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Int J Mol Sci. 2019 Sep 17;20(18). pii: E4588. doi: 10.3390/ijms20184588.

Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion.

Taha EA1,2,3, Ono K4, Eguchi T5,6.

Author information

1
Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. pj7l8pfb@s.okayama-u.ac.jp.
2
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan. pj7l8pfb@s.okayama-u.ac.jp.
3
Department of Biochemistry, Ain Shams University Faculty of Science, Cairo 11566, Egypt. pj7l8pfb@s.okayama-u.ac.jp.
4
Department of Oral and Maxillofacial Surgery, Okayama University Hospital, Okayama 700-0914, Japan. de20012@s.okayama-u.ac.jp.
5
Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. eguchi.takanori@gmail.com.
6
Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. eguchi.takanori@gmail.com.

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:

alarmin; biomarker; exosome; heat shock protein (HSP); hypoxia; immune evasion; immune surveillance; immunology; oncosome; resistance-associated secretory phenotype (RASP)

PMID:
31533245
PMCID:
PMC6770223
DOI:
10.3390/ijms20184588
[Indexed for MEDLINE]
Free PMC Article

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