Skip to main content

Advertisement

SpringerLink
Log in

Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood–brain barrier and treatment strategies

  • REVIEW ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Breast cancer (BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis (BM) reported in 17–20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood–brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length.

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

Data availability

Not Applicable.

References

  1. Yadav UP, Ansari AJ, Arora S, Joshi G, Singh T, Kaur H, et al. Design, synthesis and anticancer activity of 2-arylimidazo [1, 2-a] pyridinyl-3-amines. Bioorg Chem. 2022;118: 105464.

    Article  CAS  PubMed  Google Scholar 

  2. Yadav UP, Singh T, Kumar P, Sharma P, Kaur H, Sharma S, et al. Metabolic adaptations in cancer stem cells. Front Oncol. 2020;10:1010.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sung, H., J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, et al (2021) GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 71: 3 209–249.

  4. Parsa N. Environmental factors inducing human cancers. Iran J Public Health. 2012;41(11):1–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Li X, Wang J. Mechanical tumor microenvironment and transduction: cytoskeleton mediates cancer cell invasion and metastasis. Int J Biol Sci. 2020;16(12):2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Martelotto LG, Ng CK, Piscuoglio S, Weigelt B, Reis-Filho JS. Breast cancer intra-tumor heterogeneity. Breast Cancer Res. 2014;16(3):1–11.

    Article  Google Scholar 

  7. Chhichholiya Y, Suman P, Singh S, Munshi A. The genomic architecture of metastasis in breast cancer: focus on mechanistic aspects. Signal Pathways Therap Strat. 2021;38(8):95.

    Google Scholar 

  8. Liu L, Zhang Y, Lu J. The roles of long noncoding RNAs in breast cancer metastasis. Cell Death Dis. 2020;11(9):1–14.

    Article  CAS  Google Scholar 

  9. Hosonaga M, Saya H, Arima Y. Molecular and cellular mechanisms underlying brain metastasis of breast cancer. Cancer Metastasis Rev. 2020;39(3):711–20.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kanchan RK, Siddiqui JA, Mahapatra S, Batra SK, Nasser MW. microRNAs orchestrate pathophysiology of breast cancer brain metastasis: advances in therapy. Mol Cancer. 2020;19(1):1–16.

    Article  Google Scholar 

  11. Wanleenuwat P, Iwanowski P. Metastases to the central nervous system: molecular basis and clinical considerations. J Neurol Sci. 2020;412: 116755.

    Article  CAS  PubMed  Google Scholar 

  12. Arvanitis CD, Ferraro GB, Jain RK. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26–41.

    Article  CAS  PubMed  Google Scholar 

  13. Ulasov I, Borovjagin A, Fares J, Yakushov S, Malin D, Timashev P, et al. MicroRNA 345 (miR345) regulates KISS1-E-cadherin functional interaction in breast cancer brain metastases. Cancer Lett. 2020;481:24–31.

    Article  CAS  PubMed  Google Scholar 

  14. Fares J, Kanojia D, Rashidi A, Ulasov I, Lesniak MS. Genes that mediate metastasis across the blood–brain barrier. Trends in cancer. 2020;6(8):660–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Martin AM, Cagney DN, Catalano PJ, Warren LE, Bellon JR, Punglia RS, et al. Brain metastases in newly diagnosed breast cancer: a population-based study. JAMA Oncol. 2017;3(8):1069–77.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Niikura N, Hayashi N, Masuda N, Takashima S, Nakamura R, Watanabe K-I, et al. Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype: a multicenter retrospective analysis. Breast Cancer Res Treat. 2014;147(1):103–12.

    Article  PubMed  Google Scholar 

  17. Watase C, Shiino S, Shimoi T, Noguchi E, Kaneda T, Yamamoto Y, et al. Breast cancer brain metastasis—overview of disease state, treatment options and future perspectives. Cancers. 2021;13(5):1078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer. 2008;113(10):2638–45.

    Article  PubMed  Google Scholar 

  19. Yao Y, Chu Y. Risk factors for distant metastasis of patients with primary triple-negative. Breast Cancer. 2019;39:6.

    Google Scholar 

  20. Yomtoubian S, Lee SB, Verma A, Izzo F, Markowitz G, Choi H, et al. Inhibition of EZH2 catalytic activity selectively targets a metastatic subpopulation in triple-negative breast cancer. Cell Rep. 2020;30(3):755-770.e6.

    Article  CAS  PubMed  Google Scholar 

  21. Peluffo G, Subedee A, Harper NW. EN1 is a transcriptional dependency in triple-negative. Breast Cancer Assoc Brain Metast. 2019;79(16):4173–83.

    CAS  Google Scholar 

  22. Sartorius CA, Hanna CT, Gril B, Cruz H, Serkova NJ, Huber KM, et al. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism. Oncogene. 2016;35(22):2881–92.

    Article  CAS  PubMed  Google Scholar 

  23. Morissette M, Le Saux M, D’astous M, Jourdain S, Al Sweidi S, Morin N, et al. Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Ster Biochem Molec Biol. 2008;108(3):327–38.

    Article  CAS  Google Scholar 

  24. García-Ovejero D, Veiga S, García-Segura LM, Doncarlos LL. Glial expression of estrogen and androgen receptors after rat brain injury. J Compar Neurol. 2002;450(3):256–71.

