Anti-angiogenic therapy induces integrin-linked kinase 1 up-regulation in a mouse model of glioblastoma.
BACKGROUND
In order to improve our understanding of the molecular pathways that mediate tumor proliferation and angiogenesis, and to evaluate the biological response to anti-angiogenic therapy, we analyzed the changes in the protein profile of glioblastoma in response to treatment with recombinant human Platelet Factor 4-DLR mutated protein (PF4-DLR), an inhibitor of angiogenesis.


RESULTS
U87-derived experimental glioblastomas were grown in the brain of xenografted nude mice, treated with PF4-DLR, and processed for proteomic analysis. More than fifty proteins were differentially expressed in response to PF4-DLR treatment. Among them, integrin-linked kinase 1 (ILK1) signaling pathway was first down-regulated but then up-regulated after treatment for prolonged period. The activity of PF4-DLR can be increased by simultaneously treating mice orthotopically implanted with glioblastomas, with ILK1-specific siRNA. As ILK1 is related to malignant progression and a poor prognosis in various types of tumors, we measured ILK1 expression in human glioblastomas, astrocytomas and oligodendrogliomas, and found that it varied widely; however, a high level of ILK1 expression was correlated to a poor prognosis.


CONCLUSIONS
Our results suggest that identifying the molecular pathways induced by anti-angiogenic therapies may help the development of combinatorial treatment strategies that increase the therapeutic efficacy of angiogenesis inhibitors by association with specific agents that disrupt signaling in tumor cells.
European Laboratory for Angiogenesis and Translational Research, University of Milan, Milan, Italy.
Chiara
C
Verpelli
Giulio
G
Bertani
Valentina
V
Cea
Monica
M
Patti
Andreas
A
Bikfalvi
Lorenzo
L
Bello
Carlo
C
Sala
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D034741:RNA, Small Interfering; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015854:Up-Regulation; D000099200:Scaffold Protein ILK
D020533:Angiogenesis Inhibitors; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000099200:Scaffold Protein ILK