach, M. Loda, Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am. J. Pathol. 177, 415–423 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. S. Yano, H. Shinohara, R.S. Herbst, H. Kuniyasu, C.D. Bucana, L.M. Ellis, D.W. Davis, D.J. McConkey, I.J. Fidler, Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res. 60, 4959–4967 (2000)

    CAS  PubMed  Google Scholar 

  132. A.M. Jubb, A. Cesario, M. Ferguson, M.T. Congedo, K.C. Gatter, F. Lococo, A. Mule, F. Pezzella, Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. Br. J. Cancer 104, 1877–1881 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. B. Li, C. Wang, Y. Zhang, X.Y. Zhao, B. Huang, P.F. Wu, Q. Li, H. Li, Y.S. Liu, L.Y. Cao, W.M. Dai, W.G. Fang, D.S. Shang, L. Cao, W.D. Zhao, Y.H. Chen, Elevated PLGF contributes to small-cell lung cancer brain metastasis. Oncogene 32, 2952–2962 (2013)

    Article  CAS  PubMed  Google Scholar 

  134. S. Jothy, CD44 and its partners in metastasis. Clin. Exp. Metastasis 20, 195–201 (2003)

    Article  CAS  PubMed  Google Scholar 

  135. H.K. Shabani, G. Kitange, K. Tsunoda, T. Anda, Y. Tokunaga, S. Shibata, M. Kaminogo, T. Hayashi, H. Ayabe, M. Iseki, Immunohistochemical expression of E-cadherin in metastatic brain tumors. Brain Tumor Pathol. 20, 7–12 (2003)

  136. J.S. Desgrosellier, D.A. Cheresh, Integrins in cancer: Biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9–22 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. T. Yoshimasu, T. Sakurai, S. Oura, I. Hirai, H. Tanino, Y. Kokawa, Y. Naito, Y. Okamura, I. Ota, N. Tani, N. Matsuura, Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line. Cancer Sci. 95, 142–148 (2004)

    Article  CAS  PubMed  Google Scholar 

  138. I. Wilhelm, J. Molnar, C. Fazakas, J. Hasko, I.A. Krizbai, Role of the blood-brain barrier in the formation of brain metastases. Int. J. Mol. Sci. 14, 1383–1411 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. E. Sipos, L. Chen, I.E. Andras, J. Wrobel, B. Zhang, H. Pu, M. Park, S.Y. Eum, M. Toborek, Proinflammatory adhesion molecules facilitate polychlorinated biphenyl-mediated enhancement of brain metastasis formation. Toxicol. Sci. 126, 362–371 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. E. Huntzinger, E. Izaurralde, Gene silencing by microRNAs: Contributions of translational repression and mRNA decay. Nat. Rev. Genet. 12, 99–110 (2011)

    Article  CAS  PubMed  Google Scholar 

  141. G.S. Markopoulos, E. Roupakia, M. Tokamani, E. Chavdoula, M. Hatziapostolou, C. Polytarchou, K.B. Marcu, A.G. Papavassiliou, R. Sandaltzopoulos, E. Kolettas, A step-by-step microRNA guide to cancer development and metastasis. Cell. Oncol. 40, 303–339 (2017)

    Article  CAS  Google Scholar 

  142. S.A. Melo, M. Esteller, Dysregulation of microRNAs in cancer: Playing with fire. FEBS Lett. 585, 2087–2099 (2011)

    Article  CAS  PubMed  Google Scholar 

  143. G.A. Calin, C. Sevignani, C.D. Dumitru, T. Hyslop, E. Noch, S. Yendamuri, M. Shimizu, S. Rattan, F. Bullrich, M. Negrini, C.M. Croce, Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci. U. S. A. 101, 2999–3004 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. S. Alsidawi, E. Malek, J.J. Driscoll, MicroRNAs in brain metastases: Potential role as diagnostics and therapeutics. Int. J. Mol. Sci. 15, 10508–10526 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. A.T. Grupenmacher, A.L. Halpern, F. Bonaldo Mde, C.C. Huang, C.A. Hamm, A. de Andrade, T. Tomita, S.T. Sredni, Study of the gene expression and microRNA expression profiles of malignant rhabdoid tumors originated in the brain (AT/RT) and in the kidney (RTK). Childs Nerv. Syst. 29, 1977–1983 (2013)