    Article  Google Scholar 

  25. Contreras-Zárate MJ, Day NL, Ormond DR, Borges VF, Tobet S, Gril B, et al. Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene. 2019;38(24):4685–99.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Choy C, Ansari KI, Neman J, Hsu S, Duenas MJ, Li H, et al. Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases. Breast Cancer Res. 2017;19(1):1–11.

    Article  Google Scholar 

  27. Zhou L, Zhou W, Zhang H, Hu Y, Yu L, Zhang Y, et al. Progesterone suppresses triple-negative breast cancer growth and metastasis to the brain via membrane progesterone receptor α. Int J Mol Med. 2017;40(3):755–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Krystal cascetta, A.t. (2021). Primary invasive breast cancer. https://bestpractice.bmj.com/topics/en-us/716.

  29. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408(6810):307–10.

    Article  CAS  PubMed  Google Scholar 

  30. Powell E, Piwnica-Worms D, Piwnica-Worms H. Contribution of p53 to metastasis. Cancer Discov. 2014;4(4):405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9(10):701–13.

    Article  CAS  PubMed  Google Scholar 

  32. Wei C-L, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, et al. A global map of p53 transcription-factor binding sites in the human genome. Cell. 2006;124(1):207–19.

    Article  CAS  PubMed  Google Scholar 

  33. Pharoah PD, Day NE, Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer. 1999;80(12):1968–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Olivier M, Langerød A, Carrieri P, Bergh J, Klaar S, Eyfjord J, et al. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res. 2006;12(4):1157–67.

    Article  CAS  PubMed  Google Scholar 

  35. Lee JY, Park K, Lim SH, Kim HS, Yoo KH, Jung KS, et al. Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer. Oncotarget. 2015;6(41):43731–42.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lo Nigro C, Vivenza D, Monteverde M, Lattanzio L, Gojis O, Garrone O, et al. High frequency of complex TP53 mutations in CNS metastases from breast cancer. Br J Cancer. 2012;106(2):397–404.

    Article  CAS  PubMed  Google Scholar 

  37. Koller G, Schlomann U, Golfi P, Ferdous T, Naus S, Bartsch JW. ADAM8/MS2/CD156, an emerging drug target in the treatment of inflammatory and invasive pathologies. Curr Pharm Des. 2009;15(20):2272–81.

    Article  CAS  PubMed  Google Scholar 

  38. Conrad C, Götte M, Schlomann U, Roessler M, Pagenstecher A, Anderson P, et al. ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells. Int J Cancer. 2018;142(4):779–91.

    Article  CAS  PubMed  Google Scholar 

  39. Mohammed RAA, Green A, El-Shikh S, Paish E, Ellis I, Martin S. Prognostic significance of vascular endothelial cell growth factors-A,-C and-D in breast cancer and their relationship with angio-and lymphangiogenesis. Br J Cancer. 2007;96(7):1092–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hawinkels LJ, Zuidwijk K, Verspaget HW, de Jonge-Muller ES, van Duijn W, Ferreira V, et al. VEGF release by MMP-9 mediated heparan sulphate cleavage induces colorectal cancer angiogenesis. Eur J Cancer. 2008;44(13):1904–13.

    Article  CAS  PubMed  Google Scholar 

  41. Linderholm B, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtiö J, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 2009;20(10):1639–46.

    Article  CAS  PubMed  Google Scholar 

  42. Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D, et al. ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO Mol Med. 2014;6(2):278–94.

    Article  CAS  PubMed  Google Scholar 

  43. Vandermeersch S, Vanbeselaere J, Delannoy CP, Drolez A, Mysiorek C, Guérardel Y, et al. Accumulation of GD1α ganglioside in MDA-MB-231 breast cancer cells expressing ST6GalNAc V. Molecules. 2015;20(4):6913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Drolez A, Vandenhaute E, Delannoy CP, Dewald JH, Gosselet F, Cecchelli R, et al. ST6GALNAC5 expression decreases the interactions between breast cancer cells and the human blood-brain barrier. Int J Mol Sci. 2016;17(8):1309.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459(7249):1005–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Guenzi E, Töpolt K, Lubeseder-Martellato C, Jörg A, Naschberger E, Benelli R, et al. The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression. EMBO J. 2003;22(15):3772–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Honkala AT, Tailor D, Malhotra SV. Guanylate-binding protein 1: an emerging target in inflammation and cancer. Front Immunol. 2020;10:3139.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mustafa DAM, Pedrosa RMSM, Smid M, van der Weiden M, de Weerd V, Nigg AL, et al. T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression. Acta Neuropathol. 2018;135(4):581–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Alves dos Santos M, Smidt MP. En1 and Wnt signaling in midbrain dopaminergic neuronal development. Neural Develop. 2011;6(1):1–15.

    Article  Google Scholar 

  50. Peluffo G, Subedee A, Harper NW, Kingston N, Jovanović B, Flores F, et al. EN1 is a transcriptional dependency in triple-negative breast cancer associated with brain metastasis. Can Res. 2019;79(16):4173–83.

    Article  CAS  Google Scholar 

  51. Bachar-Dahan L, Goltzmann J, Yaniv A, Gazit A. Engrailed-1 negatively regulates β-Catenin transcriptional activity by destabilizing β-catenin via a glycogen synthase kinase-3β–independent pathway. Mol Biol Cell. 2006;17(6):2572–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Arese M, Serini G, Bussolino F. Nervous vascular parallels: axon guidance and beyond. Int J Dev Biol. 2011;55(4–5):439–45.

