Next Article in Journal
Rutin-Enriched Extract from Coriandrum sativum L. Ameliorates Ionizing Radiation-Induced Hematopoietic Injury
Next Article in Special Issue
Applying Unconventional Secretion in Ustilago maydis for the Export of Functional Nanobodies
Previous Article in Journal
CIK Cells and HDAC Inhibitors in Multiple Myeloma
Previous Article in Special Issue
Annexins as Overlooked Regulators of Membrane Trafficking in Plant Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 18
Issue 5
10.3390/ijms18050946
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Unconventional Secretion of Heat Shock Proteins in Cancer

by
Tiago Góss Santos
,
Vilma Regina Martins
and
Glaucia Noeli Maroso Hajj
*
International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, Brazil
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(5), 946; https://doi.org/10.3390/ijms18050946
Submission received: 10 March 2017 / Revised: 25 April 2017 / Accepted: 27 April 2017 / Published: 29 April 2017
(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)
Browse Figures
Versions Notes

Abstract

:
Heat shock proteins (HSPs) are abundant cellular proteins involved with protein homeostasis. They have both constitutive and inducible isoforms, whose expression levels are further increased by stress conditions, such as temperature elevation, reduced oxygen levels, infection, inflammation and exposure to toxic substances. In these situations, HSPs exert a pivotal role in offering protection, preventing cell death and promoting cell recovery. Although the majority of HSPs functions are exerted in the cytoplasm and organelles, several lines of evidence reveal that HSPs are able to induce cell responses in the extracellular milieu. HSPs do not possess secretion signal peptides, and their secretion was subject to widespread skepticism until the demonstration of the role of unconventional secretion forms such as exosomes. Secretion of HSPs may confer immune system modulation and be a cell-to-cell mediated form of increasing stress resistance. Thus, there is a wide potential for secreted HSPs in resistance of cancer therapy and in the development new therapeutic strategies.

Graphical Abstract

1. Heat Shock Protein Functions and Families

Heat shock proteins (HSPs) were identified initially as proteins necessary for stress responses, such as temperature elevation and other proteotoxic stresses, preventing the damage of cellular structures, thus protecting essential cellular functions [1]. However, it was also envisioned that HSP families have members that are constitutively expressed [2]. The major functions of HSPs are to assist protein folding and prevent the formation of nonspecific protein aggregates [3].
There are five large and ubiquitous HSP families [4]: HSP70 superfamily (that includes HSP70 and HSP100 proteins) contains 17 genes, DNAJ family (also known as HSP40 family) contains 49 genes, small heat shock proteins (that includes HSP27) contains 11 genes, the HSPC family (also known as HSP90 family) contains five genes and the chaperonin family (that includes HSP60) contains 14 genes [5]. The nomenclature for HSPs has been diverse in the literature, which generates a lot of confusion. Table 1 summarizes the HUGO Gene nomenclature and most frequent names in the literature for the HSPs cited in this review.
HSPs function as chaperones, facilitating protein folding of client proteins. Thus, they act in the co- or post-translational folding of newly synthetized proteins and on the remodeling of misfolded proteins that can be caused by heat shock and other stress conditions. They can even aid the clearance of protein aggregates and are essential for the activity of many proteins. HSPs are thus found in most cellular compartments, such as cytoplasm, endoplasmic reticulum (ER) and mitochondria [30].
From the almost one hundred known HSPs, at least 13 were found extracellularly in many different biological models, from cell lines to whole organisms, in both physiological and pathological conditions (Table 1). Unlike intracellular HSPs, the functions of secreted forms are still under debate; however, most articles in the literature suggest that they may represent a signal for immune system modulation.

2. The Discovery of Chaperone Secretion

The surprising observation that HSPs can be actively secreted from cells was reported almost 30 years ago, when investigators discovered that cultured cells released HSPH1 and HSPA8 after a short heat shock stress [31]. HSPA1A was also found in the extracellular membrane of maturing reticulocytes in association with the transferrin receptor [32]. In spite of the initial skepticism regarding the secretion of proteins that are predominantly cytoplasmic, many reports were able to replicate these findings, providing evidence that HSP release is an active mechanism rather than a non-specific event induced by cell lysis. Further reports also demonstrated in vivo extracellular HSPs, with the observation of HSPD1 and HSPA1A in normal human blood circulation [33,34].
Tumor cells were among the first systems in which extracellular HSPs were documented. HSP90AA1 and HSPA1A were detected at the surface of tumor cell lines (microcitoma, lung carcinomas, melanomas, Ewing’s sarcomas, osteosarcomas and hepatomas) [35,36]. In addition, early reports also suggested that cell surface expression of HSPA1A in colon carcinoma cells (CX2) would increase cell recognition by the immune system, thus representing an anti-tumor effect of extracellular HSPs [37,38].
Extracellular HSPs were also regarded as potential cytokines. For example, HSPA1A was pointed to have a role in the stimulation of macrophages to secrete proinflammatory cytokines and to induce the expression of antigen-presenting molecules on dendritic cells [39,40].

3. DAMP vs. DAMPER—Dual Role of Extracellular HSPs?

HSPs are frequently associated with damage-associated molecular patterns (DAMPs), a class of self-danger signals released by stressed cells that elicit immune responses [41]. This term was conceived in analogy to the term PAMP (pathogen-associated molecular patterns), which is a class of molecular signals from pathogens that activate innate immune system [42]. DAMP signals are also known as alarmins and comprise different groups of intracellular components (such as the DNA-binding protein HMGB1, S-100 family proteins, nucleosomes, ATP, uric acid and antibacterial peptides) that are released during necrotic (not apoptotic) cell death and stimulates the immune system [42]. Kono and Rock revised the criteria for the classification of DAMPs [43], which are: “(1) DAMP should be active as a highly purified molecule; (2) it is important to show that its biological activity is not owing to contamination with microbial molecules (PAMPs); (3) the DAMP should be active at concentrations that are actually present in pathophysiological situations; and (4) selectively eliminating or inactivating the DAMP should ideally inhibit the biological activity of dead cells in in vitro and in vivo assays.”
For a long time, it was a consensus in the scientific community that HSPs could act as DAMPs, due to their role in cell stress responses and for their release to extracellular milieu during stressful conditions. However, recent proposals argue against this nomination [44], since HSPs do not fulfill the criteria properly. For example, the mechanisms that promote HSP secretion are active even in physiological situations. In addition, many experiments that consider HSPs as immunostimulatory molecules were done with recombinant protein systems, which have the bias of putative Lipopolysaccharide (LPS) contamination from bacteria [45].
One example includes HSPH1 and HYOU1, which were first described to have a role in the activity of scavenger receptors on macrophages and dendritic cells [6,9]. On the contrary, further work demonstrated inhibittory effects of extracellular HSPH1 and HYOU1 upon macrophage differentiation, favoring a pro-tumor phenotype [10].
Thus, in opposition to the denomination of HSPs as DAMPs, the term DAMPER has been suggested, which means a class a molecules that would reduce the activity of the innate immune system [44,45]. Additional evidence for this immunosuppressive feature for extracellular HSPs were suggested by others [46,47,48,49,50].
Lastly, it seems that the cellular context in which HSPs reach extracellular environment is determinant for its activity. For instance, during stressful conditions that lead to massive necrosis, HSP levels could be elevated by cell lysis, which would trigger an immunostimulatory phenotype. However, during physiological conditions, the cells release HSP by controlled mechanisms that may trigger immunosuppression [49]. The determination of binding receptors for HSPs may offer and answer for the amplitude of the phenomena associated with HSPs in the extracellular milieu.