    Article  PubMed  Google Scholar 

  146. L.T. Chen, S.D. Xu, H. Xu, J.F. Zhang, J.F. Ning, S.F. Wang, MicroRNA-378 is associated with non-small cell lung cancer brain metastasis by promoting cell migration, invasion and tumor angiogenesis. Med. Oncol. 29, 1673–1680 (2012)

    Article  CAS  PubMed  Google Scholar 

  147. N.M. Teplyuk, B. Mollenhauer, G. Gabriely, A. Giese, E. Kim, M. Smolsky, R.Y. Kim, M.G. Saria, S. Pastorino, S. Kesari, A.M. Krichevsky, MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro-Oncology 14, 689–700 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. S. Arora, A.R. Ranade, N.L. Tran, S. Nasser, S. Sridhar, R.L. Korn, J.T. Ross, H. Dhruv, K.M. Foss, Z. Sibenaller, T. Ryken, M.B. Gotway, S. Kim, G.J. Weiss, MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration. Int. J. Cancer 129, 2621–2631 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. C.Y. Cheng, H.L. Hsieh, C.C. Sun, C.C. Lin, S.F. Luo, C.M. Yang, IL-1 beta induces urokinase-plasminogen activator expression and cell migration through PKC alpha, JNK1/2, and NF-kappaB in A549 cells. J. Cell. Physiol. 219, 183–193 (2009)

    Article  CAS  PubMed  Google Scholar 

  150. A. Subramani, S. Alsidawi, S. Jagannathan, K. Sumita, A.T. Sasaki, B. Aronow, R.E. Warnick, S. Lawler, J.J. Driscoll, The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis. Sci Rep 3, 2392 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  151. C. Zhao, Y. Xu, Y. Zhang, W. Tan, J. Xue, Z. Yang, Y. Lu, X. Hu, Downregulation of miR-145 contributes to lung adenocarcinoma cell growth to form brain metastases. Oncol. Rep. 30, 2027–2034 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. S.J. Hwang, H.J. Seol, Y.M. Park, K.H. Kim, M. Gorospe, D.H. Nam, H.H. Kim, MicroRNA-146a suppresses metastatic activity in brain metastasis. Mol. Cell 34, 329–334 (2012)

    Article  CAS  Google Scholar 

  153. G. Chen, I. A. Umelo, S. Lv, E. Teugels, K. Fostier, P. Kronenberger, A. Dewaele, J. Sadones, C. Geers, J. De Greve. miR-146a inhibits cell growth, cell migration and induces apoptosis in non-small cell lung cancer cells. PLoS One 8, e60317 (2013)

  154. J. Remon, D. Alvarez-Berdugo, M. Majem, T. Moran, N. Reguart, P. Lianes. miRNA-197 and miRNA-184 are associated with brain metastasis in EGFR-mutant lung cancers. Clin. Transl. Oncol. 18, 153–9 (2016)

  155. S.J. Hwang, H.W. Lee, H.R. Kim, H.J. Song, D.H. Lee, H. Lee, C.H. Shin, J.G. Joung, D.H. Kim, K.M. Joo, H.H. Kim, Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1. Oncotarget 6, 20434–20448 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  156. T. Gutschner, S. Diederichs, The hallmarks of cancer: A long non-coding RNA point of view. RNA Biol. 9, 703–719 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. M.C. Tsai, R.C. Spitale, H.Y. Chang, Long intergenic noncoding RNAs: New links in cancer progression. Cancer Res. 71, 3–7 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. M. Vitiello, A. Tuccoli, L. Poliseno, Long non-coding RNAs in cancer: Implications for personalized therapy. Cell. Oncol. 38, 17–28 (2015)