    Article  CAS  PubMed  Google Scholar 

  53. Alakbarzade V, Hameed A, Quek DQ, Chioza BA, Baple EL, Cazenave-Gassiot A, et al. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Genet. 2015;47(7):814–7.

    Article  CAS  PubMed  Google Scholar 

  54. Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M, Ben-Omran T, et al. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet. 2015;47(7):809–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tiwary S, Morales JE, Kwiatkowski SC, Lang FF, Rao G, McCarty JH. Metastatic brain tumors disrupt the blood-brain barrier and alter lipid metabolism by inhibiting expression of the endothelial cell fatty acid transporter Mfsd2a. Sci Rep. 2018;8(1):8267.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature. 2014;509(7501):507–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. O’Brown NM, Megason SG, Gu C. Suppression of transcytosis regulates zebrafish blood-brain barrier function. Elife. 2019;8:47326.

    Article  Google Scholar 

  58. Andreone BJ, Chow BW, Tata A, Lacoste B, Ben-Zvi A, Bullock K, et al. Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron. 2017;94(3):581-594.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407–24.

    Article  CAS  PubMed  Google Scholar 

  60. Zuazo-Gaztelu I, Casanovas O. Unraveling the role of angiogenesis in cancer ecosystems. Front. Oncol. 2018;8:248.

  61. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckland, NZ). 2015;3:83–92.

    Google Scholar 

  62. Tobar LE, Farnsworth RH, Stacker SA. Brain vascular microenvironments in cancer metastasis. Biomolecules. 2022;12(3):401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rodrigues G, Hoshino A, Kenific CM, Matei IR, Steiner L, Freitas D, et al. Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat Cell Biol. 2019;21(11):1403–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wu K, Fukuda K, Xing F, Zhang Y, Sharma S, Liu Y, et al. Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. J Biol Chem. 2015;290(15):9842–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Poola I, DeWitty RL, Marshalleck JJ, Bhatnagar R, Abraham J, Leffall LD. Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis. Nat Med. 2005;11(5):481–3.

    Article  CAS  PubMed  Google Scholar 

  66. Pei D. Matrix metalloproteinases target protease-activated receptors on the tumor cell surface. Cancer Cell. 2005;7(3):207–8.

    Article  CAS  PubMed  Google Scholar 

  67. McCawley LJ, Matrisian LM. Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol. 2001;13(5):534–40.

    Article  CAS  PubMed  Google Scholar 

  68. Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW, Weiss SJ. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell. 2003;114(1):33–45.

    Article  CAS  PubMed  Google Scholar 

  69. Blackburn JS, Brinckerhoff CE. Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. Am J Pathol. 2008;173(6):1736–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu H, Kato Y, Erzinger SA, Kiriakova GM, Qian Y, Palmieri D, et al. The role of MMP-1 in breast cancer growth and metastasis to the brain in a xenograft model. BMC Cancer. 2012;12:583–583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brandt, M.F.L.S.F.L.J., Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 11 ed, ed. M. Mark Feldman, Lawrence S. Friedman, MD and Lawrence J. Brandt, MD. Vol. 2. 2020, Massachusetts: elviser. 2488.

  72. Majumder M, Dunn L, Liu L, Hasan A, Vincent K, Brackstone M, et al. COX-2 induces oncogenic micro RNA miR655 in human breast cancer. Sci Rep. 2018;8(1):327.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem. 2007;282(16):11613–7.

    Article  CAS  PubMed  Google Scholar 

  74. Fujino H, Xu W, Regan JW. Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases. J Biol Chem. 2003;278(14):12151–6.

    Article  CAS  PubMed  Google Scholar 

  75. Ma X, Holt D, Kundu N, Reader J, Goloubeva O, Take Y, et al. A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE(2)-mediated immunosuppression and inhibits breast cancer metastasis. Oncoimmunology. 2013;2(1): e22647.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Majumder M, Xin X, Liu L, Girish GV, Lala PK. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions. Cancer Sci. 2014;105(9):1142–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reel B, Sala-Newby GB, Huang WC, Newby AC. Diverse patterns of cyclooxygenase-independent metalloproteinase gene regulation in human monocytes. Br J Pharmacol. 2011;163(8):1679–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lee KY, Kim Y-J, Yoo H, Lee SH, Park JB, Kim HJ. Human brain endothelial cell-derived COX-2 facilitates extravasation of breast cancer cells across the blood–brain barrier. Anticancer Res. 2011;31(12):4307–13.

    CAS  PubMed  Google Scholar 

  79. Moss LAS, Jensen-Taubman S, Stetler-Stevenson WG. Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol. 2012;181(6):1895–9.

    Article  CAS  Google Scholar 

  80. Xu C, Zhao H, Chen H, Yao Q. CXCR4 in breast cancer: oncogenic role and therapeutic targeting. Drug Des Devel Ther. 2015;9:4953–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol. 2002;169(1):424–33.

