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From the Laboratoires de CancérologieExpérimentale* and Transfert d’OncologieBiologique, Faculté de MédecineSecteur Nord, IFR Jean Roche, Marseille, France; the Service deNeurochirurgie, CHU Timone, Chemin del’Armée d’Afrique, Marseille, France; the Sanofi-SynthelaboDépartement Immunologie-Oncologie, Montpellier,France; and the Finsen Laboratory,¶ Copenhagen, Denmark
Presently, there is no effective treatment for
glioblastoma, the most malignant and common brain tumor. Growth
factors are potential targets for therapeutic strategies because they
are essential for tumor growth and progression. Peptidylglycine
-amidating monooxygenase is the enzyme producing -amidated
bioactive peptides from their inactive glycine-extended precursors. The
high expression of peptidylglycine -amidating monooxygenase mRNA in
glioblastoma and glioma cell lines points to the involvement of
-amidated peptides in tumorigenic growth processes in the brain.
After screening of amidated peptides, it was found that human
glioblastoma cell lines express high levels of adrenomedullin (AM)
mRNA, and that immunoreactive AM is released into the culture
medium. AM is a multifunctional regulatory peptide with mitogenic and
angiogenic capabilities among others. Real-time quantitative reverse
transcriptase-polymerase chain reaction analysis showed that AM mRNA
was correlated to the tumor type and grade, with high
expression in all glioblastomas analyzed, whereas a low
expression was found in anaplastic astrocytomas and barely detectable
levels in low-grade astrocytomas and oligodendrogliomas. In the present
study we also demonstrate the presence of mRNA encoding the putative AM
receptors, calcitonin receptor-like receptor/receptor
activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) in both
glioma tissues and glioblastoma cell lines and further show that
exogenously added AM can stimulate the growth of these glioblastoma
cells in vitro. These findings suggest that AM may
function as an autocrine growth factor for glioblastoma cells. One way
to test the autocrine hypothesis is to interrupt the function of the
endogenously produced AM. Herein, we demonstrate that a
polyclonal antibody specific to AM, blocks the binding of the
hormone to its cellular receptors and decreases by 33%
(P < 0.001) the growth of U87 glioblastoma cells
in vitro. Intratumoral administration of the anti-AM
antibody resulted in a 70% (P < 0.001) reduction
in subcutaneous U87 xenograft weight 21 days after treatment.
Furthermore, the density of vessels was decreased in the
antibody-treated tumors. These findings support that AM may function as
a potent autocrine/paracrine growth factor for human glioblastomas and
demonstrate that inhibition of the action of AM (produced by tumor
cells) may suppress tumor growth in
vivo.
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