Histamine in the Neural and Cancer Stem Cell Niches

  • Maria Francisca Eiriz
  • João Oliveira Malva
  • Fabienne AgasseEmail author
  • Liliana BernardinoEmail author
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 12)


Neural stem cells (NSCs) present in the subventricular zone and in the subgranular zone of the adult brain possess proliferative and self-renewal capacities and are able to generate neurons and glial cells. Under physiologic conditions, these properties are tightly regulated at the neurogenic niche consisting of soluble factors and cell-to-cell interactions that control signaling pathways and genetic expression related to the stemness state. The deregulation of these pathways has been suggested to promote the neoplasic transformation of NSCs into cancer stem cells (CSCs) and the formation of gliomas. In fact, NSCs and CSCs share several characteristics including cell surface receptors and intracellular signalling pathways, several cell markers of immaturity, and affinity for blood vessels. Therefore, understanding the cellular and molecular pathways controlling NSCs properties will shed light on brain cancer development and progression. Among soluble factors able to modulate both NSCs and tumoral cells, histamine is raising attention due to its ability to modulate proliferation, differentiation, and survival of both cell types. This may suggest that the modulation of the histaminergic system could emerge as a novel approach to promote brain repair by neurogenesis stimulation and to hamper the development of brain tumors. In this chapter we discuss recent findings regarding the role of histamine in both neurogenesis and tumorigenesis.


Stem Cell Glial Fibrillary Acidic Protein Cancer Stem Cell Dentate Gyrus Ependymal Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



 This work was supported by FCT Portugal and FEDER, PTDC/SAU-NEU/104415/2008 and PTDC/SAU-NEU/101783/2008, grant no. 96542, from the Calouste Gulbenkian Foundation and L’Oréal-UNESCO Portugal for Women in Science. Maria Francisca Eiriz acknowledges the MIT-Portugal Program, focus in Bioengineering.