4. Unconventional Mechanisms of HSP Secretion

The mechanisms related to HSP release are highly controversial. The most relevant argument against a specific HSP secretion is the absence of a signal peptide that targets these proteins for classical secretion. Indeed, the secretion HSPA1A and HSPA8 was shown to be resistant to brefeldin A, an inhibitor of classical secretion [51]. However, this observation was challenged by other groups that suggest the participation of endolysosomal compartments in the secretion of HSPA1A, through the inhibition by lysosomotropic compounds (methylamine or ammonium chloride). These studies suggest that the HSP entry into the secretory compartments may be mediated by ABC transporters, in a mechanism similar to that observed for interleukin-1β secretion [52,53]. The secretion of HSPs can also be explained by unconventional mechanisms. For example, inhibition of the lipid raft dynamics using methyl-β-cyclodextrin reduced HSPA1A and HSPA8 release [51,54,55,56]. A second mechanism was suggested with the participation of exosomes in a pathway that involved signaling through the extracellular regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3K) pathways [57,58,59,60,61].
Regardless of the controversial secretion mechanisms, the majority of the literature indicates that HSPA1A secretion is modulated by stress, with an increase in the secretion caused, for example by heat shock or other chemical stresses [54,55,56,57,62]. Interestingly, it was noted that upon heat shock or pharmacological inhibition of phospholipase C with u73122, HSPA1A is translocated from the cytoplasm to secretory-like granules and that its secretion could be blocked by brefeldin A [63,64]. In vivo, this may be responsible for the observed increase in serum HSPA1A under stress conditions such as trauma [65], cardiovascular disease [66], pulmonary edema [67], radiation therapy [68], surgery interventions [69], pathological conditions such as diabetes [70], or even exercise [71,72].
HSPA1A was also observed in the cell membrane. In colon carcinoma cellular models (CX2), hypoxia treatment triggered a co-localization of HSPA1A with phosphatidylserine on the cell surface, which reduced cell viability [73]. HSPA1A in the membrane was also observed in vivo in a variety of human tumors, such as: colorectal, lung, neuronal, and pancreas carcinomas; liver metastases; leukemic blasts [74]; squamous cell carcinomas [75,76]. A direct integration of HSPA1A on the plasma lipid bilayer was suggested as a possible mechanism, supported by the evidence that recombinant HSP can integrate in artificial membranes and create ionic channels [77,78,79,80,81].
Other HSPs were found to be secreted as well, with equal controversies regarding the mechanisms of secretion. Early reports detected HSPD1, a chaperone classically found in the mitochondria, in cell culture supernatants of neuroblastoma and glioblastoma cell lines, with an increase after cell stress [82]. This report suggested a role of classical secretion, which was supported by later findings that shows HSPD1 secretion by endoplasmic reticulum-Golgi pathways [83]. Nevertheless, additional literature in both normal tumor cells lines suggested a mechanism dependent on exosomes [84,85]. Thus, an interesting hypothesis is that there is participation of both mechanisms in HSPD1 secretion. Indeed, reports show that HSPD1 was found by electron microscopy in the membrane of human lung mucoepidermoid (H292) and lung adenocarcinoma (A549) cells and derived exosomes and its secretion was also inhibited by Brefeldin A [86]. In vivo, HSPD1 was found in the plasma of normal subjects [87]; however, it has been observed that circulating HSPD1 was enhanced in patients with borderline hypertension [88]. HSPD1 in the circulation can origin from the anterior pituitary, pancreatic acinar cells [89] and β-cells [90], where HSPD1 localizes in secretory granules. The presence of HSPD1 in the surface of exosomes was observed in large bowel patients, whose levels were reduced after tumor ablative surgery [91].
Other HSPs whose secretion has been related to exosomes are HSP90AA1 [92], HSP1B [93] and HSPB6 [25]. HSP90AA1 was shown to interact with annexin II and tissue plasminogen activator in exosomes to increase plasmin dependent cell motility [92]. HSPB1 is another chaperone secreted by cells in a non-classical pathway [94] associated to exosomes [93]. In vivo, serum HSPB1 was observed increased in pancreatic carcinoma [95], hepatocellular carcinoma [96], breast cancer [97] and gastric adenocarcinoma patients [98].
On the other hand, HSPs may have a role in the mechanism of non-classical secretion. For example, in retinal pigment epithelial cells inhibition of the small heat shock protein CRYAB (αβ-crystallin) by shRNA, reduced exosomal secretion and increased the presence of vacuoles and large vesicles, suggesting an alteration of the endolysosomal traffic associated to exosome formation [99]. αβ-crystallin itself is also secreted by exosomes [100].
Finally, no universal pathway for HSP release has been identified thus far, although there is strong evidence for exosome-mediated secretion. However, the mechanisms of the sorting of HSPs to this kind of vesicles are elusive. One suggested mechanism is related to post-translational modifications that regulate the incorporation of HSP into exosomal cargo. Ubiquitination seems to be the most prominent mechanism [101], but evidence points that SUMOylation, phosphorylation, glycosylation, myristoylation and oxidation are also involved in sorting proteins to multivesicular bodies to be later released to extracellular milieu [102]. Interestingly, exosome formation pathways can be controlled by several oncogenes [103,104,105,106] and tumor suppressor genes [107,108,109], highlighting the importance of exosomes and their cargos to promote oncogenic signals and also to establish therapeutic strategies focused in the endocytic system [110].