    Article  CAS  Google Scholar 

  159. R.A. Gupta, N. Shah, K.C. Wang, J. Kim, H.M. Horlings, D.J. Wong, M.C. Tsai, T. Hung, P. Argani, J.L. Rinn, Y. Wang, P. Brzoska, B. Kong, R. Li, R.B. West, M.J. van de Vijver, S. Sukumar, H.Y. Chang, Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. S. Sharma Saha, R. Roy Chowdhury, N.R. Mondal, B. Chakravarty, T. Chatterjee, S. Roy, S. Sengupta, Identification of genetic variation in the lncRNA HOTAIR associated with HPV16-related cervical cancer pathogenesis. Cell. Oncol. 39, 559–572 (2016)

    Article  CAS  Google Scholar 

  161. F.Q. Nie, M. Sun, J.S. Yang, M. Xie, T.P. Xu, R. Xia, Y.W. Liu, X.H. Liu, E.B. Zhang, K.H. Lu, Y.Q. Shu, Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol. Cancer Ther. 14, 268–277 (2015)

    Article  CAS  PubMed  Google Scholar 

  162. T. Gutschner, M. Hammerle, S. Diederichs, MALAT1 -- a paradigm for long noncoding RNA function in cancer. J. Mol. Med. 91, 791–801 (2013)

    Article  CAS  PubMed  Google Scholar 

  163. L. Shen, L. Chen, Y. Wang, X. Jiang, H. Xia, Z. Zhuang, Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer. J. Neuro-Oncol. 121, 101–108 (2015)

    Article  CAS  Google Scholar 

  164. A. Stoffel, Targeted therapies for solid tumors. BioDrugs 24, 303–316 (2010)

    Article  CAS  PubMed  Google Scholar 

  165. A. Chi, R. Komaki, Treatment of brain metastasis from lung cancer. Cancer 2, 2100–2137 (2010)

    Article  CAS  Google Scholar 

  166. D.-B. Chang, P.-C. Yang, K.-T. Luh, S.-H. Kuo, R.-L. Hong, L.-N. Lee, Late survival of non-small cell lung cancer patients with brain metastases. Influence of treatment. CHEST J. 101, 1293–1297 (1992)

  167. P. Richards, W. McKissock, Intracranial metastases. Br. Med. J. 1, 15 (1963)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. A. Zabel, J. Debus, Treatment of brain metastases from non-small-cell lung cancer (NSCLC): Radiotherapy. Lung Cancer 45, S247–SS52 (2004)

    Article  PubMed  Google Scholar 

  169. R. Soffietti, A. Costanza, E. Laguzzi, M. Nobile, R. Ruda, Radiotherapy and chemotherapy of brain metastases. J. Neuro-Oncol. 75, 31–42 (2005)

    Article  CAS  Google Scholar 

  170. W.A. Castrucci, J.P. Knisely, An update on the treatment of CNS metastases in small cell lung cancer. Cancer J. 14, 138–146 (2008)

    Article  PubMed  Google Scholar 

  171. J.P. Sheehan, M.-H. Sun, D. Kondziolka, J. Flickinger, L.D. Lunsford, Radiosurgery for non-small cell lung carcinoma metastatic to the brain: Long-term outcomes and prognostic factors influencing patient survival time and local tumor control. J. Neurosurg. 97, 1276–1281 (2002)

    Article  PubMed  Google Scholar 

  172. R.A. Patchell, P.A. Tibbs, J.W. Walsh, R.J. Dempsey, Y. Maruyama, R.J. Kryscio, W.R. Markesbery, J.S. Macdonald, B. Young, A randomized trial of surgery in the treatment of single metastases to the brain. N. Engl. J. Med. 322, 494–500 (1990)

    Article  CAS  PubMed  Google Scholar 

  173. E. M. Noordijk, C. J. Vecht, H. Haaxma-Reiche, G. W. Padberg, J. H. Voormolen, F. H. Hoekstra, J. T. J. Tans, N. Lambooij, J. A. Metsaars, A. R. Wattendorff. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. International Journal of Radiation Oncology* Biology* Physics 29, 711–7 (1994)

