Abstract
Emerging evidence suggests endothelial cells (EC) play a critical role in promoting Glioblastoma multiforme (GBM) cell proliferation and resistance to therapy. The molecular basis for GBM-EC interactions is incompletely understood. We hypothesized that the chemokine CXCL12 and its receptor CXCR4 could mediate direct interactions between GBM cells and tumor-associated endothelial cells and that disruption of this interaction might be the molecular basis for the anti-tumor effects of CXCR4 antagonists. We investigated this possibility in vivo and in an in vitro co-culture model that incorporated extracellular matrix, primary human brain microvascular ECs (HBMECs) and either an established GBM cell line or primary GBM specimens. Depletion of CXCR4 in U87 GBM cells blocked their growth as intracranial xenografts indicating that tumor cell CXCR4 is required for tumor growth in vivo. In vitro, co-culture of either U87 cells or primary GBM cells with HBMECs resulted in their co-localization and enhanced GBM cell growth. Genetic manipulation of CXCL12 expression and pharmacological inhibition of its receptors CXCR4 and CXCR7 revealed that the localizing and trophic effects of endothelial cells on GBM cells were dependent upon CXCL12 and CXCR4. These findings indicate that the CXCL12/CXCR4 pathway directly mediates endothelial cell trophic function in GBMs and that inhibition of CXCL12-CXCR4 signaling may uniquely target this activity. Therapeutic disruption of endothelial cell trophic functions could complement the structural disruption of anti-angiogenic regimens and, in combination, might also improve the efficacy of radiation and chemotherapy in treating GBMs.
Highlights
Tissue architecture, including cell-cell and cell-extracellular matrix interactions, is an essential determinant of cellular behavior in normal and pathological states
We previously demonstrated that systemic administration of the specific CXCR4 antagonist AMD 3100, inhibited the intracranial growth of U87 glioblastoma xenografts by increasing apoptosis and decreasing proliferation of tumor cells [14]
Both tumor cells and endothelial cells express CXCR4, and to distinguish whether tumor cell-CXCR4 function is required for tumor growth, we depleted CXCR4 by short hairpin interfering RNA (shRNA)-mediated knock-down in U87 glioblastoma cells that had been engineered to express a fusion protein of firefly luciferase and eGFP
Summary
Tissue architecture, including cell-cell and cell-extracellular matrix interactions, is an essential determinant of cellular behavior in normal and pathological states. The earliest histopathological descriptions of glioblastoma multiforme (GBM) recognized the involvement of vascular endothelial cells (ECs) in tumor architecture. In GBMs, there is an abundance of vascular endothelial cells, which was initially assumed to maintain the high metabolic rates observed in these tumors through the formation of perfusing blood vessels [4]. Despite a redundancy in microvessels, tumors exist in a relatively hypoxic state in which they utilize anaerobic metabolism to a greater degree than normal brain tissue [5]. These observations call into question the role of the abundant vasculature in GBM
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