    Article  CAS  PubMed  Google Scholar 

  82. Shi Y, Riese DJ, Shen J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front. Pharmacol. 2020;11:574667.

  83. Kang H, Watkins G, Parr C, Douglas-Jones A, Mansel RE, Jiang WG. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer. Breast Cancer Res. 2005;7(4):R402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fares J, Kanojia D, Rashidi A, Ulasov I, Lesniak MS. Genes that mediate metastasis across the blood-brain barrier. Trends Cancer. 2020;6(8):660–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Würth R, Bajetto A, Harrison JK, Barbieri F, Florio T. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment. Front. Cell. Neurosci. 2014;8:144.

  86. Gong X, Hou Z, Endsley MP, Gronseth EI, Rarick KR, Jorns JM, et al. Interaction of tumor cells and astrocytes promotes breast cancer brain metastases through TGF-β2/ANGPTL4 axes. npj Prec Oncol. 2019;3(1):24.

    Article  Google Scholar 

  87. Zhu P, Tan MJ, Huang R-L, Tan CK, Chong HC, Pal M, et al. Angiopoietin-like 4 protein elevates the prosurvival intracellular O2−:H2O2 ratio and confers anoikis resistance to tumors. Cancer Cell. 2011;19(3):401–15.

    Article  CAS  PubMed  Google Scholar 

  88. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133(1):66–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Akhtar M, Haider A, Rashid S, Al-Nabet A. Paget’s “seed and soil” theory of cancer metastasis: an idea whose time has come. Adv Anat Pathol. 2019;26(1):69–74.

    Article  CAS  PubMed  Google Scholar 

  90. Suman P, Chhichholiya Y, Kaur P, Ghosh S, Munshi A. Long non-coding RNAs involved in different steps of cancer metastasis. Clin. Transl. Oncol. 2022;1–17.

  91. Ostrand-Rosenberg S, Fenselau C. Myeloid-derived suppressor cells: immune-suppressive cells that impair antitumor immunity and are sculpted by their environment. J Immunol (Baltim Md 1950). 2018;200(2):422–31.

    Article  CAS  Google Scholar 

  92. Fulmer CG, VonDran MW, Stillman AA, Huang Y, Hempstead BL, Dreyfus CF. Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci. 2014;34(24):8186–96.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Miyamoto N, Maki T, Shindo A, Liang AC, Maeda M, Egawa N, et al. Astrocytes promote oligodendrogenesis after white matter damage via brain-derived neurotrophic factor. J Neurosci Off J Soc Neurosci. 2015;35(41):14002–8.

    Article  CAS  Google Scholar 

  94. Ding H, Roncari L, Shannon P, Wu X, Lau N, Karaskova J, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Can Res. 2001;61(9):3826–36.

    CAS  Google Scholar 

  95. Huang Y, Rane SG. Potassium channel induction by the Ras/Raf signal transduction cascade. J Biol Chem. 1994;269(49):31183–9.

    Article  CAS  PubMed  Google Scholar 

  96. Khaitan D, Sankpal UT, Weksler B, Meister EA, Romero IA, Couraud P-O, et al. Role of KCNMA1 gene in breast cancer invasion and metastasis to brain. BMC Cancer. 2009;9(1):1–11.

    Article  Google Scholar 

  97. Stylianou S, Clarke RB, Brennan K. Aberrant activation of notch signaling in human breast cancer. Can Res. 2006;66(3):1517–25.

    Article  CAS  Google Scholar 

  98. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)–dependent inhibition of p53. Can Res. 2006;66(9):4715–24.

    Article  CAS  Google Scholar 

  99. Lee CW, Simin K, Liu Q, Plescia J, Guha M, Khan A, et al. A functional Notch–survivin gene signature in basal breast cancer. Breast Cancer Res. 2008;10(6):1–12.

    Article  CAS  Google Scholar 

  100. Dickson BC, Mulligan AM, Zhang H, Lockwood G, O’Malley FP, Egan SE, et al. High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Mod Pathol. 2007;20(6):685–93.

    Article  CAS  PubMed  Google Scholar 

  101. McGowan PM, Simedrea C, Ribot EJ, Foster PJ, Palmieri D, Steeg PS, et al. Notch1 inhibition alters the CD44hi/CD24lo population and reduces the formation of brain metastases from breast cancer. Mol Cancer Res. 2011;9(7):834–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fazakas C, Wilhelm I, Nagyőszi P, Farkas AE, Haskó J, Molnár J, et al. Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE. 2011;6(6): e20758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lee T-H, Avraham HK, Jiang S, Avraham S. Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem. 2003;278(7):5277–84.

    Article  CAS  PubMed  Google Scholar 

  104. Mine S, Fujisaki T, Kawahara C, Tabata T, Iida T, Yasuda M, et al. Hepatocyte growth factor enhances adhesion of breast cancer cells to endothelial cells in vitro through up-regulation of CD44. Exp Cell Res. 2003;288(1):189–97.

    Article  CAS  PubMed  Google Scholar 

  105. Draffin JE, McFarlane S, Hill A, Johnston PG, Waugh DJ. CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Can Res. 2004;64(16):5702–11.

    Article  CAS  Google Scholar 

  106. Avraham HK, Jiang S, Fu Y, Nakshatri H, Ovadia H, Avraham S. Angiopoietin-2 mediates blood–brain barrier impairment and colonization of triple-negative breast cancer cells in brain. J Pathol. 2014;232(3):369–81.