5. Functions of Extracellular HSPs in Cancer

One of the proposed functions for extracellular HSPs is the modulation of immune activity (Figure 1A and B). For example, secreted HSPA1A induced the production of tumor necrosis factor α (TNFα) and IL-6 in mast cells through the activation of the toll-like receptor 4 (TLR4) and toll-like receptor 2 (TLR2) pathways [111,112,113,114] and the release of interleukin 12 (IL-12) by naive dendritic cells [115]. Additional experiments demonstrated that macrophages infected with bacteria released more HSPA1A containing exosomes and that HSPA1A treatment led to macrophage activation and TNFα release [116]. Tumor cell lines, such as hepatocellular carcinoma cell line HepG2 and murine leukemia monocytes cell lines, were described to secrete HSPD1, HSPA1A, and HSP90AA1 in exosomes, which augmented the cytolytic activity of natural killer cells, macrophages and mononuclear cells [117,118,119,120]. In addition, stimulation of a monocytic cell line with HSPA1A increased cell motility through upregulation of matrix metalloprotease 9 (MMP-9) [121], which could reduce the time necessary for the immune response to infections [122]. Conversely, conflicting results described immunosuppressive functions for HSPA1A. HSPA1A associated with exosomes was shown to reduce tumor immune surveillance by promoting activation of myeloid-derived suppressor cells [123]. However, the data on the function of HSPA1A as a cytokine was challenged by the information of contamination by LPS, as many reports used bacterially derived HSPA1A [124,125,126,127]. To cope with these critics, non-bacterially derived HSPA1A was also used [77,128].
Several other secreted HSPs were linked to immunomodulation (Figure 1). Exogenous HSPD1 treatments induce cytokine release by T cells and macrophages [18]. The secretion of HYOU1 (Grp170), the largest stress protein, stimulates macrophages, which leads to a proinflammatory response that enables pathogen recognition [129]. In cancer, the secretion of HYOU1 enhances immunogenicity and suppresses tumor growth in murine models of melanoma [8] and prostate cancer [7].
Other secreted HSPs may favor an immune escape that presents tumor growth-supporting mechanism (Figure 1B). HSPH1 secreted from colorectal carcinoma cells induced macrophage differentiation favoring a pro-tumor, anti-inflammatory profile [10]. HSPB1 secreted by primary breast tumor cells trigger differentiation of monocytes to macrophages with immunotolerizing phenotypes that lose tumoricidal activity and become proangiogenic [81].
Another proposed function for extracellular HSPs includes modulation of invasiveness and metastasis (Figure 1E). Secretion of HSP90AA1 was implicated in increased cell mobility and cancer invasiveness [3]. HSP90AA1 was first spotted in functional screens for proteins required for the invasion of fibrosarcoma cells [130]. Accordingly, secreted HSP90AA1 promoted breast cancer and melanoma invasion in vitro and increased metastatic potential in animal models. In addition, the presence of serum HSP90AA1 was positively correlated with tumor malignancy in patients presenting cancer of the liver, breast, lung, pancreas or melanoma [131,132]. The inhibition of secreted HSP90AA1 with chemical inhibitors, such as 17-allylamino-17 demethoxygeldanamycin (17AAG) and monoclonal antibody against HSP90AA1 (mAb 4C5), thus reduced in vitro invasion and metastasis in mouse melanoma models [133,134]. The mechanism proposed for the increased invasion is through binding to extracellular receptors, such as the human epidermal growth factor receptor 2 (HER-2), inducing ERK1/2 and PI3K-Akt pathways [135,136]. In non-tumor cell models such as fibroblasts, HSP90AA1 secretion was observed after hypoxia, which triggered increased mobility [137]. Accordingly, motogenic activity of secreted HSP90AA1 was also observed in keratinocytes, triggered by tumor growth factor α (TGFα)-stimulation [138]. Serum starvation also increased HSP90AA1 secretion in colon cancer cells, increasing migration and invasion through NF-κB activation [139].
Other secreted HSPs such as HSPB1 were also linked to increased metastatic properties. In vivo models of murine mammary adenocarcinoma expressing high levels HSPB1 in the cell surface displayed larger tumors when implanted in nude mice, also presenting increased lung metastatic rates [140]. HSPA9 was shown to be secreted by oral squamous carcinoma cells and interact with the adhesion molecule podoplanin, which is involved in cell growth and invasiveness [15].
Secreted HSPs were also linked to angiogenic functions, acting as pro-tumor molecules (Figure 1D). The HSP resident in the ER called HSPA5 (GRP78 or BiP) was observed in cell culture medium and cell membrane after ER stress in human rabdomiosarcoma cells (TE671) and breast cancer cells (MCF7) [141,142] and the ability to secrete HSPA5 has been linked to resistance to the antiangiogenic agent Bortezomib. In angiogenesis experiments, prostate tumor cells (PC-3) and colon (HCT-8) that were able to promote angiogenesis in spite of Bortezomib were shown to secrete HSPA5 and knockdown of this protein abrogated such resistance phenotype [14]. In vivo, antibodies against HSPA5 were found in the circulation of prostate cancer patients [143], and targeting HSPA5 in the surface of tumor cells by the use of chimeric peptides composed of HSPA5 binding motifs fused to a programmed cell death-inducing sequence reduced the tumor growth in preclinical animal models of prostate and breast cancer [144]. Secreted HSPB6 also displayed angiogenic properties. Soluble HSPB6 induced proliferation, migration and tube formation in endothelial cells. In vivo, HSPB6 overexpressing mice also display increased capillary densities in the heart [25]. The angiogenic properties of secreted HSPB1 were related to an ability to cause local differentiation of monocytes into tumor associated macrophages that lose tumoricidal activity but elicit angiogenic responses in breast cancer [23].
In addition to roles in cellular invasion, secreted chaperones were linked to proliferation control (Figure 1C). HSPA8 is secreted in response to high cell density in rat mammary adenocarcinoma cells, inhibiting cell proliferation. Removing HSPA8 from the media by immunodepletion restores proliferation and is associated with the formation of multilayer cell cultures [11].
Additional proposed functions for extracellular HSPs are the transmission of stress resistance, which was demonstrated in neuronal systems. For example, glioma secreted HSPA1A can be up taken by neuroblastoma cells, which increases resistance to induced apoptosis [145]. In cellular and Drosophila models, exosomal secretion of DNAJB1 and HSPA1 contributes to the elimination of poly-glutamine aggregates in distant cells [100,146]. Recently, the existence was described of epichaperome machinery, an assembly of multiple chaperone and co-chaperones in cytoplasm, which enables tumor survival [147]. Interestingly, many components of this epichaperome complex were identified as extracellular proteins secreted by exosomes that present biological activity [148,149,150,151,152,153].

6. Extracellular HSP-Based Cancer Therapies

The immunomodulatory effects of extracellular HSPs have revealed a potential in the development of cancer therapies. Currently, large classes of chemical inhibitors of intracellular HSPs are under investigation and many are in clinical trials [154,155,156,157]. However, in this review, we will focus only on therapies based on the extracellular activity of HSPs [158].
Examples of anti-tumor activity of secreted HSPs include HSPA1A and HSP90AA1. Heat shock induces the release of exosomes with increased amounts of HSPA1A, which promote antitumor immune responses, with increased expression of major histocompatibility complex (MHC) class II in colon (CT26) and melanoma (B16) models [159], migration and reactivity of natural killer (NK) cells metastatic pancreatic adenocarcinoma Colo357 cells [160], thus inhibiting tumor growth and prolonging survival of tumor-bearing mice (Lewis lung carcinoma cell line and B16 melanoma cell line) [161]. In accordance, when human prostate cell lines overexpressing HSPA1A are injected in mice, there is a significant decrease of tumor growth and increased survival [162]. Similarly, HSP90AA1 and HSPD1 presence in exosomes were related to an increase in immune ability to elicit antitumor immune responses in lymphomas [163].
With the ability of binding to a wide range of extracellular proteins, HSPs are suggested as potential cancer vaccines to control cancer growth. The presence of immunogenic peptides (derived from chaperoned proteins) naturally associated to HSP also reinforces HSP-based vaccines [164]. The antigen-presenting activity of HSP90B1 (Grp96) made this HSP as the prototype for HSP-based vaccines [165]. Clinical studies (from pilot studies to phase I–III trials) were conducted and several are ongoing trying to address the effect of HSP90B1-based vaccines in different tumor types, such as late-stage melanoma [166], metastatic colon carcinoma [167], renal cell carcinoma [168], glioblastoma [169], among others. In general, this type of vaccine is safe, well tolerated, with no toxicity or auto-immune reactions [170]. The outcomes were diverse and clinical response was observed in a limited number of studies [164], such as longer overall survival in stage IV melanoma [171], increased CD8+ T cell response in colon cancer patients with metastatic disease [167], reduced tumor-induced lymphopenia and improved survival in glioblastoma patients [169]. An ongoing trial is addressing the effect of vaccination in combination with bevacizumab versus bevacizumab alone in patients with recurrent glioblastoma that underwent surgery (clinical trial number NCT01814813 [172]).
Regarding HSPA1A-based vaccines, a clinical trial was conducted to address the effect of a specific peptide corresponding to a region of HSPA1A, which activates NK cells in refractory metastatic colon cancer and non-small cell lung cancer patients [173]. Peripheral blood lymphocytes from patients were stimulated with the peptide ex vivo and reinfused to address immunological responses. Increased reactivity in NK cells were found together with increased cytolytic activity against HSPA1A-positive tumor targets [173]. Another study in myelogenous leukemia patients in chronic phase addressed the effect of vaccination with patient derived-HSPA1A peptide complexes combined with imatinib mesylate [174]. Clinical responses were observed in 13 of 20 patients, assessed by cytogenetic bone marrow analysis (search for Philadelphia chromosome) and IFN-γ-producing cells with significant correlation between clinical responses and immunological responses when vaccination were combined with imatinib mesylate [174].

