The tumor microenvironment (TME) plays an important role in the process of tumorigenesis, regulating the growth, metabolism, proliferation, and invasion of cancer cells, as well as contributing to tumor resistance to the conventional chemoradiotherapies. Several types of cells with relatively stable phenotypes have been identified within the TME, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), neutrophils, and natural killer (NK) cells, which have been shown to modulate cancer cell proliferation, metastasis, and interaction with the immune system, thus promoting tumor heterogeneity. Growing evidence suggests that tumor-cell-derived extracellular vesicles (EVs), via the transfer of various molecules (e.g., RNA, proteins, peptides, and lipids), play a pivotal role in the transformation of normal cells in the TME into their tumor-associated protumorigenic counterparts. This review article focuses on the functions of EVs in the modulation of the TME with a view to how exosomes contribute to the transformation of normal cells, as well as their importance for cancer diagnosis and therapy.

Molecular chaperones, especially 70 kDa heat shock protein, in addition to their intracellular localization in cancer cells, can be exposed on the surface of the plasma membrane. We report that the membrane-associated chaperone mHsp70 of malignant brain tumors is required for high migratory and invasive activity of cancer cells. Live-cell inverted confocal microscopy of tumor samples from adult (n = 23) and pediatric (n = 9) neurooncologic patients showed pronounced protein expression on the membrane, especially in the perifocal zone. Mass spectrometry analysis of lipid rafts isolated from tumor cells confirmed the presence of the protein in the chaperone cluster (including representatives of other families, such as Hsp70, Hsc70, Hsp105, and Hsp90), which in turn, during interactome analysis, was associated with proteins involved in cell migration (e.g., Rac1, RhoC, and myosin-9). The use of small-molecule inhibitors of HSP70 (PES and JG98) led to a substantial decrease in the invasive potential of cells isolated from a tumor sample of patients, which indicates the role of the chaperone in invasion. Moreover, the use of HSP70 inhibitors in animal models of orthotopic brain tumors significantly delayed tumor progression, which was accompanied by an increase in overall survival. Data demonstrate that chaperone inhibitors, particularly JG98, disrupt the function of mHsp70, thereby providing an opportunity to better understand the diverse functions of this protein and offer aid in the development of novel cancer therapies. Significance: Membrane-bound mHsp70 is required for brain tumor cell migration and invasion and therefore could be employed as a target for anticancer therapies.

Over the past several decades, nanocarriers have demonstrated diagnostic and therapeutic (i.e., theranostic) potencies in translational oncology, and some agents have been further translated into clinical trials. However, the practical application of nanoparticle-based medicine in living organisms is limited by physiological barriers (blood–tissue barriers), which significantly hampers the transport of nanoparticles from the blood into the tumor tissue. This review focuses on several approaches that facilitate the translocation of nanoparticles across blood–tissue barriers (BTBs) to efficiently accumulate in the tumor. To overcome the challenge of BTBs, several methods have been proposed, including the functionalization of particle surfaces with cell-penetrating peptides (e.g., TAT, SynB1, penetratin, R8, RGD, angiopep-2), which increases the passing of particles across tissue barriers. Another promising strategy could be based either on the application of various chemical agents (e.g., efflux pump inhibitors, disruptors of tight junctions, etc.) or physical methods (e.g., magnetic field, electroporation, photoacoustic cavitation, etc.), which have been shown to further increase the permeability of barriers.

Extracellular vesicles (EVs) are an important mediator of intercellular communication and the regulation of processes occurring in cells and tissues. The processes of EVs secretion by cells into the extracellular space (ECS) leads to their interaction with its participants. The ECS is a dynamic structure that also takes direct part in many processes of intercellular communication and regulation. Changes in the ECS can also be associated with pathological processes, such as increased acidity during the development of solid tumors, changes in the composition and nature of the organization of the extracellular matrix (ECM) during fibroblast activation, an increase in the content of soluble molecules during necrosis, and other processes. The interaction of these two systems, the EVs and the ESC, leads to structural and functional alteration in both participants. In the current review, we will focus on these alterations in the EVs which we termed post-secretory modification and processes (PSMPs) of EVs. PSPMs can have a significant effect on the immediate cellular environment and on the spread of the pathological process in the body as a whole. Thus, it can be assumed that PSPMs are one of the important stages in the regulation of intercellular communication, which has significant differences in the norm and in pathology.

Motility analysis of sorted C6, T98G, and U251 cell lines by the level of mHsp70 expression. A, Representative scheme of mHsp70 expression analysis and FACS for subsequent determination of cell migration characteristics. B, Confocal microscopy images of C6, T98G, and U251. DAPI was applied for nucleus staining (blue). FITC-IgG1 and FITC-anti-Hsp70 antibody was used for detecting mHsp70 on the plasma membrane (green). Scale bars, 50 μm. C, Mean fluorescence intensity of FITC-anti-Hsp70 antibody in arbitrary units measured by flow cytometry (n = 4). D, Example of tracks rose plots in motility analysis. E, C6, T98G, and U251 cell tracks violin plots. F, Phase contrast live images of wound healing assay of subpopulations with different mHsp70 expression and plots of wound area vs. healing time. Scale bars for images, 400 μm.

Grade content and co-localization of biomarkers (Hsp70, Nestin, SOX2) on histological preparations of human GBM.