title: Transmigration characteristics of breast cancer and melanoma cells through the brain endothelium: Role of Rac and PI3K.
abstract: Brain metastases are common and devastating complications of both breast cancer and melanoma. Although mammary carcinoma brain metastases are more frequent than those originating from melanoma, this latter has the highest tropism to the brain. Using static and dynamic in vitro approaches, here we show that melanoma cells have increased adhesion to the brain endothelium in comparison to breast cancer cells. Moreover, melanoma cells can transmigrate more rapidly and in a higher number through brain endothelial monolayers than breast cancer cells. In addition, melanoma cells have increased ability to impair tight junctions of cerebral endothelial cells. We also show that inhibition of Rac or PI3K impedes adhesion of breast cancer cells and melanoma cells to the brain endothelium. In addition, inhibition of Rac or PI3K inhibits the late phase of transmigration of breast cancer cells and the early phase of transmigration of melanoma cells. On the other hand, the Rac inhibitor EHT1864 impairs the junctional integrity of the brain endothelium, while the PI3K inhibitor LY294002 has no damaging effect on interendothelial junctions. We suggest that targeting the PI3K/Akt pathway may represent a novel opportunity in preventing the formation of brain metastases of melanoma and breast cancer.
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Molnár
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: Fazakas
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Haskó
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Sipos
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Nagy
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Nyúl-Tóth
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Attila E
authors.initials: AE
authors.lastname: Farkas
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Attila G
authors.initials: AG
authors.lastname: Végh
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Váró
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Galajda
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.|b Institute of Life Sciences, Vasile Goldis Western University of Arad , Arad , Romania.
authors.forename: István A
authors.initials: IA
authors.lastname: Krizbai
authors.affiliation: a Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary.
authors.forename: Imola
authors.initials: I
authors.lastname: Wilhelm
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D011804:Quinolines; D020830:rac1 GTP-Binding Protein; C506907:EHT 1864
keywords: PI3K; Rac; adhesion; blood-brain barrier; brain metastasis; breast cancer; cerebral endothelial cell; melanoma; transmigration