7. Conclusions

The idea that intracellular chaperones can achieve the extracellular milieu through an active process of cellular secretion was the subject of dispute for decades. However, it is clear today that secretion of HSPs serves many roles and that a number of proteins from this large superfamily are secreted. The mechanisms of secretion are not completely elucidated, even though there is strong evidence for the participation of unconventional secretion, such as exosomes. Especially in the cancer field, the immunomodulatory properties of secreted HSPs may be useful for new vaccine-based therapies and will be the subject of intense exploration in the future.

Acknowledgments

This work was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) grants to Glaucia Noeli Maroso Hajj (2014/15550-9); Tiago Góss Santos (2015/02098-3) and Vilma Regina Martins (2009/14027-2). The authors declare no conflict of interest.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lindquist, S.L.; Kelly, J.W. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: Progress and prognosis. Cold Spring Harb. Perspect. Biol. 2011, 3. [Google Scholar] [CrossRef] [PubMed]
  2. Richter, K.; Haslbeck, M.; Buchner, J. The heat shock response: Life on the verge of death. Mol. Cell 2010, 40, 253–266. [Google Scholar] [CrossRef] [PubMed]
  3. Whitesell, L.; Lindquist, S.L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761–772. [Google Scholar] [CrossRef] [PubMed]
  4. HUGO Gene Nomenclature Committee. Available online: http://www.genenames.org/genefamilies/HSP (accessed on 1 January 2017).
  5. Kampinga, H.H.; Hageman, J.; Vos, M.J.; Kubota, H.; Tanguay, R.M.; Bruford, E.A.; Cheetham, M.E.; Chen, B.; Hightower, L.E. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 2009, 14, 105–111. [Google Scholar] [CrossRef] [PubMed]
  6. Facciponte, J.G.; Wang, X.Y.; Subjeck, J.R. HSP110 and Grp170, members of the HSP70 superfamily, bind to scavenger receptor-A and scavenger receptor expressed by endothelial cells-I. Eur. J. Immunol. 2007, 37, 2268–2279. [Google Scholar] [CrossRef] [PubMed]
  7. Gao, P.; Sun, X.; Chen, X.; Subjeck, J.; Wang, X.Y. Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor. Cancer Immunol. Immunother. 2009, 58, 1319–1328. [Google Scholar] [CrossRef] [PubMed]
  8. Wang, X.Y.; Arnouk, H.; Chen, X.; Kazim, L.; Repasky, E.A.; Subjeck, J.R. Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J. Immunol. 2006, 177, 1543–1551. [Google Scholar] [CrossRef] [PubMed]
  9. Qian, J.; Yi, H.; Guo, C.; Yu, X.; Zuo, D.; Chen, X.; Kane, J.M.; Repasky, E.A.; Subjeck, J.R.; Wang, X.Y. CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone vaccine activity against mouse melanoma. J. Immunol. 2011, 187, 2905–2914. [Google Scholar] [CrossRef] [PubMed]
  10. Berthenet, K.; Boudesco, C.; Collura, A.; Svrcek, M.; Richaud, S.; Hammann, A.; Causse, S.; Yousfi, N.; Wanherdrick, K.; Duplomb, L.; et al. Extracellular HSP110 skews macrophage polarization in colorectal cancer. Oncoimmunology 2016, 5, e1170264. [Google Scholar] [CrossRef] [PubMed]
  11. Nirdé, P.; Derocq, D.; Maynadier, M.; Chambon, M.; Basile, I.; Gary-Bobo, M.; Garcia, M. Heat shock cognate 70 protein secretion as a new growth arrest signal for cancer cells. Oncogene 2010, 29, 117–127. [Google Scholar] [CrossRef] [PubMed]
  12. Rodríguez, L.S.; Barreto, A.; Franco, M.A.; Angel, J. Immunomodulators released during rotavirus infection of polarized caco-2 cells. Viral Immunol. 2009, 22, 163–172. [Google Scholar] [CrossRef] [PubMed]
  13. Zou, N.; Ao, L.; Cleveland, J.C.; Yang, X.; Su, X.; Cai, G.Y.; Banerjee, A.; Fullerton, D.A.; Meng, X. Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 2008, 294, H2805–H2813. [Google Scholar] [CrossRef] [PubMed]
  14. Kern, J.; Untergasser, G.; Zenzmaier, C.; Sarg, B.; Gastl, G.; Gunsilius, E.; Steurer, M. GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. Blood 2009, 114, 3960–3967. [Google Scholar] [CrossRef] [PubMed]
  15. Tsuneki, M.; Maruyama, S.; Yamazaki, M.; Xu, B.; Essa, A.; Abé, T.; Babkair, H.; Cheng, J.; Yamamoto, T.; Saku, T. Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells. Biochem. Biophys. Res. Commun. 2013, 434, 124–130. [Google Scholar] [CrossRef] [PubMed]
  16. Pei, W.; Tanaka, K.; Huang, S.C.; Xu, L.; Liu, B.; Sinclair, J.; Idol, J.; Varshney, G.K.; Huang, H.; Lin, S.; et al. Extracellular HSP60 triggers tissue regeneration and wound healing by regulating inflammation and cell proliferation. Npj Regen. Med. 2016, 1, 16013. [Google Scholar] [CrossRef]
  17. Sarikonda, G.; Sachithanantham, S.; Miller, J.F.; Pagni, P.P.; Coppieters, K.T.; von Herrath, M. The HSP60 peptide p277 enhances anti-CD3 mediated diabetes remission in non-obese diabetic mice. J. Autoimmun. 2015, 59, 61–66. [Google Scholar] [CrossRef] [PubMed]
  18. Breloer, M.; Dorner, B.; Moré, S.H.; Roderian, T.; Fleischer, B.; von Bonin, A. Heat shock proteins as “danger signals”: Eukaryotic HSP60 enhances and accelerates antigen-specific IFN-γ production in T cells. Eur. J. Immunol. 2001, 31, 2051–2059. [Google Scholar] [CrossRef]
  19. Bohonowych, J.E.; Hance, M.W.; Nolan, K.D.; Defee, M.; Parsons, C.H.; Isaacs, J.S. Extracellular HSP90 mediates an NF-κB dependent inflammatory stromal program: Implications for the prostate tumor microenvironment. Prostate 2014, 74, 395–407. [Google Scholar] [CrossRef] [PubMed]
  20. Dong, H.; Zou, M.; Bhatia, A.; Jayaprakash, P.; Hofman, F.; Ying, Q.; Chen, M.; Woodley, D.T.; Li, W. Breast cancer MDA-MB-231 cells use secreted heat shock protein-90α (HSP90α) to survive a hostile hypoxic environment. Sci. Rep. 2016, 6, 20605. [Google Scholar] [CrossRef] [PubMed]
  21. Berwin, B.; Hart, J.P.; Rice, S.; Gass, C.; Pizzo, S.V.; Post, S.R.; Nicchitta, C.V. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J. 2003, 22, 6127–6136. [Google Scholar] [CrossRef] [PubMed]
