g(m1)-ganglioside and Glioblastoma

Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis that is highly heterogeneous and invasive. One of the most major challenges of GBM treatment in the clinic is the blood-brain barrier (BBB). Additionally, the tumor microenvironment (TME) is highly enriched with immunosuppressed M2-like tumor-associated macrophages (M2 TAMs) and glioblastoma stem cells (GSCs), which promoted the malignancy of GBM through the PTN-PTPRZ1 signaling axis. Here, we developed a self-assembled dual-targeted hybrid micelle (DT-GM1) as a nanocarrier to deliver the chemotherapeutic agent doxorubicin (DOX). We demonstrated that this DT-GM1/DOX can cross the BBB using in vitro and in vivo GBM models, and that M2pep and PTPRZ1 antibodies allow it to precisely target the tumor microenvironment where M2 TAMs and GSCs are enriched, increasing intracellular drug accumulation via multiple internalization pathways. Additionally, simultaneous elimination of M2 TAMs and GSCs blocked the PTN-PTPRZ1 signaling axis, resulting in less M2 TAM infiltration and increased polarization to the M1 phenotype, reshaping the immune microenvironment. Overall, we have established a nanocarrier that can penetrate the BBB and target the TME while also synergizing with GBM chemotherapeutic agents, providing a promising new strategy for GBM treatment.

Topics: Brain Neoplasms; Cell Line, Tumor; Doxorubicin; G(M1) Ganglioside; Glioblastoma; Humans; Macrophages; Receptor-Like Protein Tyrosine Phosphatases, Class 5; Signal Transduction; Tumor Microenvironment

The cancer stem cells (CSCs) of glioblastoma multiforme (GBM), a grade IV astrocytoma, have been enriched by the expressed marker CD133. However, recent studies have shown that CD133(-) cells also possess tumor-initiating potential. By analysis of gangliosides on various cells, we show that ganglioside D3 (GD3) is overexpressed on eight neurospheres and tumor cells; in combination with CD133, the sorted cells exhibit a higher expression of stemness genes and self-renewal potential; and as few as six cells will form neurospheres and 20-30 cells will grow tumor in mice. Furthermore, GD3 synthase (GD3S) is increased in neurospheres and human GBM tissues, but not in normal brain tissues, and suppression of GD3S results in decreased GBM stem cell (GSC)-associated properties. In addition, a GD3 antibody is shown to induce complement-dependent cytotoxicity against cells expressing GD3 and inhibition of GBM tumor growth in vivo. Our results demonstrate that GD3 and GD3S are highly expressed in GSCs, play a key role in glioblastoma tumorigenicity, and are potential therapeutic targets against GBM.

Topics: AC133 Antigen; Animals; Brain Neoplasms; Cell Line, Tumor; G(M1) Ganglioside; Gangliosides; Glioblastoma; Humans; Mice; Neoplastic Stem Cells; Proto-Oncogene Proteins c-met; Sialyltransferases

High-affinity anti-GM1 antibodies are frequently described in several nervous system diseases, mainly in multifocal motor neuropathy (MMN) and some acute neuropathies. These antibodies are currently detected using enzyme-linked immunosorbent assay (ELISA) and immuno-thin-layer-chromatography (immuno-TLC) methods. We report in this article a new method based on the incorporation of exogenous GM1 in a selected cell line to detect anti-GM1 antibodies using flow cytometry (FC). This method is evaluated on 80 sera from normal blood donors (NBD) and patients suffering various nervous system diseases. It appears to be as sensitive as our method ELISA for the diagnosis of some motor neuron syndromes.

Topics: Autoantibodies; Flow Cytometry; G(M1) Ganglioside; Glioblastoma; Humans; Motor Neuron Disease; Neuroblastoma; Sensitivity and Specificity; Tumor Cells, Cultured

This study is intended to demonstrate the versatility and feasibility of custom-made oligosaccharide-exposing neoglycoconjugates including histo-blood group epitopes in various human lesions, including nasal polyps. The binding of the biotinylated probes was determined on formalin-fixed paraffin-embedded sections from archive materials. The general aspects of our results may be interpreted as follows: the neoglycoconjugates used here can readily detect differences in the ability of cells to bind glycan residues in tissue sections, thereby enabling the extent of the binding capacity of various types of human lesions to be compared. Furthermore, the reactivity to glycan may reflect characteristics of the cells and their environment. The investigation into pathological disorders with respect to the binding capacity of these carrier-immobilized mono- or oligosaccharide structures derived from custom-made synthesis or biochemical purification is based on the prospect of translating progress in this field into the establishment of potentially beneficial procedures for medical diagnosis and pathological classification.

Topics: Adenocarcinoma; Binding Sites; Blood Group Antigens; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Transitional Cell; Colonic Neoplasms; Feasibility Studies; Female; Fibroadenoma; G(M1) Ganglioside; Glioblastoma; Glycoconjugates; Histocytochemistry; Humans; Hyaluronic Acid; Male; Melanoma; Nasal Polyps; Neoplasms; Prostatic Hyperplasia; Skin Neoplasms; Trisaccharides; Urinary Bladder Neoplasms

Limitations of classification schemes for brain tumors based solely on morphology have stimulated searches for molecular markers of nosologic and prognostic value. Gangliosides are logical candidates because there are high concentrations of them in the nervous system, there is evidence of their roles in regulation of growth and differentiation, and data from small series suggest correlations between ganglioside composition and glioma type.. Ganglioside compositions were determined for 70 primary human brain tumors: 16 low grade astrocytomas (LG), 12 anaplastic astrocytomas (AA), 34 glioblastoma multiformes (GBM), and 8 primitive neuroectodermal tumors (PNET). This method involved identification and quantitation of specific gangliosides using chemical analysis and immunoanalysis.. Among all tumor types, histologic grade correlated with a progressive loss of 1b gangliosides (P < 0.0001). GQ1b was higher in LGs than in AAs (P < 0.001). Both GT1b and GD1b were higher in AAs than GBMs (P < 0.01 and 0.05, respectively) and lower in PNETs than in GBMs (P < 0.05). GM3 was higher in PNETs than in any astrocytoma group and higher in GBMs than in either AAs or LGs. There was a significant difference in the content of 3'-LM1 among all groups (P < 0.005), between AAs and GBMs (P < 0.05), and between low grade ordinary and juvenile pilocytic astrocyomas (P < 0.01). The lacto-series ganglioside 3'-isoLM1 was present in all groups except PNET.. These results indicate that patterns of gangliosides could be of considerable value in refining the classification and diagnosis of primary human brain tumors.

Topics: Adult; Aged; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Female; G(M1) Ganglioside; G(M3) Ganglioside; Gangliosides; Glioblastoma; Humans; Male; Middle Aged; Nerve Growth Factors; Neuroectodermal Tumors, Primitive, Peripheral