engleski

A high-performance mass spectrometric ganglioside profile as a brain tumor-specific fingerprinting

Introduction: Gangliosides (GGs), sialylated glycosphingolipids, are highly abundant in cells of the central nervous system, primarily as components of the outer leaflet of plasma membranes. They participate in cell-signaling, cell-to-cell recognition, regulation of cell proliferation and growth, as well as in malignant transformation. Tumor transformed cells contain an aberrant GG composition, which is considered to be a tumor type-specific and to correlate with a tumor grade and invasiveness. Therefore, tumor-associated GG antigens are intensively studied as potential diagnostic biomarkers and therapeutic targets/agents. The aim of this study was to define and compare detailed GG compositions of several human brain tumor types using high-performance mass spectrometry (MS) methods we developed and demonstrated to provide the most complete profiling of bioglycoconjugate mixtures. Materials & Methods: GGs were extracted and purified from the following brain tumor types: gliosarcoma, meningioma, haemangioma and brain metastasis of adenocarcinoma. A purified native GG mixture from normal adult human brain (frontal lobe) was used as the reference. MS instrumentation employed for direct compositional (MS1) and structural (MS/MS) analysis of the tumor-associated GGs in complex mixtures was: chip- and capillary-based nanoelectrospray (nanoESI) quadrupole time-of-flight (QTOF) MS, and nanoESI Fourier-transform ion cyclotron resonance (FT-ICR) MS, operating in the negative ion mode. Results: Each of the determined tumor GG compositions was distinctive i.e. specific for the particular type of tumor. Mass spectra of the gliosarcoma-associated GG pattern enabled assignment of 73 different structures. All major brain-associated species were present, however in very altered proportions, dominated by GD3. Surprisingly, an abundant species was structurally identified as a novel O-Ac-GD3 isomer O-acetylated at the inner Neu5Ac-residue, previously not evidenced. Additional unusual minor species, some of them known as antigens of a fetal brain development, were also revealed. The presence of typical brain GG species is in accordance with, at least in part, the astrocytic origin of gliosarcoma. Analyzed meningioma was characterized by less complex GG composition, containing mostly GM3, GM1, and minor GM2 and GD1 ; each glycan entity was, however, represented by several species due to high heterogeneity of their ceramide portions, often modified by additional hydroxylation. Aberrant GG patterns of haemangioma and adenocarcinoma brain metastasis were quite simple, but distinguishable, reflecting the respective extraneural origin of these tumors. Conclusion: The results indicate that tumor-associated GG profiles determined by sophisticated, high resolution and sensitivity MS approaches could serve as diagnostically valuable tumor fingerprinting, complementing histopathological diagnosis. Also, modern MS represents the most efficient analytical technique for identifying novel molecular targets for tumor treatment.

gangliosides; brain tumor markers; mass spectrometry; novel O-Ac-GD3 isomer

Časopis je indeksiran u Neuroscience Citation indeksu i EMBASE/Excerpta Medica.