    Article  CAS  PubMed  Google Scholar 

  107. Lee, B.-C., T.-H. Lee, S. Avraham, and H.K. Avraham, Involvement of the Chemokine Receptor CXCR4 and Its Ligand Stromal Cell-Derived Factor 1α in Breast Cancer Cell Migration Through Human Brain Microvascular Endothelial Cells11NIH grant NS39558 (S. Avraham), the Susan G. Komen Fellowship (S. Avraham), the Milheim Foundation (S. Avraham), CA97153 (H. Avraham), and K18 PAR-02–069 (H. Avraham). Note: This work was done during the term of an established investigatorship from the American Heart Association (H. Avraham). This article is dedicated to Charlene Engelhard for her continuing friendship and support for our research program. Molecular Cancer Research, 2004. 2(6): p. 327–338.

  108. Szmulewitz, R., J. Taylor, and C. Rinker-Schaffer, Metastatic Colonization, in Encyclopedia of Cancer, M. Schwab, Editor. 2011, Springer Berlin Heidelberg: Berlin, Heidelberg. p. 2271–2273.

  109. Fidler IJ. The biology of brain metastasis: challenges for therapy. Cancer J. 2015;21(4):284–93.

    Article  CAS  PubMed  Google Scholar 

  110. Lee JY, Park K, Lee E, Ahn T, Jung HH, Lim SH, et al. Gene expression profiling of breast cancer brain metastasis. Sci Rep. 2016;6(1):28623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhou M, Hua W, Sun Y. Cell migration inducing hyaluronidase 1 promotes growth and metastasis of papillary thyroid carcinoma. Bioengineered. 2022;13(5):11822–11831. https://doi.org/10.1080/21655979.2022.2074110

  112. Burri PH, Hlushchuk R, Djonov V. Intussusceptive angiogenesis: its emergence, its characteristics, and its significance. Dev Dyn. 2004;231(3):474–88.

    Article  PubMed  Google Scholar 

  113. Dimova I, Hlushchuk R, Makanya A, Styp-Rekowska B, Ceausu A, Flueckiger S, et al. Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells. Angiogenesis. 2013;16(4):921–37.

    Article  CAS  PubMed  Google Scholar 

  114. Giacomini A, Ackermann M, Belleri M, Coltrini D, Nico B, Ribatti D, et al. Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease. Angiogenesis. 2015;18(4):499–510.

    Article  CAS  PubMed  Google Scholar 

  115. Gene, N. SOX Sry box transription factor 2. [english] 2022 [cited 2022 27th march]; description about SOX2 gene and its function]. Available from: https://www.who.int/news-room/fact-sheets/detail/breast-cancer.

  116. Xiao W, Zheng S, Xie X, Li X, Zhang L, Yang A, et al. SOX2 promotes brain metastasis of breast cancer by upregulating the expression of FSCN1 and HBEGF. Molecular therapy oncolytics. 2020;17:118–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells. 2014;6(3):305–11.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL, et al. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol. 2004;63(5):499–509.

    Article  CAS  PubMed  Google Scholar 

  119. Park ES, Kim SJ, Kim SW, Yoon SL, Leem SH, Kim SB, et al. Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis. Proc Natl Acad Sci U S A. 2011;108(42):17456–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Eckhardt BL, Parker BS, van Laar RK, Restall CM, Natoli AL, Tavaria MD, et al. Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix. Mol Cancer Res. 2005;3(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  121. Magnussen SN, Toraskar J, Wilhelm I, Hasko J, Figenschau SL, Molnar J, et al. Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains. Sci Rep. 2020;10(1):12237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Iliff JJ, Goldman SA, Nedergaard M. Implications of the discovery of brain lymphatic pathways. The Lancet Neurology. 2015;14(10):977–9.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Feldman, M., L.S. Friedman, and L.J. Brandt, Sleisenger and Fordtran's gastrointestinal and liver disease E-book: pathophysiology, diagnosis, management. 2020: Elsevier health sciences.

  124. Majumder M, Xin X, Liu L, Girish GV, Lala PK. Prostaglandin E2 receptor EP 4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions. Cancer Sci. 2014;105(9):1142–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shi Y, Riese DJ, Shen J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front. Pharmacol. 2020;11:574667.

  126. Gong X, Hou Z, Endsley MP, Gronseth EI, Rarick KR, Jorns JM, et al. Interaction of tumor cells and astrocytes promotes breast cancer brain metastases through TGF-β2/ANGPTL4 axes. NPJ Prec Oncol. 2019;3(1):1–9.

    CAS  Google Scholar 

  127. Zhu P, Tan MJ, Huang R-L, Tan CK, Chong HC, Pal M, et al. Angiopoietin-like 4 protein elevates the prosurvival intracellular O2−: H2O2 ratio and confers anoikis resistance to tumors. Cancer Cell. 2011;19(3):401–15.

    Article  CAS  PubMed  Google Scholar 

  128. Padua D, Zhang XH-F, Wang Q, Nadal C, Gerald WL, Gomis RR, et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133(1):66–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Guan Z, Lan H, Cai X, Zhang Y, Liang A, Li J. Blood–brain barrier, cell junctions, and tumor microenvironment in brain metastases, the biological prospects and dilemma in therapies. Front. Cell Dev. Biol. 2021;9:722917.