  174. R.A. Patchell, P.A. Tibbs, W.F. Regine, R.J. Dempsey, M. Mohiuddin, R.J. Kryscio, W.R. Markesbery, K.A. Foon, B. Young, Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA 280, 1485–1489 (1998)

    Article  CAS  PubMed  Google Scholar 

  175. M.A. Chidel, J.H. Suh, J.F. Greskovich, P.A. Kupelian, G.H. Barnett, Treatment outcome for patients with primary nonsmall-cell lung cancer and synchronous brain metastasis. Radiat. Oncol. Investig. 7, 313–319 (1999)

    Article  CAS  PubMed  Google Scholar 

  176. J.H. Suh, Stereotactic radiosurgery for the management of brain metastases. N. Engl. J. Med. 362, 1119–1127 (2010)

    Article  CAS  PubMed  Google Scholar 

  177. H. Aoyama, H. Shirato, M. Tago, K. Nakagawa, T. Toyoda, K. Hatano, M. Kenjyo, N. Oya, S. Hirota, H. Shioura, Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA 295, 2483–2491 (2006)

    Article  CAS  PubMed  Google Scholar 

  178. H. Qin, C. Wang, Y. Jiang, X. Zhang, Y. Zhang, Z. Ruan, Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: A systematic review. Med. Sci. Monit Intern. Med. J. Exp. Clin. Res. 21, 144 (2015)

    Google Scholar 

  179. R. Hoffman, P. K. Sneed, M. W. McDermott, S. Chang, K. R. Lamborn, E. Park, W. Wara, D. A. Larson. Radiosurgery for brain metastases from primary lung carcinoma. Cancer J. (Sudbury, Mass) 7, 121–31 (2000)

  180. W. F. Regine, J. L. Huhn, R. A. Patchell, W. H. S. Clair, J. Strottmann, A. Meigooni, M. Sanders, A. B. Young. Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagonised brain metastases: results and implications. Int. J. Radiat. Oncol. Biol. Phys. 52, 333–8 (2002)

  181. B. Li, J. Yu, M. Suntharalingam, A.S. Kennedy, P.P. Amin, Z. Chen, R. Yin, S. Guo, T. Han, Y. Wang, Comparison of three treatment options for single brain metastasis from lung cancer. Int. J. Cancer 90, 37–45 (2000)

    Article  CAS  PubMed  Google Scholar 

  182. Z. Wang, Y. Li, A. Ahmad, A.S. Azmi, D. Kong, S. Banerjee, F.H. Sarkar, Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist. Updat. 13, 109–118 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. D.S. Ettinger, W. Akerley, H. Borghaei, A.C. Chang, R.T. Cheney, L.R. Chirieac, T.A. D’Amico, T.L. Demmy, A.K.P. Ganti, R. Govindan, Non–small cell lung cancer. J. Natl. Compr. Cancer Netw. 10, 1236–1271 (2012)

    Article  CAS  Google Scholar 

  184. H.B. Newton, M.A. Slivka, C. Volpi, E.C. Bourekas, G.A. Christoforidis, M.A. Baujan, W. Slone, D.W. Chakeres, Intra-arterial carboplatin and intravenous etoposide for the treatment of metastatic brain tumors. J. Neuro-Oncol. 61, 35–44 (2003)

    Article  Google Scholar 

  185. D. Fortin, C. Gendron, M. Boudrias, M.P. Garant, Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in the treatment of cerebral metastasis. Cancer 109, 751–760 (2007)

    Article  CAS  PubMed  Google Scholar 

  186. L.E. Abrey, J.D. Olson, J.J. Raizer, M. Mack, A. Rodavitch, D.Y. Boutros, M.G. Malkin, A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J. Neuro-Oncol. 53, 259–265 (2001)

    Article  CAS  Google Scholar 

  187. E.R. Gerstner, R.L. Fine, Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: Establishing a treatment paradigm. J. Clin. Oncol. 25, 2306–2312 (2007)