  1. Abel TW, Clark C, Bierie B, Chytil A, Aakre M, Gorska A et al (2009) GFAP-Cre-mediated activation of oncogenic K-ras results in expansion of the subventricular zone and infiltrating glioma. Mol Cancer Res 7:645–653PubMedCentralPubMedCrossRefGoogle Scholar
  2. Adams WJ, Lawson JA, Morris DL (1994) Cimetidine inhibits in vivo growth of human colon cancer and reverses histamine stimulated in vitro and in vivo growth. Gut 35:1632–1636PubMedCrossRefGoogle Scholar
  3. Agasse F, Bernardino L, Silva B, Ferreira R, Grade S, Malva JO (2008) Response to histamine allows the functional identification of neuronal progenitors, neurons, astrocytes, and immature cells in subventricular zone cell cultures. Rejuvenation Res 11:187–200PubMedCrossRefGoogle Scholar
  4. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRefGoogle Scholar
  5. Bernardino L, Eiriz MF, Santos T, Xapelli S, Grade S, Rosa AI et al (2012) Histamine stimulates neurogenesis in the rodent subventricular zone. Stem Cells 30:773–784PubMedCrossRefGoogle Scholar
  6. Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW et al (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4:226–235PubMedCentralPubMedCrossRefGoogle Scholar
  7. Brown RE, Stevens DR, Haas HL (2001) The physiology of brain histamine. Prog Neurobiol 63:637–672PubMedCrossRefGoogle Scholar
  8. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG et al (2012a) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526PubMedCentralPubMedCrossRefGoogle Scholar
  9. Chen J, McKay RM, Parada LF (2012b) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47PubMedCentralPubMedCrossRefGoogle Scholar
  10. Cianchi F, Cortesini C, Schiavone N, Perna F, Magnelli L, Fanti E et al (2005) The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res 11:6807–6815PubMedCrossRefGoogle Scholar
  11. Clarke L, van der Kooy D (2011) The adult mouse dentate gyrus contains populations of committed progenitor cells that are distinct from subependymal zone neural stem cells. Stem Cells 29:1448–1458PubMedGoogle Scholar
  12. Cricco G, Martin G, Medina V, Nunez M, Mohamad N, Croci M et al (2006) Histamine inhibits cell proliferation and modulates the expression of Bcl-2 family proteins via the H2 receptor in human pancreatic cancer cells. Anticancer Res 26:4443–4450PubMedGoogle Scholar
  13. Cricco GP, Mohamad NA, Sambuco LA, Genre F, Croci M, Gutierrez AS et al (2008) Histamine regulates pancreatic carcinoma cell growth through H3 and H4 receptors. Inflamm Res 57(Suppl 1):S23–S24PubMedCrossRefGoogle Scholar
  14. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317PubMedCrossRefGoogle Scholar
  15. Falus A, Pos Z, Darvas Z (2010) Histamine in normal and malignant cell proliferation. Adv Exp Med Biol 709:109–123PubMedCrossRefGoogle Scholar
  16. Francis H, DeMorrow S, Venter J, Onori P, White M, Gaudio E et al (2012) Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma. Gut 61:753–764PubMedCentralPubMedCrossRefGoogle Scholar
  17. Fuentealba LC, Obernier K, Alvarez-Buylla A (2012) Adult neural stem cells bridge their niche. Cell Stem Cell 10:698–708PubMedCentralPubMedCrossRefGoogle Scholar
  18. Fukuda M, Kusama K, Sakashita H (2008) Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression. BMC Cancer 8:376–389PubMedCentralPubMedCrossRefGoogle Scholar
  19. Galan-Moya EM, Le Guelte A, Lima Fernandes E, Thirant C, Dwyer J, Bidere N et al (2011) Secreted factors from brain endothelial cells maintain glioblastoma stem-like cell expansion through the mTOR pathway. EMBO Rep 12:470–476PubMedCentralPubMedCrossRefGoogle Scholar
  20. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021PubMedCrossRefGoogle Scholar
  21. Gil-Perotin S, Marin-Husstege M, Li J, Soriano-Navarro M, Zindy F, Roussel MF et al (2006) Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. J Neurosci 26:1107–1116PubMedCrossRefGoogle Scholar
  22. Hernandez-Angeles A, Soria-Jasso LE, Ortega A, Arias-Montano JA (2001) Histamine H1 receptor activation stimulates mitogenesis in human astrocytoma U373 MG cells. J Neurooncol 55:81–89PubMedCrossRefGoogle Scholar
  23. Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H et al (2010) Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28:1019–1029PubMedCrossRefGoogle Scholar
  24. Ihrie RA, Alvarez-Buylla A (2011) Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron 70:674–686PubMedCentralPubMedCrossRefGoogle Scholar
  25. Jacques TS, Swales A, Brzozowski MJ, Henriquez NV, Linehan JM, Mirzadeh Z et al (2010) Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. EMBO J 29:222–235PubMedCrossRefGoogle Scholar
  26. Jiang CG, Liu FR, Yu M, Li JB, Xu HM (2010) Cimetidine induces apoptosis in gastric cancer cells in vitro and inhibits tumor growth in vivo. Oncol Rep 23:693–700PubMedCrossRefGoogle Scholar