  22. Genereux, J.C.; Qu, S.; Zhou, M.; Ryno, L.M.; Wang, S.; Shoulders, M.D.; Kaufman, R.J.; Lasmézas, C.I.; Kelly, J.W.; Wiseman, R.L. Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J. 2015, 34, 4–19. [Google Scholar] [CrossRef] [PubMed]
  23. Banerjee, S.; Lin, C.F.L.; Skinner, K.A.; Schiffhauer, L.M.; Peacock, J.; Hicks, D.G.; Redmond, E.M.; Morrow, D.; Huston, A.; Shayne, M.; et al. Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression. Cancer Res. 2011, 71, 318–327. [Google Scholar] [CrossRef] [PubMed]
  24. Batulan, Z.; Pulakazhi Venu, V.K.; Li, Y.; Koumbadinga, G.; Alvarez-Olmedo, D.G.; Shi, C.; O’Brien, E.R. Extracellular release and signaling by heat shock protein 27: Role in modifying vascular inflammation. Front. Immunol. 2016, 7, 285. [Google Scholar] [CrossRef] [PubMed]
  25. Zhang, X.; Wang, X.; Zhu, H.; Kranias, E.G.; Tang, Y.; Peng, T.; Chang, J.; Fan, G.C. HSP20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. PLoS ONE 2012, 7, e32765. [Google Scholar] [CrossRef] [PubMed]
  26. Kozawa, O.; Matsuno, H.; Niwa, M.; Hatakeyama, D.; Oiso, Y.; Kato, K.; Uematsu, T. HSP20, low-molecular-weight heat shock-related protein, acts extracellularly as a regulator of platelet functions: A novel defense mechanism. Life Sci. 2002, 72, 113–124. [Google Scholar] [CrossRef]
  27. Bhat, S.P.; Gangalum, R.K. Secretion of αB-Crystallin via exosomes: New clues to the function of human retinal pigment epithelium. Commun. Integr. Biol. 2011, 4, 739–741. [Google Scholar] [CrossRef] [PubMed]
  28. Sreekumar, P.G.; Kannan, R.; Kitamura, M.; Spee, C.; Barron, E.; Ryan, S.J.; Hinton, D.R. αB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS ONE 2010, 5, e12578. [Google Scholar] [CrossRef] [PubMed]
  29. Cortesi, L.; Barchetti, A.; De Matteis, E.; Rossi, E.; Della Casa, L.; Marcheselli, L.; Tazzioli, G.; Lazzaretti, M.G.; Ficarra, G.; Federico, M.; et al. Identification of protein clusters predictive of response to chemotherapy in breast cancer patients. J. Proteome Res. 2009, 8, 4916–4933. [Google Scholar] [CrossRef] [PubMed]
  30. Doyle, S.M.; Genest, O.; Wickner, S. Protein rescue from aggregates by powerful molecular chaperone machines. Nat. Rev. Mol. Cell Biol. 2013, 14, 617–629. [Google Scholar] [CrossRef] [PubMed]
  31. Hightower, L.E.; Guidon, P.T. Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J. Cell. Physiol. 1989, 138, 257–266. [Google Scholar] [CrossRef] [PubMed]
  32. Mathew, A.; Bell, A.; Johnstone, R.M. HSP-70 is closely associated with the transferrin receptor in exosomes from maturing reticulocytes. Biochem. J. 1995, 308 Pt 3, 823–830. [Google Scholar] [CrossRef] [PubMed]
  33. Pockley, A.G.; Bulmer, J.; Hanks, B.M.; Wright, B.H. Identification of human heat shock protein 60 (HSP60) and anti-HSP60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 1999, 4, 29–35. [Google Scholar] [CrossRef]
  34. Pockley, A.G.; Shepherd, J.; Corton, J.M. Detection of heat shock protein 70 (HSP70) and anti-HSP70 antibodies in the serum of normal individuals. Immunol. Investig. 1998, 27, 367–377. [Google Scholar] [CrossRef]
  35. Ferrarini, M.; Heltai, S.; Zocchi, M.R.; Rugarli, C. Unusual expression and localization of heat-shock proteins in human tumor cells. Int. J. Cancer 1992, 51, 613–619. [Google Scholar] [CrossRef] [PubMed]
  36. Multhoff, G.; Botzler, C.; Wiesnet, M.; Müller, E.; Meier, T.; Wilmanns, W.; Issels, R.D. A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int. J. Cancer 1995, 61, 272–279. [Google Scholar] [CrossRef] [PubMed]
  37. Multhoff, G.; Botzler, C.; Jennen, L.; Schmidt, J.; Ellwart, J.; Issels, R. Heat shock protein 72 on tumor cells: A recognition structure for natural killer cells. J. Immunol. 1997, 158, 4341–4350. [Google Scholar] [PubMed]
  38. Théry, C.; Regnault, A.; Garin, J.; Wolfers, J.; Zitvogel, L.; Ricciardi-Castagnoli, P.; Raposo, G.; Amigorena, S. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein HSC73. J. Cell Biol. 1999, 147, 599–610. [Google Scholar] [CrossRef] [PubMed]
  39. Asea, A.; Kraeft, S.K.; Kurt-Jones, E.A.; Stevenson, M.A.; Chen, L.B.; Finberg, R.W.; Koo, G.C.; Calderwood, S.K. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 2000, 6, 435–442. [Google Scholar] [PubMed]
  40. Basu, S. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway. Int. Immunol. 2000, 12, 1539–1546. [Google Scholar] [CrossRef] [PubMed]
  41. Fuchs, E.J.; Matzinger, P. Is cancer dangerous to the immune system? Semin. Immunol. 1996, 8, 271–280. [Google Scholar] [CrossRef] [PubMed]
  42. Liston, A.; Masters, S.L. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat. Rev. Immunol. 2017, 17, 208–214. [Google Scholar] [CrossRef] [PubMed]
  43. Kono, H.; Rock, K.L. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 2008, 8, 279–289. [Google Scholar] [CrossRef] [PubMed]
  44. Van Eden, W.; Spiering, R.; Broere, F.; van der Zee, R. A case of mistaken identity: HSPs are no DAMPs but DAMPERs. Cell Stress Chaperones 2012, 17, 281–292. [Google Scholar] [CrossRef] [PubMed]
  45. Broere, F.; van der Zee, R.; van Eden, W. Heat shock proteins are no DAMPs, rather “DAMPERs”. Nat. Rev. Immunol. 2011, 11, 565. [Google Scholar] [CrossRef] [PubMed]
  46. Motta, A.; Schmitz, C.; Rodrigues, L.; Ribeiro, F.; Teixeira, C.; Detanico, T.; Bonan, C.; Zwickey, H.; Bonorino, C. Mycobacterium tuberculosis heat-shock protein 70 impairs maturation of dendritic cells from bone marrow precursors, induces interleukin-10 production and inhibits T-cell proliferation in vitro. Immunology 2007, 121, 462–472. [Google Scholar] [CrossRef] [PubMed]
  47. Bendz, H.; Marincek, B.C.; Momburg, F.; Ellwart, J.W.; Issels, R.D.; Nelson, P.J.; Noessner, E. Calcium signaling in dendritic cells by human or mycobacterial HSP70 is caused by contamination and is not required for HSP70-mediated enhancement of cross-presentation. J. Biol. Chem. 2008, 283, 26477–26483. [Google Scholar] [CrossRef] [PubMed]
  48. Wieten, L.; van der Zee, R.; Spiering, R.; Wagenaar-Hilbers, J.; van Kooten, P.; Broere, F.; van Eden, W. A novel heat-shock protein coinducer boosts stress protein HSP70 to activate T cell regulation of inflammation in autoimmune arthritis. Arthritis Rheum. 2010, 62, 1026–1035. [Google Scholar] [CrossRef] [PubMed]