    Article  PubMed  Google Scholar 

  188. W. Schuette, Treatment of brain metastases from lung cancer: Chemotherapy. Lung Cancer 45, S253–S2S7 (2004)

    Article  PubMed  Google Scholar 

  189. N. Zakaria, N.A. Satar, N.H. Abu Halim, S.H. Ngalim, N.M. Yusoff, J. Lin, B.H. Yahaya, Targeting lung cancer stem cells: Research and clinical impacts. Front. Oncol. 7 (2017)

  190. H. Yue, D. Huang, L. Qin, Z. Zheng, L. Hua, G. Wang, J. Huang, H. Huang, Targeting lung cancer stem cells with antipsychological drug thioridazine. Biomed Res Int 2016, 1–7 (2016)

  191. N. Zakaria, N.M. Yusoff, Z. Zakaria, M.N. Lim, P.J.N. Baharuddin, K.S. Fakiruddin, B. Yahaya, Human non-small cell lung cancer expresses putative cancer stem cell markers and exhibits the transcriptomic profile of multipotent cells. BMC Cancer 15, 84 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. T. Borovski, E.M.F. De Sousa, L. Vermeulen, J.P. Medema, Cancer stem cell niche: The place to be. Cancer Res. 71, 634–639 (2011)

    Article  CAS  PubMed  Google Scholar 

  193. C. Calabrese, H. Poppleton, M. Kocak, T.L. Hogg, C. Fuller, B. Hamner, E.Y. Oh, M.W. Gaber, D. Finklestein, M. Allen, A. Frank, I.T. Bayazitov, S.S. Zakharenko, A. Gajjar, A. Davidoff, R.J. Gilbertson, A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007)

    Article  CAS  PubMed  Google Scholar 

  194. Y. Zheng, C.C. de la Cruz, L.C. Sayles, C. Alleyne-Chin, D. Vaka, T.D. Knaak, M. Bigos, Y. Xu, C.D. Hoang, J.B. Shrager, H.J. Fehling, D. French, W. Forrest, Z. Jiang, R.A. Carano, K.H. Barck, E.L. Jackson, E.A. Sweet-Cordero, A rare population of CD24(+)ITGB4(+)notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal. Cancer Cell 24, 59–74 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. H.L. Goel, T. Gritsko, B. Pursell, C. Chang, L.D. Shultz, D.L. Greiner, J.H. Norum, R. Toftgard, L.M. Shaw, A.M. Mercurio, Regulated splicing of the alpha6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. Cell Rep. 7, 747–761 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. E. Dickreuter, I. Eke, M. Krause, K. Borgmann, M.A. van Vugt, N. Cordes, Targeting of beta1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells. Oncogene 35, 1353–1362 (2016)

    Article  CAS  PubMed  Google Scholar 

  197. A. Voulgari, A. Pintzas, Epithelial–mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta (BBA)-reviews on Cancer 1796, 75–90 (2009)

  198. S. Singh, S. Chellappan, Lung cancer stem cells: Molecular features and therapeutic targets. Mol. Asp. Med. 39, 50–60 (2014)

    Article  CAS  Google Scholar 

  199. L. You, B. He, Z. Xu, K. Uematsu, J. Mazieres, I. Mikami, N. Reguart, T.W. Moody, J. Kitajewski, F. McCormick, Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells. Oncogene 23, 6170–6174 (2004)

    Article  CAS  PubMed  Google Scholar 

  200. R.A. Winn, M. Van Scoyk, M. Hammond, K. Rodriguez, J.T. Crossno, L.E. Heasley, R.A. Nemenoff, Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor γ. J. Biol. Chem. 281, 26943–26950 (2006)

    Article  CAS  PubMed  Google Scholar 

  201. H. Yue, D. Huang, L. Qin, Z. Zheng, L. Hua, G. Wang, J. Huang, H. Huang. Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine. 2016, 6709828 (2016)

