This review overview current epidemiology data of malignant tumors of the central nervous system, and determines the significance of molecular diagnostics and expression of heat shock proteins in tumorigenesis. Particular attention is paid to the description of molecular chaperones as diagnostic and prognostic markers, as well as the prospects for chaperones using in personalized therapy the central nervous system tumors. The search for literature was carried out on the database platforms Medline (via PubMed) and Scopus, Cochrane Library, The Lancet Public Health Journal published between 1988 and 2022. The material was searched for keywords and terms, including “heat shock proteins”, “tumors of the central nervous system”, “brain tumors”, “molecular diagnostics”, “expression of molecular chaperones”, Hsp110, Hsp90, Hsp70, Hsp60, Hsp40, small HSPs. Molecular chaperones, due to their important role in physiological processes in the cell, are highly expressed in brain tumors, and the expression level of HSPs strongly correlates with the degree of malignancy, invasive potential, and resistance to radiochemotherapy. For some HSPs (i.e. HSP10, HSPB1, DNAJC10, HSPA7, HSP90) a direct correlation has been found between the level of protein expression (based on IHC analysis) and a poor overall survival prognosis for patients with glial tumors. This indicates the prognostic value of these markers, which in the future may be included in the diagnostic panel when examining a tumor sample.
An approach to develop a hybrid microsystem for the isolation and purification of magnetosomes produced by magnetotactic bacteria (MTB) with the aim of their further use in oncotherapy was considered. Ultrasonic MTB disintegration, dielectrophoretic and magnetophoretic nodes integrated with microfluidic systems were developed.
Biomedical nanotechnologies based on superparamagnetic iron oxide nanoparticles (SPIONs) represent a promising instrument for malignant brain tumor theranostics. Due to their unique physico-chemical properties, they can be used for multimodal cancer therapy (including hyperthermia), diagnostics, and targeted delivery of therapeutic molecules. To enhance the tumor-homing properties of nanoparticles the latter were conjugated with bioligands (i.e., monoclonal antibodies, Fab-fragments, peptides, and proteins such serine protease granzyme B) that recognize 72 kDa membrane-bound heat shock protein (mHsp70) that is expressed on the plasma membrane of tumor cells, including multiforme glioblastoma (GBM), but not on normal corresponding cells. Therapeutic potential of magnetic conjugates can be attenuated by binding to the particles surface of granzyme B (GrB-SPIONs) that exerts pro-apoptotic activity. Functionalized particles significantly contrast-enhanced the orthotopic glioblastoma (U87 glioma in NMRI nu/nu mice, GL261 glioma in C57/Bl6 mice) in preclinical animal models when high-field (11 ) magnetic resonance tomography (Bruker) was employed. Furthermore, when GrB-SPIONs were applied, we detected a statistically significant delay of tumor progression and increase of overall animal survival. Anti-tumor activity of GrB-SPIONs was further synergistically potentiated by stereotactic radiotherapy combined with immune check-point inhibitors (i.e., CTLA-4). In conclusion, synthesized superparamagnetic nanoparticles targeting mHsp70-positive could be employed for theranostics of malignant brain tumors and translated into further clinical trials.This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement № 075-15-2020-901). Citation Format: Ruslana Tagaeva, Vyacheslav Fedorov, Natalia Yudintceva, Luidmila Yakovleva, Boris Nikolaev, Veronica Osnach, Maxim Shevtsov. Functionalized superparamagnetic nanoparticles for theranostics of membrane-bound Hsp70 positive malignant brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5068.
Heat shock proteins (HSPs) constitute a large family of highly conserved proteins acting as molecular chaperones that play a key role in intracellular proteostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSPs families such as Hsp70 have been found to be localized on the plasma membrane of malignantly transformed cells, including multiforme glioblastoma (GBM). However, the role of the membrane-bound mHsp70 has not yet been elucidated in the pathophysiology of GBM. We have assessed the mHsp70 expression in biopsies obtained from neuro-oncological patients employing inverted confocal microscopy (Leica Microsystems) and CellVoyager CQ1 Benchtop High-Content Analysis System (Yokogawa). Live-cell imaging of the patient-derived biopsy revealed the increased cellular density of mHsp70-positive tumor cells particularly in the tissue along the tumor-brain margin (biopsy was derived 3 mm from contrast-enhancing margin and also within hyperintense FLAIR). Time-lapse analysis of the tumor sample further demonstrated the migration of mHsp70-positive cells into the surrounding culture medium. Subsequent high-powered multiplex immunofluorescence analysis (Akoya Biosystems Inc.) confirmed markedly increased single-cell infiltration of mHsp70(+) tumor cells (that were also co-immunofluorescently stained for SOX2, Nestin, and Oct4) in the normal brain tissues. In conclusion, expression of mHsp70 on the plasma membrane of tumor cells corresponds to the highly invasive potential of the GBM cells and recurrence of these tumors in neuro-oncological patients. This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement № 075-15-2020-901). Citation Format: Maxim Shevtsov, Ruslana Tagaeva, Natalia Yudintceva, Danila Bobkov, Darya Goncharova, Alexander Kim, Evgeniy Fedorov, Anastasia Nechaeva, Anastasia Mihrina, Anna Patruhina, Vyacheslav Fedorov, Konstantin Samochernykh. Membrane-associated heat shock protein mHsp70 is involved in cancer cell invasion and tumor recurrence in malignant brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 504.
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