  27. Johansson M, Henriksson R, Bergenheim AT, Koskinen LO (2000) Interleukin-2 and histamine in combination inhibit tumour growth and angiogenesis in malignant glioma. Br J Cancer 83:826–832PubMedCentralPubMedCrossRefGoogle Scholar
  28. Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S et al (2009) CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 32:181–187PubMedGoogle Scholar
  29. Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432PubMedCentralPubMedCrossRefGoogle Scholar
  30. Lefranc F, Yeaton P, Brotchi J, Kiss R (2006) Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review). Int J Oncol 28:1021–1030PubMedGoogle Scholar
  31. Malaviya R, Uckun FM (2000) Histamine as an autocrine regulator of leukemic cell proliferation. Leuk Lymphoma 36:367–373PubMedCrossRefGoogle Scholar
  32. Mannello F, Medda V, Tonti GA (2011) Hypoxia and neural stem cells: from invertebrates to brain cancer stem cells. Int J Dev Biol 55:569–581PubMedCrossRefGoogle Scholar
  33. Massari NA, Medina VA, Martinel Lamas DJ, Cricco GP, Croci M, Sambuco L et al (2011) Role of H4 receptor in histamine-mediated responses in human melanoma. Melanoma Res 21:395–404PubMedCrossRefGoogle Scholar
  34. Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T (2002) Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. Br J Cancer 86:161–167PubMedCentralPubMedCrossRefGoogle Scholar
  35. Medina V, Croci M, Crescenti E, Mohamad N, Sanchez-Jimenez F, Massari N et al (2008) The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol Ther 7:28–35PubMedCrossRefGoogle Scholar
  36. Medina VA, Brenzoni PG, Lamas DJ, Massari N, Mondillo C, Nunez MA et al (2011) Role of histamine H4 receptor in breast cancer cell proliferation. Front Biosci (Elite Ed) 3:1042–1060Google Scholar
  37. Meng F, Han Y, Staloch D, Francis T, Stokes A, Francis H (2011) The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. Hepatology 54:1718–1728PubMedCrossRefGoogle Scholar
  38. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702PubMedCentralPubMedCrossRefGoogle Scholar
  39. Molina-Hernandez A, Velasco I (2008) Histamine induces neural stem cell proliferation and neuronal differentiation by activation of distinct histamine receptors. J Neurochem 106:706–717PubMedCrossRefGoogle Scholar
  40. Mu Y, Lee SW, Gage FH (2010) Signaling in adult neurogenesis. Curr Opin Neurobiol 20:416–423PubMedCentralPubMedCrossRefGoogle Scholar
  41. Panula P, Lintunen M, Karlstedt K (2000) Histamine in brain development and tumors. Semin Cancer Biol 10:11–14PubMedCrossRefGoogle Scholar
  42. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedCrossRefGoogle Scholar
  43. Rodriguez-Martinez G, Velasco I, Garcia-Lopez G, Solis KH, Flores-Herrera H, Diaz NF et al (2012) Histamine is required during neural stem cell proliferation to increase neuron differentiation. Neuroscience 216:10–17PubMedCrossRefGoogle Scholar
  44. Sanai N, Nguyen T, Ihrie RA, Mirzadeh Z, Tsai HH, Wong M et al (2011) Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478:382–386PubMedCentralPubMedCrossRefGoogle Scholar
  45. Soya A, Song YH, Kodama T, Honda Y, Fujiki N, Nishino S (2008) CSF histamine levels in rats reflect the central histamine neurotransmission. Neurosci Lett 430:224–229PubMedCentralPubMedCrossRefGoogle Scholar
  46. Stoyanov E, Uddin M, Mankuta D, Dubinett SM, Levi-Schaffer F (2012) Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells. Lung Cancer 75:38–44PubMedCrossRefGoogle Scholar
  47. Szincsak N, Hegyesi H, Hunyadi J, Falus A, Juhasz I (2002a) Different h2 receptor antihistamines dissimilarly retard the growth of xenografted human melanoma cells in immunodeficient mice. Cell Biol Int 26:833–836PubMedCrossRefGoogle Scholar
  48. Szincsak N, Hegyesi H, Hunyadi J, Martin G, Lazar-Molnar E, Kovacs P et al (2002b) Cimetidine and a tamoxifen derivate reduce tumour formation in SCID mice xenotransplanted with a human melanoma cell line. Melanoma Res 12:231–240PubMedCrossRefGoogle Scholar
  49. Tomita K, Nakamura E, Okabe S (2005) Histamine regulates growth of malignant melanoma implants via H2 receptors in mice. Inflammopharmacology 13:281–289PubMedCrossRefGoogle Scholar
  50. Vaysse L, Labie C, Canolle B, Jozan S, Beduer A, Arnauduc F et al (2012) Adult human progenitor cells from the temporal lobe: another source of neuronal cells. Brain Inj 26:1636–1645PubMedCrossRefGoogle Scholar
  51. Yang XD, Ai W, Asfaha S, Bhagat G, Friedman RA, Jin G et al (2011) Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b + Ly6G + immature myeloid cells. Nat Med 17:87–95PubMedCentralPubMedCrossRefGoogle Scholar
  52. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  2. 2.Faculty of Health SciencesUniversity of Beira InteriorCovilhãPortugal

Personalised recommendations