  202. S.S. Lin, K.C. Lai, S.C. Hsu, J.S. Yang, C.L. Kuo, J.P. Lin, Y.S. Ma, C.C. Wu, J.G. Chung, Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor (VEGF). Cancer Lett. 285, 127–133 (2009)

    Article  CAS  PubMed  Google Scholar 

  203. Y. Li, T. Zhang, Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett. 346, 197–205 (2014)

    Article  CAS  PubMed  Google Scholar 

  204. E. Robles-Escajeda, U. Das, N.M. Ortega, K. Parra, G. Francia, J.R. Dimmock, A. Varela-Ramirez, R.J. Aguilera, A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells. Cell. Oncol. 39, 265–277 (2016)

    Article  CAS  Google Scholar 

  205. J.Y. Zhu, X. Yang, Y. Chen, Y. Jiang, S.J. Wang, Y. Li, X.Q. Wang, Y. Meng, M.M. Zhu, X. Ma, C. Huang, R. Wu, C.F. Xie, X.T. Li, S.S. Geng, J.S. Wu, C.Y. Zhong. Curcumin Suppresses Lung Cancer Stem Cells via Inhibiting Wnt/beta-catenin and Sonic Hedgehog Pathways. 31, 680–688 (2017)

  206. P. Baharuddin, N. Satar, K.S. Fakiruddin, N. Zakaria, M.N. Lim, N.M. Yusoff, Z. Zakaria, B.H. Yahaya, Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines. Oncol. Rep. 35, 13–25 (2016)

    Article  CAS  PubMed  Google Scholar 

  207. X. Meng, M. Li, X. Wang, Y. Wang, D. Ma, Both CD133+ and CD133- subpopulations of A549 and H446 cells contain cancer-initiating cells. Cancer Sci. 100, 1040–1046 (2009)

    Article  CAS  PubMed  Google Scholar 

  208. R. Roudi, Z. Madjd, M. Ebrahimi, F.S. Samani, A. Samadikuchaksaraei, CD44 and CD24 cannot act as cancer stem cell markers in human lung adenocarcinoma cell line A549. Cell. Mol. Biol. Lett. 19, 23–36 (2014)

    Article  CAS  PubMed  Google Scholar 

  209. Y. Lu, R. Govindan, L. Wang, P.-y. Liu, B. Goodgame, W. Wen, A. Sezhiyan, J. Pfeifer, Y.-f. Li, X. Hua. MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer. Carcinogenesis 33, 1046-1054 (2012)

  210. A. Subramani, S. Alsidawi, S. Jagannathan, K. Sumita, A.T. Sasaki, B. Aronow, R.E. Warnick, S. Lawler, J.J. Driscoll, The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis. Sci Rep 3 (2013)

  211. N.M. Teplyuk, B. Mollenhauer, G. Gabriely, A. Giese, E. Kim, M. Smolsky, R.Y. Kim, M.G. Saria, S. Pastorino, S. Kesari. MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro-oncol. 14, 689-700 (2012)

  212. P.S. Mitchell, R.K. Parkin, E.M. Kroh, B.R. Fritz, S.K. Wyman, E.L. Pogosova-Agadjanyan, A. Peterson, J. Noteboom, K.C. O'Briant, A. Allen, Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. 105, 10513–10518 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. S. Alsidawi, E. Malek, J.J. Driscoll, MicroRNAs in brain metastases: Potential role as diagnostics and therapeutics. Int. J. Mol. Sci. 15, 10508–10526 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. J. Kota, R.R. Chivukula, K.A. O'Donnell, E.A. Wentzel, C.L. Montgomery, H.-W. Hwang, T.-C. Chang, P. Vivekanandan, M. Torbenson, K.R. Clark, Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137, 1005–1017 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Y. Wu, M. Crawford, B. Yu, Y. Mao, S.P. Nana-Sinkam, L.J. Lee, MicroRNA delivery by cationic lipoplexes for lung cancer therapy. Mol. Pharm. 8, 1381–1389 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. H.Y. Lee, K.A. Mohammed, F. Kaye, P. Sharma, B.M. Moudgil, W.L. Clapp, N. Nasreen, Targeted delivery of let-7a microRNA encapsulated ephrin-A1 conjugated liposomal nanoparticles inhibit tumor growth in lung cancer. Int. J. Nanomedicine 8, 4481–4494 (2013)