  49. Tanaka, K.I.; Namba, T.; Arai, Y.; Fujimoto, M.; Adachi, H.; Sobue, G.; Takeuchi, K.; Nakai, A.; Mizushima, T. Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis. J. Biol. Chem. 2007, 282, 23240–23252. [Google Scholar] [CrossRef] [PubMed]
  50. Kovalchin, J.T.; Mendonca, C.; Wagh, M.S.; Wang, R.; Chandawarkar, R.Y. In vivo treatment of mice with heat shock protein, gp 96, improves survival of skin grafts with minor and major antigenic disparity. Transpl. Immunol. 2006, 15, 179–185. [Google Scholar] [CrossRef] [PubMed]
  51. Hunter-Lavin, C.; Davies, E.L.; Bacelar, M.M.F.V.G.; Marshall, M.J.; Andrew, S.M.; Williams, J.H.H. HSP70 release from peripheral blood mononuclear cells. Biochem. Biophys. Res. Commun. 2004, 324, 511–517. [Google Scholar] [CrossRef] [PubMed]
  52. Mambula, S.S.; Calderwood, S.K. Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J. Immunol. 2006, 177, 7849–7857. [Google Scholar] [CrossRef] [PubMed]
  53. Mambula, S.S.; Stevenson, M.A.; Ogawa, K.; Calderwood, S.K. Mechanisms for HSP70 secretion: Crossing membranes without a leader. Methods 2007, 43, 168–175. [Google Scholar] [CrossRef] [PubMed]
  54. Broquet, A.H.; Thomas, G.; Masliah, J.; Trugnan, G.; Bachelet, M. Expression of the molecular chaperone HSP70 in detergent-resistant microdomains correlates with its membrane delivery and release. J. Biol. Chem. 2003, 278, 21601–21606. [Google Scholar] [CrossRef] [PubMed]
  55. Evdokimovskaya, Y.; Skarga, Y.; Vrublevskaya, V.; Morenkov, O. Secretion of the heat shock proteins HSP70 and HSC70 by baby hamster kidney (BHK-21) cells. Cell Biol. Int. 2010, 34, 985–990. [Google Scholar] [CrossRef] [PubMed]
  56. Mambula, S.S.; Calderwood, S.K. Heat induced release of HSP70 from prostate carcinoma cells involves both active secretion and passive release from necrotic cells. Int. J. Hyperth. 2006, 22, 575–585. [Google Scholar] [CrossRef] [PubMed]
  57. Lancaster, G.I.; Febbraio, M.A. Exosome-dependent trafficking of HSP70: A novel secretory pathway for cellular stress proteins. J. Biol. Chem. 2005, 280, 23349–23355. [Google Scholar] [CrossRef] [PubMed]
  58. Taylor, A.R.; Robinson, M.B.; Gifondorwa, D.J.; Tytell, M.; Milligan, C.E. Regulation of heat shock protein 70 release in astrocytes: Role of signaling kinases. Dev. Neurobiol. 2007, 67, 1815–1829. [Google Scholar] [CrossRef] [PubMed]
  59. Zhan, R.; Leng, X.; Liu, X.; Wang, X.; Gong, J.; Yan, L.; Wang, L.; Wang, Y.; Wang, X.; Qian, L.J. Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes. Biochem. Biophys. Res. Commun. 2009, 387, 229–233. [Google Scholar] [CrossRef] [PubMed]
  60. Hegmans, J.P.J.J.; Bard, M.P.L.; Hemmes, A.; Luider, T.M.; Kleijmeer, M.J.; Prins, J.B.; Zitvogel, L.; Burgers, S.A.; Hoogsteden, H.C.; Lambrecht, B.N. Proteomic analysis of exosomes secreted by human mesothelioma cells. Am. J. Pathol. 2004, 164, 1807–1815. [Google Scholar] [CrossRef]
  61. Takeuchi, T.; Suzuki, M.; Fujikake, N.; Popiel, H.A.; Kikuchi, H.; Futaki, S.; Wada, K.; Nagai, Y. Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. Proc. Natl. Acad. Sci. USA 2015, 112, E2497–E2506. [Google Scholar] [CrossRef] [PubMed]
  62. Barreto, A.; Gonzalez, J.M.; Kabingu, E.; Asea, A.; Fiorentino, S. Stress-induced release of HSC70 from human tumors. Cell. Immunol. 2003, 222, 97–104. [Google Scholar] [CrossRef]
  63. Evdonin, A.L.; Guzhova, I.V.; Margulis, B.A.; Medvedeva, N.D. Phospholipse c inhibitor, u73122, stimulates release of HSP-70 stress protein from A431 human carcinoma cells. Cancer Cell Int. 2004, 4, 2. [Google Scholar] [CrossRef] [PubMed]
  64. Evdonin, A.L.; Martynova, M.G.; Bystrova, O.A.; Guzhova, I.V.; Margulis, B.A.; Medvedeva, N.D. The release of HSP70 from A431 carcinoma cells is mediated by secretory-like granules. Eur. J. Cell Biol. 2006, 85, 443–455. [Google Scholar] [CrossRef] [PubMed]
  65. Pittet, J.F.; Lee, H.; Morabito, D.; Howard, M.B.; Welch, W.J.; Mackersie, R.C. Serum levels of HSP72 measured early after trauma correlate with survival. J. Trauma 2002, 52, 611–617. [Google Scholar] [PubMed]
  66. Chan, Y.C.; Shukla, N.; Abdus-Samee, M.; Berwanger, C.S.; Stanford, J.; Singh, M.; Mansfield, A.O.; Stansby, G. Anti-heat-shock protein 70 kDa antibodies in vascular patients. Eur. J. Vasc. Endovasc. Surg. 1999, 18, 381–385. [Google Scholar] [CrossRef] [PubMed]
  67. Ganter, M.T. Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. AJP Lung Cell. Mol. Physiol. 2006, 291, L354–L361. [Google Scholar] [CrossRef] [PubMed]
  68. Hurwitz, M.D.; Kaur, P.; Nagaraja, G.M.; Bausero, M.A.; Manola, J.; Asea, A. Radiation therapy induces circulating serum HSP72 in patients with prostate cancer. Radiother. Oncol. 2010, 95, 350–358. [Google Scholar] [CrossRef] [PubMed]
  69. Kimura, F.; Itoh, H.; Ambiru, S.; Shimizu, H.; Togawa, A.; Yoshidome, H.; Ohtsuka, M.; Shimamura, F.; Kato, A.; Nukui, Y.; et al. Circulating heat-shock protein 70 is associated with postoperative infection and organ dysfunction after liver resection. Am. J. Surg. 2004, 187, 777–784. [Google Scholar] [CrossRef] [PubMed]
  70. Pagetta, A.; Folda, A.; Brunati, A.M.; Finotti, P. Identification and purification from the plasma of Type 1 diabetic subjects of a proteolytically active Grp94. Diabetologia 2003, 46, 996–1006. [Google Scholar] [CrossRef] [PubMed]
  71. Walsh, R.C.; Koukoulas, I.; Garnham, A.; Moseley, P.L.; Hargreaves, M.; Febbraio, M.A. Exercise increases serum HSP72 in humans. Cell Stress Chaperones 2001, 6, 386–393. [Google Scholar] [CrossRef]
  72. Febbraio, M.A.; Ott, P.; Nielsen, H.B.; Steensberg, A.; Keller, C.; Krustrup, P.; Secher, N.H.; Pedersen, B.K. Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J. Physiol. 2002, 544, 957–962. [Google Scholar] [CrossRef] [PubMed]
  73. Schilling, D.; Gehrmann, M.; Steinem, C.; de Maio, A.; Pockley, A.G.; Abend, M.; Molls, M.; Multhoff, G. Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J. 2009, 23, 2467–2477. [Google Scholar] [CrossRef] [PubMed]
