Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis. © 1999 Cancer Research Campaign

We have cloned, expressed, and partially purified a naturally occurring, truncated, soluble form of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha subunit to investigate its biochemical and biologic properties. The soluble receptor species lacks the transmembrane and cytoplasmic domains that are presumably removed from the intact receptor cDNA by a mechanism of alternative splicing. The resulting soluble 55- to 60-kD glycosylated receptor species binds GM-CSF with a dissociation constant (kd) of 3.8 nmol/L. The soluble GM-CSF receptor successfully competes for GM-CSF binding not only with the transmembrane-anchored GM-CSF receptor alpha subunit but also with the native oligomeric high-affinity receptor complex. In addition, in human bone marrow colony-forming assays, the soluble GM-CSF receptor species can antagonize the activity of GM-CSF. Our data suggest that the soluble GM-CSF receptor may be capable of acting in vivo as a modulator of the biologic activity of GM-CSF.

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We observed that gelatinases-A and -B are present in most gliomas but we found active gelatinase-A only in the GBMs with extraneural metastases suggesting that the active form of this enzyme may determine the metastatic potential of GBMs. We propose that high levels of gelatinolytic activities are associated with intracerebral invasion and rarely, metastases of GBMs.

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