    PubMed  PubMed Central  Google Scholar 

  217. A. Esquela-Kerscher, F.J. Slack, Oncomirs - microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006)

    Article  CAS  PubMed  Google Scholar 

  218. O. Fortunato, M. Boeri, C. Verri, M. Moro, G. Sozzi, Therapeutic use of microRNAs in lung cancer. Biomed. Res. Int. 2014, 756975 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Y. Zhang, Y.-f. Zhang, J. Bryant, A. Charles, R.J. Boado, W.M. Pardridge, Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin. Cancer Res. 10, 3667–3677 (2004)

    Article  CAS  PubMed  Google Scholar 

  220. T.K. Owonikoko, J. Arbiser, A. Zelnak, H.-K.G. Shu, H. Shim, A.M. Robin, S.N. Kalkanis, T.G. Whitsett, B. Salhia, N.L. Tran, Current approaches to the treatment of metastatic brain tumours. Nat. Rev. Clin. Oncol. 11, 203 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. S. Zimmermann, R. Dziadziuszko, S. Peters, Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat. Rev. 40, 716–722 (2014)

    Article  CAS  PubMed  Google Scholar 

  222. F.A. Shepherd, J. Rodrigues Pereira, T. Ciuleanu, E.H. Tan, V. Hirsh, S. Thongprasert, D. Campos, S. Maoleekoonpiroj, M. Smylie, R. Martins, Erlotinib in previously treated non–small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005)

    Article  CAS  PubMed  Google Scholar 

  223. J. Baselga, The EGFR as a target for anticancer therapy—Focus on cetuximab. Eur. J. Cancer 37, 16–22 (2001)

    Article  Google Scholar 

  224. M. Fukuoka, S. Yano, G. Giaccone, T. Tamura, K. Nakagawa, J.-Y. Douillard, Y. Nishiwaki, J. Vansteenkiste, S. Kudoh, D. Rischin, Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer. J. Clin. Oncol. 21, 2237–2246 (2003)

    Article  CAS  PubMed  Google Scholar 

  225. J. Sato, T. Kawamoto, A. Le, J. Mendelsohn, J. Polikoff, G. Sato, Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Molecular Biol. Med. 1, 511–529 (1983)

    CAS  Google Scholar 

  226. Y.-L. Wu, C. Zhou, Y. Cheng, S. Lu, G.-Y. Chen, C. Huang, Y.-S. Huang, H.-H. Yan, S. Ren, Y. Liu, Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: A phase II study (CTONG–0803). Ann. Oncol. 24, 993–999 (2013)

    Article  PubMed  Google Scholar 

  227. D.B. Costa, A.T. Shaw, S.-H. I. Ou, B.J. Solomon, G.J. Riely, M.-J. Ahn, C. Zhou, S.M. Shreeve, P. Selaru, A. Polli. Clinical experience with crizotinib in patients with advanced ALK-rearranged non–small-cell lung cancer and brain metastases. J. Clin. Oncol. 33, 1881-1888 (2015)

  228. A. T. Shaw, R. Mehra, D. S. Tan, E. Felip, L. Chow, D. R. Camidge, J. Vansteenkiste, S. Sharma, T. De Pas, G. J. Riely. 1293Pevaluation of ceritinib-treated patients (PTS) with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ascend-1 study. Ann. Oncol. 25, iv455-iv6 (2014)

  229. S.-H. I. Ou, J. S. Ahn, L. De Petris, R. Govindan, J. C.-H. Yang, B. G. M. Hughes, H. Lena, D. Moro-Sibilot, A. Bearz, S. V. Ramirez, editors. Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673). ASCO Annual Meeting Proceedings; 2015