  130. Berghoff AS, Lassmann H, Preusser M, Höftberger R. Characterization of the inflammatory response to solid cancer metastases in the human brain. Clin Exp Metas. 2013;30(1):69–81.

    Article  CAS  Google Scholar 

  131. Lee JY, Park K, Lee E, Ahn T, Jung HH, Lim SH, et al. Gene expression profiling of breast cancer brain metastasis. Sci Rep. 2016;6(1):1–10.

    Google Scholar 

  132. Xiao W, Zheng S, Xie X, Li X, Zhang L, Yang A, et al. SOX2 promotes brain metastasis of breast cancer by upregulating the expression of FSCN1 and HBEGF. Molec Therapy-Oncol. 2020;17:118–29.

    Article  CAS  Google Scholar 

  133. Arshad F, Wang L, Sy C, Avraham S, Avraham HK. Blood-brain barrier integrity and breast cancer metastasis to the brain. Pathol Res Int. 2010;2011:920509–920509.

    Google Scholar 

  134. Bos PD, Nguyen DX, Massagué J. Modeling metastasis in the mouse. Curr Opin Pharmacol. 2010;10(5):571–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14(11):1398–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ballabh P, Braun A, Nedergaard M. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  137. Orr FW, Wang HH, Lafrenie RM, Scherbarth S, Nance DM. Interactions between cancer cells and the endothelium in metastasis. J Pathol. 2000;190(3):310–29.

    Article  CAS  PubMed  Google Scholar 

  138. Yano S, Shinohara H, Herbst RS, Kuniyasu H, Bucana CD, Ellis LM, et al. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Can Res. 2000;60(17):4959–67.

    CAS  Google Scholar 

  139. Yang C, Robbins PD. The roles of tumor-derived exosomes in cancer pathogenesis. Clin. Dev. Immunol. 2011;842849. https://doi.org/10.1155/2011/842849

  140. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, et al. Rab27a supports exosome-dependent and-independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Can Res. 2012;72(19):4920–30.

    Article  CAS  Google Scholar 

  141. Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Serlin Y, Shelef I, Knyazer B, Friedman A. Anatomy and physiology of the blood–brain barrier. In: Seminars in cell & developmental biology (2015). (Vol. 38, pp. 2–6). Academic Press.

  143. Seelbach M, Chen L, Powell A, Choi YJ, Zhang B, Hennig B, et al. Polychlorinated biphenyls disrupt blood–brain barrier integrity and promote brain metastasis formation. Environ Health Perspect. 2010;118(4):479–84.

    Article  CAS  PubMed  Google Scholar 

  144. Godinho-Pereira J, Garcia AR, Figueira I, Malhó R, Brito MA. Behind Brain Metastases Formation: Cellular and Molecular Alterations and Blood-Brain Barrier Disruption. Int J Mol Sci. 2021;22(13):7057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Dejana E. Endothelial cell–cell junctions: happy together. Nat Rev Mol Cell Biol. 2004;5(4):261–70.

    Article  CAS  PubMed  Google Scholar 

  146. Feng S, Cen J, Huang Y, Shen H, Yao L, Wang Y, et al. Matrix metalloproteinase-2 and-9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS ONE. 2011;6(8): e20599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533(7604):493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci. 2010;11(2):87–99.

    Article  CAS  PubMed  Google Scholar 

  149. Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, et al. Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533(7604):493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zou Y, Watters A, Cheng N, Perry CE, Xu K, Alicea GM, et al. Polyunsaturated fatty acids from astrocytes activate PPARγ signaling in cancer cells to promote brain metastasis. Cancer Discov. 2019;9(12):1720–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pozzobon T, Goldoni G, Viola A, Molon B. CXCR4 signaling in health and disease. Immunol Lett. 2016;177:6–15.

    Article  CAS  PubMed  Google Scholar 

  152. Kawaguchi N, Zhang T-T, Nakanishi T. Involvement of CXCR4 in normal and abnormal development. Cells. 2019;8(2):185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Berghoff AS, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. 2016;5(1): e1057388.

    Article  PubMed  Google Scholar 

  154. Fujimoto T, Nakagawa S, Morofuji Y, Watanabe D, Ujifuku K, Horie N, et al. Pericytes suppress brain metastasis from lung cancer in vitro. Cell Mol Neurobiol. 2020;40(1):113–21.

    Article  PubMed  Google Scholar 

  155. Zheng Z, Chopp M, Chen J. Multifaceted roles of pericytes in central nervous system homeostasis and disease. J Cereb Blood Flow Metab. 2020;40(7):1381–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. He BP, Wang JJ, Zhang X, Wu Y, Wang M, Bay B-H, et al. Differential reactions of microglia to brain metastasis of lung cancer. Mol Med. 2006;12(7):161–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ransohoff RM, Cardona AE. The myeloid cells of the central nervous system parenchyma. Nature. 2010;468(7321):253–62.

    Article  CAS  PubMed  Google Scholar 

  158. Louie E, Chen X, Coomes A, Ji K, Tsirka S, Chen E. Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis. Oncogene. 2013;32(35):4064–77.

    Article  CAS  PubMed  Google Scholar 

  159. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hablitz LM, Plá V, Giannetto M, Vinitsky HS, Stæger FF, Metcalfe T, et al. Circadian control of brain glymphatic and lymphatic fluid flow. Nat Commun. 2020;11(1):1–11.