  74. Hantschel, M.; Pfister, K.; Jordan, A.; Scholz, R.; Andreesen, R.; Schmitz, G.; Schmetzer, H.; Hiddemann, W.; Multhoff, G. HSP70 plasma membrane expression on primary tumor biopsy material and bone marrow of leukemic patients. Cell Stress Chaperones 2000, 5, 438–442. [Google Scholar] [CrossRef]
  75. Kaur, J.; Das, S.N.; Srivastava, A.; Ralhan, R. Cell surface expression of 70 kDa heat shock protein in human oral dysplasia and squamous cell carcinoma: Correlation with clinicopathological features. Oral Oncol. 1998, 34, 93–98. [Google Scholar] [CrossRef]
  76. Kleinjung, T.; Arndt, O.; Feldmann, H.J.; Bockmühl, U.; Gehrmann, M.; Zilch, T.; Pfister, K.; Schönberger, J.; Marienhagen, J.; Eilles, C.; et al. Heat shock protein 70 (HSP70) membrane expression on head-and-neck cancer biopsy-a target for natural killer (NK) cells. Int. J. Radiat. Oncol. Biol. Phys. 2003, 57, 820–826. [Google Scholar] [CrossRef]
  77. Vega, V.L.; Rodriguez-Silva, M.; Frey, T.; Gehrmann, M.; Diaz, J.C.; Steinem, C.; Multhoff, G.; Arispe, N.; de Maio, A. HSP70 Translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J. Immunol. 2008, 180, 4299–4307. [Google Scholar] [CrossRef] [PubMed]
  78. Alder, G.M.; Austen, B.M.; Bashford, C.L.; Mehlert, A.; Pasternak, C.A. Heat shock proteins induce pores in membranes. Biosci. Rep. 1990, 10, 509–518. [Google Scholar] [CrossRef] [PubMed]
  79. Negulyaev, Y.A.; Vedernikova, E.A.; Kinev, A.V.; Voronin, A.P. Exogenous heat shock protein HSP70 activates potassium channels in U937 cells. Biochim. Biophys. Acta 1996, 1282, 156–162. [Google Scholar] [CrossRef]
  80. Arispe, N.; de Maio, A. ATP and ADP modulate a cation channel formed by HSC70 in acidic phospholipid membranes. J. Biol. Chem. 2000, 275, 30839–30843. [Google Scholar] [CrossRef] [PubMed]
  81. Arispe, N.; Doh, M.; de Maio, A. Lipid interaction differentiates the constitutive and stress-induced heat shock proteins HSC70 and HSP70. Cell Stress Chaperones 2002, 7, 330–338. [Google Scholar] [CrossRef]
  82. Bassan, M.; Zamostiano, R.; Giladi, E.; Davidson, A.; Wollman, Y.; Pitman, J.; Hauser, J.; Brenneman, D.E.; Gozes, I. The identification of secreted heat shock 60-like protein from rat glial cells and a human neuroblastoma cell line. Neurosci. Lett. 1998, 250, 37–40. [Google Scholar] [CrossRef]
  83. Hayoun, D.; Kapp, T.; Edri-Brami, M.; Ventura, T.; Cohen, M.; Avidan, A.; Lichtenstein, R.G. HSP60 is transported through the secretory pathway of 3-MCA-induced fibrosarcoma tumour cells and undergoes N-glycosylation. FEBS J. 2012, 279, 2083–2095. [Google Scholar] [CrossRef] [PubMed]
  84. Merendino, A.M.; Bucchieri, F.; Campanella, C.; Marcianò, V.; Ribbene, A.; David, S.; Zummo, G.; Burgio, G.; Corona, D.F.V.; Conway de Macario, E.; et al. HSP60 is actively secreted by human tumor cells. PLoS ONE 2010, 5, e9247. [Google Scholar] [CrossRef] [PubMed]
  85. Gupta, S.; Knowlton, A.A. HSP60 trafficking in adult cardiac myocytes: Role of the exosomal pathway. AJP Hear. Circ. Physiol. 2007, 292, H3052–H3056. [Google Scholar] [CrossRef] [PubMed]
  86. Campanella, C.; Bucchieri, F.; Merendino, A.M.; Fucarino, A.; Burgio, G.; Corona, D.F.V.; Barbieri, G.; David, S.; Farina, F.; Zummo, G.; et al. The odyssey of HSP60 from tumor cells to other destinations includes plasma membrane-associated stages and golgi and exosomal protein-trafficking modalities. PLoS ONE 2012, 7, e42008. [Google Scholar] [CrossRef] [PubMed]
  87. Lewthwaite, J.; Owen, N.; Coates, A.; Henderson, B.; Steptoe, A. Circulating human heat shock protein 60 in the plasma of British civil servants: Relationship to physiological and psychosocial stress. Circulation 2002, 106, 196–201. [Google Scholar] [CrossRef] [PubMed]
  88. Pockley, A.G.; Wu, R.; Lemne, C.; Kiessling, R.; de Faire, U.; Frostegård, J. Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertens 2000, 36, 303–307. [Google Scholar] [CrossRef]
  89. Cechetto, J.D.; Soltys, B.J.; Gupta, R.S. Localization of mitochondrial 60-kD heat shock chaperonin protein (HSP60) in pituitary growth hormone secretory granules and pancreatic zymogen granules. J. Histochem. Cytochem. 2000, 48, 45–56. [Google Scholar] [CrossRef] [PubMed]
  90. Brudzynski, K.; Martinez, V.; Gupta, R.S. Immunocytochemical localization of heat-shock protein 60-related protein in β-cell secretory granules and its altered distribution in non-obese diabetic mice. Diabetologia 1992, 35, 316–324. [Google Scholar] [CrossRef] [PubMed]
  91. Campanella, C.; Rappa, F.; Sciumè, C.; Marino Gammazza, A.; Barone, R.; Bucchieri, F.; David, S.; Curcurù, G.; Caruso Bavisotto, C.; Pitruzzella, A.; et al. Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. Cancer 2015, 121, 3230–3239. [Google Scholar] [CrossRef] [PubMed]
  92. McCready, J.; Sims, J.D.; Chan, D.; Jay, D.G. Secretion of extracellular HSP90α via exosomes increases cancer cell motility: A role for plasminogen activation. BMC Cancer 2010, 10, 294. [Google Scholar] [CrossRef] [PubMed]
  93. Clayton, A.; Turkes, A.; Navabi, H.; Mason, M.D.; Tabi, Z. Induction of heat shock proteins in B-cell exosomes. J. Cell Sci. 2005, 118, 3631–3638. [Google Scholar] [CrossRef] [PubMed]
  94. Weiss, M.; Stope, M.; Klinkmann, G.; Könsgen, D.; Brucker, S.; Wallwiener, D.; Burchardt, M.; Mustea, A. Induction and secretion of pro-oncogenic heat shock protein 27 in ovarian cancer cells. Geburtshilfe Frauenheilkd. 2016, 76. [Google Scholar] [CrossRef]
  95. Liao, W.C.; Wu, M.S.; Wang, H.P.; Tien, Y.W.; Lin, J.T. Serum heat shock protein 27 Is increased in chronic pancreatitis and pancreatic carcinoma. Pancreas 2009, 38, 422–426. [Google Scholar] [CrossRef] [PubMed]
  96. Feng, J.T.; Liu, Y.K.; Song, H.Y.; Dai, Z.; Qin, L.X.; Almofti, M.R.; Fang, C.Y.; Lu, H.J.; Yang, P.Y.; Tang, Z.Y. Heat-shock protein 27: A potential biomarker for hepatocellular carcinoma identified by serum proteome analysis. Proteomics 2005, 5, 4581–4588. [Google Scholar] [CrossRef] [PubMed]