  230. A. T. Shaw, T. M. Bauer, E. Felip, B. Besse, L. P. James, J. S. Clancy, G. Mugundu, J.-F. Martini, A. Abbattista, B. J. Solomon, editors. Clinical activity and safety of PF-06463922 from a dose escalation study in patients with advanced ALK+ or ROS1+ NSCLC. ASCO Annual Meeting Proceedings; 2015

  231. M.G. Kris, R.B. Natale, R.S. Herbst, T.J. Lynch Jr., D. Prager, C.P. Belani, J.H. Schiller, K. Kelly, H. Spiridonidis, A. Sandler, Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non–small cell lung cancer: A randomized trial. JAMA 290, 2149–2158 (2003)

    Article  CAS  PubMed  Google Scholar 

  232. S.B. Goldberg, J.N. Contessa, S.B. Omay, V. Chiang, Lung cancer brain metastases. Cancer J. 21, 398–403 (2015)

    Article  PubMed  Google Scholar 

  233. A. Salmaninejad, V. Khoramshahi, A. Azani, E. Soltaninejad, S. Aslani, M.R. Zamani, M. Zal, A. Nesaei, S.M. Hosseini, PD-1 and cancer: Molecular mechanisms and polymorphisms. Immunogenetics. https://doi.org/10.1007/s00251-017-1015-5 (2017)

  234. J.V. Cohen, H.M. Kluger, Systemic immunotherapy for the treatment of brain metastases. Front. Oncol. 6, 49 (2016)

  235. T. Bahrami, S. Mokmeli, H. Hossieni, R. Pourpaknia, Z. Makani, A. Salmaninejad, M.A. Estiar, A. Hossieni, A. Farshbaf, The molecular signature of breast cancer metastasis to bone. Anti-Cancer Drugs 27, 824–831 (2016)

    Article  CAS  PubMed  Google Scholar 

  236. N.K. Gerber, Y. Yamada, A. Rimner, W. Shi, G.J. Riely, K. Beal, A.Y. Helena, T.A. Chan, Z. Zhang, A.J. Wu. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 89, 322–329 (2014)

  237. S.H. Lim, J.Y. Lee, M.-Y. Lee, H. Kim, J. Lee, J.-M. Sun, J. Ahn, S.-W. Um, H. Kim, B. Kim. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small cell lung cancer. Ann. Oncol. 26, 762-768 (2014)

  238. L. Liu, M. Yang, J. Guan, Y. Zhang, Q. Li, Y. Zhang, M. Chen, L. Li, N. Xiao, Y. Dai, editors. Whole Brain Radiotherapy (WBRT) plus EGFR tyrosine kinase inhibitors (TKIs) versus WBRT alone for brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients: A meta-analysis. ASCO Annual Meeting Proceedings; 2015

  239. M.E. Fiori, C. Barbini, T.L. Haas, N. Marroncelli, M. Patrizii, M. Biffoni, R. De Maria, Antitumor effect of miR-197 targeting in p53 wild-type lung cancer. Cell Death Differ. 21, 774–782 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Z. Liu, C. Mai, H. Yang, Y. Zhen, X. Yu, S. Hua, Q. Wu, Q. Jiang, Y. Zhang, X. Song, W. Fang, Candidate tumour suppressor CCDC19 regulates miR-184 direct targeting of C-Myc thereby suppressing cell growth in non-small cell lung cancers. J. Cell. Mol. Med. 18, 1667–1679 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the faculty members of the Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences for their assistance.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Meysam Yousefi

  2. Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Meysam Yousefi, Parisa Ghaffari & Seyed H. Ghaffari

  3. Genetic Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    Tayyeb Bahrami

  4. Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Arash Salmaninejad

  5. Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Rahim Nosrati

Authors
  1. Meysam Yousefi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tayyeb Bahrami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arash Salmaninejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahim Nosrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Parisa Ghaffari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seyed H. Ghaffari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seyed H. Ghaffari.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yousefi, M., Bahrami, T., Salmaninejad, A. et al. Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options. Cell Oncol. 40, 419–441 (2017). https://doi.org/10.1007/s13402-017-0345-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-017-0345-5

Keywords

Search

Navigation