A novel molecular diagnostic of glioblastomas: detection of an extracellular fragment of protein tyrosine phosphatase mu.
We recently found that normal human brain and low-grade astrocytomas express the receptor protein tyrosine phosphatase mu (PTPmu) and that the more invasive astrocytomas, glioblastoma multiforme (GBM), downregulate full-length PTPmu expression. Loss of PTPmu expression in GBMs is due to proteolytic cleavage that generates an intracellular and potentially a cleaved and released extracellular fragment of PTPmicro. Here, we identify that a cleaved extracellular fragment containing the domains required for PTPmicro-mediated adhesion remains associated with GBM tumor tissue. We hypothesized that detection of this fragment would make an excellent diagnostic tool for the localization of tumor tissue within the brain. To this end, we generated a series of fluorescently tagged peptide probes that bind the PTPmu fragment. The peptide probes specifically recognize GBM cells in tissue sections of surgically resected human tumors. To test whether the peptide probes are able to detect GBM tumors in vivo, the PTPmu peptide probes were tested in both mouse flank and intracranial xenograft human glioblastoma tumor model systems. The glial tumors were molecularly labeled with the PTPmu peptide probes within minutes of tail vein injection using the Maestro FLEX In Vivo Imaging System. The label was stable for at least 3 hours. Together, these results indicate that peptide recognition of the PTPmu extracellular fragment provides a novel molecular diagnostic tool for detection of human glioblastomas. Such a tool has clear translational applications and may lead to improved surgical resections and prognosis for patients with this devastating disease.
Burden-Gulley
Susan M
SM
Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4960, USA.
Gates
Theresa J
TJ
Burgoyne
Adam M
AM
Cutter
Jennifer L
JL
Lodowski
David T
DT
Robinson
Shenandoah
S
Sloan
Andrew E
AE
Miller
Robert H
RH
Basilion
James P
JP
Brady-Kalnay
Susann M
SM
D000595:Amino Acid Sequence; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D005909:Glioblastoma / Q000175:diagnosis* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000032:analysis* / Q000302:isolation & purification / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D007527:Isoenzymes; D010446:Peptide Fragments; D017027:Protein Tyrosine Phosphatases