    Article  Google Scholar 

  161. Song E, Mao T, Dong H, Boisserand LSB, Antila S, Bosenberg M, et al. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature. 2020;577(7792):689–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 2015;5(11):1164–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhang Q, Zhang Y, Chen Y, Qian J, Zhang X, Yu K. A novel mTORC1/2 inhibitor (MTI-31) inhibits tumor growth, epithelial–mesenchymal transition, metastases, and improves antitumor immunity in preclinical models of lung cancer. Clin Cancer Res. 2019;25(12):3630–42.

    Article  CAS  PubMed  Google Scholar 

  164. Lee HY, Cha J, Kim SK, Park JH, Song KH, Kim P, et al. c-MYC drives breast cancer metastasis to the brain, but promotes synthetic lethality with TRAIL. Mol Cancer Res. 2019;17(2):544–54.

    Article  CAS  PubMed  Google Scholar 

  165. Eales KL, Hollinshead KE, Tennant DA. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis. 2016;5(1): e190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379(6560):88–91.

    Article  CAS  PubMed  Google Scholar 

  167. Lee KE, Simon MC. From stem cells to cancer stem cells: HIF takes the stage. Curr Opin Cell Biol. 2012;24(2):232–5.

    Article  CAS  PubMed  Google Scholar 

  168. Lee JW, Ko J, Ju C, Eltzschig HK. Hypoxia signaling in human diseases and therapeutic targets. Exp. Mol. Med. 2019:51(6);1–13.

  169. Tirpe AA, Gulei D, Ciortea SM, Crivii C, Berindan-Neagoe I. Hypoxia: overview on hypoxiamediated mechanisms with a focus on the role of HIF genes. Int. J. Mol. Sci. 2019:20(24);6140.

  170. Achrol AS, Rennert RC, Anders C, Soffietti R, Ahluwalia MS, Nayak L, et al. Brain metastases. Nat Rev Dis Primers. 2019;5(1):1–26.

    Article  Google Scholar 

  171. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321(3):288–300.

    Article  CAS  PubMed  Google Scholar 

  172. Tsakonas G, De Petris L, Ekman S. Management of brain metastasized non-small cell lung cancer (NSCLC)–From local treatment to new systemic therapies. Cancer Treat Rev. 2017;54:122–31.

    Article  CAS  PubMed  Google Scholar 

  173. Cheng X, Hung MC. Breast cancer brain metastases. Cancer Metastasis Rev. 2007;26(3–4):635–43.

    Article  PubMed  Google Scholar 

  174. Lauko A, Rauf Y, Ahluwalia MS. Medical management of brain metastases. Neuro-Oncol Adv. 2020;2(1):015–015.

    Google Scholar 

  175. Suh JH. Efaproxiral: a novel radiation sensitiser. Expert Opin Investig Drugs. 2004;13(5):543–50.

    Article  CAS  PubMed  Google Scholar 

  176. Suh JH, Stea B, Nabid A, Kresl JJ, Fortin A, Mercier JP, et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol. 2006;24(1):106–14.

    Article  CAS  PubMed  Google Scholar 

  177. Shaw E, Scott C, Suh J, Kadish S, Stea B, Hackman J, et al. RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the radiation therapy oncology group recursive partitioning analysis brain metastases database. J Clin Oncol. 2003;21(12):2364–71.

    Article  CAS  PubMed  Google Scholar 

  178. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30(7):658–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8.

    Article  CAS  PubMed  Google Scholar 

  180. Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced unresectable melanoma. J Clin Oncol. 2018;36(17):1658–67.

    Article  CAS  PubMed  Google Scholar 

  181. Ferguson MS, Lemoine NR, Wang Y. Systemic delivery of oncolytic viruses: hopes and hurdles. Adv Virol. 2012;2012: 805629.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Ikeda K, Ichikawa T, Wakimoto H, Silver JS, Deisboeck TS, Finkelstein D, et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nat Med. 1999;5(8):881–7.

    Article  CAS  PubMed  Google Scholar 

  183. Du W, Seah I, Bougazzoul O, Choi G, Meeth K, Bosenberg MW, et al. Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. Proc Natl Acad Sci U S A. 2017;114(30):E6157-e6165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Jiang H, Shin DH. Localized treatment with oncolytic adenovirus delta-24-RGDOX induces systemic immunity against. Dissem Subcutan Intracr Melan. 2019;25(22):6801–14.

    CAS  Google Scholar 

  185. Mansfield AS, Aubry MC, Moser JC, Harrington SM, Dronca RS, Park SS, et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol. 2016;27(10):1953–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VL, Sznol M, et al. Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res. 2015;21(13):3052–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, 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. 2016;17(7):976–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672–81.

    Article  CAS  PubMed  Google Scholar 

  189. Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, Wesseling P, et al. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro Oncol. 2009;11(4):394–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5(200):200116.

    Article  Google Scholar 

  191. Steindl A, Alpar D, Heller G, Mair MJ, Gatterbauer B, Dieckmann K, et al. Tumor mutational burden and immune infiltrates in renal cell carcinoma and matched brain metastases. ESMO Open. 2021;6(2): 100057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Zhao P, Zhang J, Wu A, Zhang M, Zhao Y, Tang Y, et al. Biomimetic codelivery overcomes osimertinib-resistant NSCLC and brain metastasis via macrophage-mediated innate immunity. J Control Release. 2021;329:1249–61.

