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.
Highlights
Heat shock proteins (HSP) were initially found in cells, later studies discovered extracellularly released HSP, membrane-surface HSP, and extracellular vesicles (EVs) such as HSP-rich oncosomes/exosomes [1] (Figure 1)
Cell surface receptors known to be bound with ex-HSP90 are (i) CD91/LRP1/A2MR expressed on tumor cells, immune cells, and EVs, (ii) toll-like receptors (TLRs), (iii) scavenger receptor expressed by endothelial cells-1 (SREC-1), and (iv) CD94/killer cell lectin-like receptor D1 (KLRD1) expressed on killer cells
Extracellular HSPs including HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, known as alarmins
Summary
Heat shock proteins (HSP) were initially found in cells, later studies discovered extracellularly released HSP (ex-HSP), membrane-surface HSP (mHSP), and extracellular vesicles (EVs) such as HSP-rich oncosomes/exosomes [1] (Figure 1). 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 [2,3,4,5]. Ex-HSP, including mHSP, can activate malignancy events in tumor cells and, in contrast, can trigger antigen cross-presentation and cross-priming by APCs and stimulate the cytolytic immune cells such as natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTL) [34,35,36,37] (see Sections 3 and 4)
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