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Roles of Extracellular Hsps As Biomarkers in Immune Surveillance and Immune Evasion

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Roles of Extracellular Hsps As Biomarkers in Immune Surveillance and Immune Evasion International Journal of Molecular Sciences Review Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion 1,2,3, 4, 1,5, , Eman A. Taha y, Kisho Ono y and Takanori Eguchi * y 1 Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan; [email protected] 2 Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan 3 Department of Biochemistry, Ain Shams University Faculty of Science, Cairo 11566, Egypt 4 Department of Oral and Maxillofacial Surgery, Okayama University Hospital, Okayama 700-0914, Japan; [email protected] 5 Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan * Correspondence: [email protected]; Tel.: +81-86-235-6662 These authors contributed equally to this work. y Received: 16 August 2019; Accepted: 14 September 2019; Published: 17 September 2019 Abstract: Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed. Keywords: heat shock protein (HSP); exosome; oncosome; alarmin; immunology; immune evasion; resistance-associated secretory phenotype (RASP); immune surveillance; hypoxia; biomarker 1. Introduction Heat shock proteins (HSP) were initially found in cells, although later studies discovered extracellularly released HSP (ex-HSP), membrane-surface HSP (mHSP), and extracellular vesicles (EVs) such as HSP-rich oncosomes/exosomes [1] (Figure1). Tumor cells are often exposed to stresses such as hypoxic stress, immune response, inflammatory stress, microbial stimuli, and therapeutic stress. These stresses induce HSPs, molecular chaperones essential for protein folding and balancing between proteostasis and proteolysis, and play anti-apoptotic roles in cancer [2–5]. Int. J. Mol. Sci. 2019, 20, 4588; doi:10.3390/ijms20184588 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 4588 2 of 32 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 33 FigureFigure 1. Extracellular, 1. Extracellular, vesicular, vesicular, and and membrane membrane heat heat shockshock proteinsproteins (HSPs). (HSPs). Extracellular Extracellular vesicles vesicles (EVs)(EVs) are often are often a heterogeneous a heterogeneous mixture mixture of of exosomes, exosomes, ectosomesectosomes (also (also known known asas microvesicles, microvesicles, MVs), MVs), oncosomes, large oncosomes, and apoptotic bodies. Exosomes are secreted via membrane fusion of oncosomes, large oncosomes, and apoptotic bodies. Exosomes are secreted via membrane fusion of multivesicular bodies (MVBs), thereby intraluminal vesicles (ILVs) are exocytosed (top left). HSP90 multivesicular bodies (MVBs), thereby intraluminal vesicles (ILVs) are exocytosed (top left). HSP90 was shown to mediate MVB-to-plasma-membrane fusion. Distinctively, the shedding of the plasma was shown to mediate MVB-to-plasma-membrane fusion. Distinctively, the shedding of the plasma membrane generates ectosomes (center). Cell-free, vesicle-free HSPs can be released from cells upon membranecell damage generates and stress ectosomes (the so-called (center). alarmin Cell-free, or chaperokine). vesicle-free HSPsTransmembrane can be released proteins from (TMP) cells such upon as cell damageCD91 and can stress keep (the binding so-called of HSPs alarmin on the or surface chaperokine). of EVs and Transmembrane cells (blue bars proteinsand red balls). (TMP) Membrane- such as CD91 can keepsurface binding HSPs (mHSP) of HSPs are on known the surface as tumor of EVs antigens and cells(red). (blue Intracellular bars and HSPs red can balls). be kept Membrane-surface bound to the HSPsintracellular (mHSP) are domains known of asthe tumorTMPs, such antigens as epiderma (red).l growth Intracellular factor receptor HSPs can (EGFR) be keptfamily bound members to the intracellularon the cells domains and EVs. of EVs the TMPs,are often such taken as up epidermal by recipient growth cells in factor a variety receptor of ways (EGFR) such as family endocytosis, members on themacropinocytosis, cells and EVs. EVs membrane are often fusi takenon, and up phagocytosis by recipient (right). cells in a variety of ways such as endocytosis, macropinocytosis, membrane fusion, and phagocytosis (right). Meanwhile, ex-HSPs, including mHSP, HSP-rich exosomes, and oncosomes, play key roles in Meanwhile,intercellular communication ex-HSPs, including in cancer, mHSP, immunity, HSP-rich and exosomes,various pathological and oncosomes, conditions play (Table key 1). roles in intercellularHSPs are released communication from cells either in cancer, by passive immunity, release, ande.g., variousfrom damaged, pathological stressed, conditions or dead cells, (Table or 1). active release, including secretion of HSP-containing exosomes. Free ex-HSPs have been also called HSPs are released from cells either by passive release, e.g., from damaged, stressed, or dead cells, alarmin or chaperokine. Exosome HSPs were initially found in B cells, from which Hsp27, Hsc70, or active release, including secretion of HSP-containing exosomes. Free ex-HSPs have been also Hsp70, and Hsp90 are released with exosomes upon heat shock stress [6]. Proteomics revealed that calledoral alarmin cancer oroncosomes chaperokine. are enriched Exosome in HSPsHSP90 weremembers, initially HSP70 found members, in B cells, Hsc70, from HSP105, which and Hsp27, Hsc70,chaperonin Hsp70, and [1]. Hsp90Notably, are HSP90 releasedα is withhighly exosomes expressed upon in cancer heat shockcells and stress secreted [6]. Proteomics to extracellular revealed that oralspace cancer as free oncosomes HSP90α [5] as are well enriched as cargo in of HSP90 oncosome members, [1]. Additionally, HSP70 members, HSP90β, TRAP1, Hsc70, and HSP105, some and chaperoninmembers [1 ].of Notably, HSP70 are HSP90 foundα is in highly oncosomes expressed [1]. However, in cancer cellsthe mechanism and secreted by towhich extracellular HSPs are space as freeincorporated HSP90α [5 ]within as well the as vesicles cargo of and oncosome their biological [1]. Additionally, significance HSP90is still unknown.β, TRAP1, We and here some propose members of HSP70two models are found of EV-HSPs: in oncosomes (i) intra-vesicular [1]. However, packag theed HSPs mechanism and (ii) byEV-membrane which HSPs associated are incorporated HSPs withinon thethe vesiclesouter surface and of their EVs biological(Figure 1). significance is still unknown. We here propose two models of EV-HSPs:Ex-HSP, (i) intra-vesicular EV-HSP, and mHSP packaged can HSPsbind to and cell (ii) su EV-membranerface receptors (i) associated stimulating HSPs intracellular on the outer signaling pathways, (ii) taken up by endocytosis, or (iii) molecularly transferred to recipient cells (see surface of EVs (Figure1). Section 4). Such recipient cells include various immune cells, cancer cells themselves, as well as Ex-HSP,potential EV-HSP,cancer stem and cells mHSP [CSC, can bindalso known to cell surfaceas cancer-initiating receptors (i) cells stimulating (CIC)], epithelial intracellular cells signaling [7], pathways,cancer-associated (ii) taken up fibroblasts by endocytosis, (CAFs), mesenchymal or (iii) molecularly stem cells transferred (MSC), tumor to recipient endothelial cells cells (see (TEC), Section 4). Suchand recipient lymphatic cells endothelial include various cells. immune cells, cancer cells themselves, as well as potential cancer stem cells [CSC, also known as cancer-initiating cells (CIC)], epithelial cells [7], cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSC), tumor endothelial cells (TEC), and lymphatic endothelial cells. Int. J. Mol. Sci. 2019, 20, 4588 3 of 32 Table 1. HSPs Found Extracellularly, in Exosomes and on Membranes. Prototypical Subfamily
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