    Article  CAS  PubMed  Google Scholar 

  193. Berghoff AS, Venur VA, Preusser M, Ahluwalia MS. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am Soc Clin Oncol Educ Book. 2016;36:e116–22.

    Article  Google Scholar 

  194. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Lee JJ, Loh K, Yap YS. PI3K/Akt/mTOR inhibitors in breast cancer. Cancer Biol Med. 2015;12(4):342–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68(15):6084–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Chen IC, Hsiao LP, Huang IW, Yu HC, Yeh LC, Lin CH, et al. Phosphatidylinositol-3 kinase inhibitors, buparlisib and alpelisib, sensitize estrogen receptor-positive breast cancer cells to tamoxifen. Sci Rep. 2017;7(1):9842.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Annals of translational medicine. 2018;6(9):163–163.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Owens T, Renno T, Taupin V, Krakowski M. Inflammatory cytokines in the brain: does the CNS shape immune responses? Immunol Today. 1994;15(12):566–71.

    Article  CAS  PubMed  Google Scholar 

  201. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65.

    Article  CAS  PubMed  Google Scholar 

  202. Fitzgerald DP, Emerson DL, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, et al. TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol Cancer Ther. 2012;11(9):1959–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Hu ZI, McArthur HL, Ho AY. The abscopal effect of radiation therapy: what is it and how can we use it in breast cancer? Curr Breast Cancer Rep. 2017;9(1):45–51.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):1262–78.

    Article  CAS  PubMed Central  Google Scholar 

  205. Wang T, Wei JJ, Sabatini DM, Lander ES. Genetic screens in human cells using the CRISPR-Cas9 system. Science. 2014;343(6166):80–4.

    Article  CAS  PubMed  Google Scholar 

  206. Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS, et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2014;343(6166):84–7.

    Article  CAS  PubMed  Google Scholar 

  207. Kühnöl J, Kühnöl C, Vordermark D. Radiotherapy of brain metastases from breast cancer: treatment results and prognostic factors. Oncol Lett. 2016;11(5):3223–7.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Chen Y, Jiang T, Zhang H, Gou X, Han C, Wang J, et al. LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy. Nat Cell Biol. 2020;22(10):1276–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Wang S, Liang K, Hu Q, Li P, Song J, Yang Y, et al. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. J Clin Investig. 2017;127(12):4498–515.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Márquez-Ortiz RA, Contreras-Zárate MJ, Tesic V, Alvarez-Eraso KL, Kwak G, Littrell Z, et al. IL13Rα2 promotes proliferation and outgrowth of breast cancer brain metastases. Clin Cancer Res. 2021;27(22):6209–21.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Papageorgis P, Ozturk S, Lambert AW, Neophytou CM, Tzatsos A, Wong CK, et al. Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis. Breast Cancer Res. 2015;17(1):1–15.

    Article  CAS  Google Scholar 

  212. Yoo B, Ross A, Pantazopoulos P, Medarova Z. MiRNA10b-directed nanotherapy effectively targets brain metastases from breast cancer. Sci Rep. 2021;11(1):1–7.

    Article  Google Scholar 

  213. Masiero M, Nardo G, Indraccolo S, Favaro E. RNA interference: implications for cancer treatment. Mol Aspects Med. 2007;28(1):143–66.

    Article  CAS  PubMed  Google Scholar 

  214. Nam D-H, Jeon H-M, Kim S, Kim MH, Lee Y-J, Lee MS, et al. Activation of notch signaling in a xenograft model of brain metastasis. Clin Cancer Res. 2008;14(13):4059–66.

    Article  CAS  PubMed  Google Scholar 

  215. Wei Y, Sun Y, Wei J, Qiu X, Meng F, Storm G, et al. Selective transferrin coating as a facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer in vivo. J Control Release. 2021;337:521–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the Central University of Punjab for providing infrastructure and facilities. Council of Scientific and Industrial Research (CSIR), New Delhi, for Senior Research Fellowship (SRF) to Yogita Chhichholiya. and Junior Research Fellowship (JRF) to Ruthuparna Malayil for PhD. DST-FIST grant (SR/FST/LS-I/2017/49) to the Department of Human Genetics and Molecular Medicine, Central University of Punjab, is acknowledged with thanks.

Funding

Financial support to Yogita Chhichholiya (Award No- 09/1051(0038)/2019-EMR-1) and Ruthuparna Malayil (Award No- KL1216200313) from Council of Scientific and Industrial Research (CSIR) India is highly acknowledged.

Author information

Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India

    Yogita Chhichholiya, Malayil Ruthuparna, Harini Velagaleti & Anjana Munshi

Authors
  1. Yogita Chhichholiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malayil Ruthuparna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harini Velagaleti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anjana Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AM and YC conceptualized the idea of the review. YC, Rm and HV curated the data, and prepared the draft. AM critically revised and edited the manuscript.

Corresponding author

Correspondence to Anjana Munshi.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chhichholiya, Y., Ruthuparna, M., Velagaleti, H. et al. Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood–brain barrier and treatment strategies. Clin Transl Oncol 25, 1218–1241 (2023). https://doi.org/10.1007/s12094-022-03050-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-022-03050-z

Keywords

Search

Navigation