Integrins mediate adhesion of medulloblastoma cells to tenascin and activate pathways associated with survival and proliferation

Abstract

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 a9 and b1 integrin subunits; antibody and disintegrin blockade of a9 and b1 binding eliminated the adhesion. The H4 ECM was enriched in tenascin, a binding partner for the a9b1 integrin heterodimer. Purified tenascin-C supported D283 cell adhesion. The adhesion was blocked by antibodies to a9 and b1 integrin. In vivo data were similar; immunohistochemistry of primary human medulloblastomas with leptomeningeal extension demonstrated increased expression of a9 and b1 integrins as well as tenascin at the interface of brain and leptomeningeal tumor. These data suggest that tumor-cell expressions of a9 and b1 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 a9 and b1 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.

Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors

“…It was shown that ITGA9 is expressed in melanoma cells, 27 aberrantly upregulated in small-cell lung cancers, both cell lines and primary tumors 28 and medulloblastoma cells, 29 the expression level of integrin a9b1 on astrocytomas is correlated with increased grade of this brain tumor and is highest on glioblastoma, whereas normal astrocytes do not express this integrin, 30 ITGA9 is absent in normal adults colon tissues but it is expressed in 6 of 10 primary colon adenocarcinomas and 2 of 7 colon adenocarcinoma cell lines (Caco-2 and T84). 31 According to another study, ITGA9 has significantly higher expression levels in colorectal tumors with high microsatellite instability ( mechanisms of ITGA9 activation in cancer cells remain unclear; however the effect may unfavorably contribute to the cancer prognosis supporting ITGA9 as a potential target for anti-integrin therapy.…”

“…37 Here, two different aspects of the changes are to be discussed. From the one side, an activation of ITGA9 expression was shown for different human tumors and cancer cells-smallcell lung cancer, 28 medulloblastoma cells, 29 astrocytomas and glioblastoma. 30 From the other side, frequent genetic/epigenetic aberrations (deletions, methylation) of ITGA9 were identified in different epithelial cancers using NotI-microarray.…”

LKB1 Represses Focal Adhesion Kinase (FAK) Signaling via a FAK-LKB1 Complex to Regulate FAK Site Maturation and Directional Persistence

“…physiologic processes such as embryogenesis and wound healing, but it is also an integral characteristic in pathological conditions such as cancer metastasis (1)(2)(3)(4)(5)(6)(7)(8). Cell motility itself has been studied in a variety of organisms to create a general model.…”

“…Focal adhesion kinase (FAK) 2 acts as a signaling node at cell adhesion sites called focal contacts to promote cytoskeletal reorganization, adhesion, migration, and survival (11). FAK regulates cell motility through integrins and growth factor receptors (11) by relaying cues from the extracellular matrix through the plasma membrane, and into the cytoplasm.…”

Extraneural metastases in medulloblastoma

“…There are few theories to explain this phenomenon. Fiorilli et al 7 in 2008 described some medulloblastoma molecular features that can help our understanding in this matter. He described increased expression levels of integrins and tenascins in the medulloblatoma cells.…”