Integrins mediate adhesion of medulloblastoma cells to tenascin and activate pathways associated with survival and proliferation.
Medulloblastoma spreads by leptomeningeal dissemination rather than by infiltration that characterizes other CNS tumors, eg, gliomas. This study represents an initial attempt to identify both the molecules that mediate medulloblastoma adhesion to leptomeninges and the pathways that are key to survival and proliferation of tumor following adhesion. As a first step in molecule identification, we produced adhesion of D283 medulloblastoma cells to the extracellular matrix (ECM) of H4 glioma cells in vitro. Within this context, D283 cells preferentially expressed the alpha9 and beta1 integrin subunits; antibody and disintegrin blockade of alpha9 and beta1 binding eliminated the adhesion. The H4 ECM was enriched in tenascin, a binding partner for the alpha9beta1 integrin heterodimer. Purified tenascin-C supported D283 cell adhesion. The adhesion was blocked by antibodies to alpha9 and beta1 integrin. In vivo data were similar; immunohistochemistry of primary human medulloblastomas with leptomeningeal extension demonstrated increased expression of alpha9 and beta1 integrins as well as tenascin at the interface of brain and leptomeningeal tumor. These data suggest that tumor-cell expressions of alpha9 and beta1 integrins in combination with extracellular tenascin are necessary for medulloblastoma adhesion to the leptomeninges. As a first step in the identification of pathways that mediate survival and proliferation of tumor following adhesion, we demonstrated that adhesion to H4 ECM was associated with survival and proliferation of D283 cells as well as activation of the MAPK pathway in a growth factor deficient environment. Antibody blockade of alpha9 and beta1 integrin binding that eliminated adhesion also eliminated the in vitro survival benefit. These data suggest that adhesion of medulloblastoma to the meninges is necessary for the survival and proliferation of these tumor cells at the secondary site.
Fiorilli
Paul
P
Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA.
Partridge
Darren
D
Staniszewska
Izabela
I
Wang
Jin Y
JY
Grabacka
Maja
M
So
Kelvin
K
Marcinkiewicz
Cezary
C
Reiss
Krzysztof
K
Khalili
Kamel
K
Croul
Sidney E
SE
D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008527:Medulloblastoma / Q000503:physiopathology*; D008577:Meningeal Neoplasms / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000503:physiopathology; D019063:Tenascin / Q000502:physiology*
C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; D016023:Integrins; D019063:Tenascin; C113256:integrin alpha 9 beta 1
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