  97. Fanelli, M.A.; Cuello Carrión, F.D.; Dekker, J.; Schoemaker, J.; Ciocca, D.R. Serological detection of heat shock protein HSP27 in normal and breast cancer patients. Cancer Epidemiol. Biomark. Prev. 1998, 7, 791–795. [Google Scholar]
  98. Huang, Q.; Ye, J.; Huang, Q.; Chen, W.; Wang, L.; Lin, W.; Lin, J.; Lin, X. Heat shock protein 27 is over-expressed in tumor tissues and increased in sera of patients with gastric adenocarcinoma. Clin. Chem. Lab. Med. 2010, 48, 263–269. [Google Scholar] [CrossRef] [PubMed]
  99. Gangalum, R.K.; Bhat, A.M.; Kohan, S.A.; Bhat, S.P. Inhibition of the expression of the small heat shock protein αb-crystallin inhibits exosome secretion in human retinal pigment epithelial cells in culture. J. Biol. Chem. 2016, 291, 12930–12942. [Google Scholar] [CrossRef] [PubMed]
  100. Gangalum, R.K.; Atanasov, I.C.; Zhou, Z.H.; Bhat, S.P. B-Crystallin Is Found in detergent-resistant membrane microdomains and is secreted via exosomes from human retinal pigment epithelial cells. J. Biol. Chem. 2011, 286, 3261–3269. [Google Scholar] [CrossRef] [PubMed]
  101. Smith, V.L.; Jackson, L.; Schorey, J.S. Ubiquitination as a mechanism to transport soluble mycobacterial and eukaryotic proteins to exosomes. J. Immunol. 2015, 195, 2722–2730. [Google Scholar] [CrossRef] [PubMed]
  102. Moreno-Gonzalo, O.; Villarroya-Beltri, C.; Sánchez-Madrid, F. Post-translational modifications of exosomal proteins. Front. Immunol. 2014, 5, 383. [Google Scholar] [CrossRef] [PubMed]
  103. Ploper, D.; Taelman, V.F.; Robert, L.; Perez, B.S.; Titz, B.; Chen, H.W.; Graeber, T.G.; von Euw, E.; Ribas, A.; de Robertis, E.M. MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells. Proc. Natl. Acad. Sci. USA 2015, 112, E420–E429. [Google Scholar] [CrossRef] [PubMed]
  104. Bunney, T.D.; Katan, M. Phosphoinositide signalling in cancer: Beyond PI3K and PTEN. Nat. Rev. Cancer 2010, 10, 342–352. [Google Scholar] [CrossRef] [PubMed]
  105. Kurrle, N.; Ockenga, W.; Meister, M.; Völlner, F.; Kühne, S.; John, B.A.; Banning, A.; Tikkanen, R. Phosphatidylinositol 3-Kinase dependent upregulation of the epidermal growth factor receptor upon Flotillin-1 depletion in breast cancer cells. BMC Cancer 2013, 13, 575. [Google Scholar] [CrossRef] [PubMed]
  106. Tzeng, H.T.; Wang, Y.C. Rab-mediated vesicle trafficking in cancer. J. Biomed. Sci. 2016, 23, 70. [Google Scholar] [CrossRef] [PubMed]
  107. Fortini, M.E.; Bilder, D. Endocytic regulation of Notch signaling. Curr. Opin. Genet. Dev. 2009, 19, 323–328. [Google Scholar] [CrossRef] [PubMed]
  108. Feng, Z. p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb. Perspect. Biol. 2010, 2, a001057. [Google Scholar] [CrossRef] [PubMed]
  109. Sun, Y.; Zheng, W.; Guo, Z.; Ju, Q.; Zhu, L.; Gao, J.; Zhou, L.; Liu, F.; Xu, Y.; Zhan, Q.; et al. A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer. Sci. Rep. 2016, 6, 28083. [Google Scholar] [CrossRef] [PubMed]
  110. Mellman, I.; Yarden, Y. Endocytosis and cancer. Cold Spring Harb. Perspect. Biol. 2013, 5, a016949. [Google Scholar] [CrossRef] [PubMed]
  111. Mortaz, E.; Redegeld, F.A.; Nijkamp, F.P.; Wong, H.R.; Engels, F. Acetylsalicylic acid-induced release of HSP70 from mast cells results in cell activation through TLR pathway. Exp. Hematol. 2006, 34, 8–18. [Google Scholar] [CrossRef] [PubMed]
  112. Dybdahl, B.; Wahba, A.; Lien, E.; Flo, T.H.; Waage, A.; Qureshi, N.; Sellevold, O.F.M.; Espevik, T.; Sundan, A. Inflammatory response after open heart surgery: Releas e of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 2002, 105, 685–690. [Google Scholar] [CrossRef] [PubMed]
  113. Vabulas, R.M.; Ahmad-Nejad, P.; Ghose, S.; Kirschning, C.J.; Issels, R.D.; Wagner, H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 2002, 277, 15107–15112. [Google Scholar] [CrossRef] [PubMed]
  114. Asea, A.; Rehli, M.; Kabingu, E.; Boch, J.A.; Bare, O.; Auron, P.E.; Stevenson, M.A.; Calderwood, S.K. Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 2002, 277, 15028–15034. [Google Scholar] [CrossRef] [PubMed]
  115. Bausero, M.A.; Gastpar, R.; Multhoff, G.; Asea, A. Alternative mechanism by which IFN-enhances tumor recognition: Active release of heat shock protein 72. J. Immunol. 2005, 175, 2900–2912. [Google Scholar] [CrossRef] [PubMed]
  116. Anand, P.K.; Anand, E.; Bleck, C.K.E.; Anes, E.; Griffiths, G. Exosomal HSP70 Induces a Pro-inflammatory response to foreign particles including mycobacteria. PLoS ONE 2010, 5, e10136. [Google Scholar] [CrossRef] [PubMed]
  117. Lv, L.H.; Wan, Y.L.; Lin, Y.; Zhang, W.; Yang, M.; Li, G.L.; Lin, H.M.; Shang, C.Z.; Chen, Y.J.; Min, J. Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in Vitro. J. Biol. Chem. 2012, 287, 15874–15885. [Google Scholar] [CrossRef] [PubMed]
  118. Wang, R.; Kovalchin, J.T.; Muhlenkamp, P.; Chandawarkar, R.Y. Exogenous heat shock protein 70 binds macrophage lipid raft microdomain and stimulates phagocytosis, processing, and MHC-II presentation of antigens. Blood 2006, 107, 1636–1642. [Google Scholar] [CrossRef] [PubMed]
  119. Aneja, R.; Odoms, K.; Dunsmore, K.; Shanley, T.P.; Wong, H.R. Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells. J. Immunol. 2006, 177, 7184–7192. [Google Scholar] [CrossRef] [PubMed]
  120. Kovalchin, J.T.; Wang, R.; Wagh, M.S.; Azoulay, J.; Sanders, M.; Chandawarkar, R.Y. In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis. Wound Repair Regen. 2006, 14, 129–137. [Google Scholar] [CrossRef] [PubMed]
  121. Lee, K.J.; Kim, Y.M.; Kim, D.Y.; Jeoung, D.; Han, K.; Lee, S.T.; Lee, Y.S.; Park, K.H.; Park, J.H.; Kim, D.J.; et al. Release of heat shock protein 70 (HSP70) and the effects of extracellular HSP70 on matric metalloproteinase-9 expression in human monocytic U937 cells. Exp. Mol. Med. 2006, 38, 364–374. [Google Scholar] [CrossRef] [PubMed]
  122. Campisi, J.; Leem, T.H.; Fleshner, M. Stress-induced extracellular HSP72 is a functionally significant danger signal to the immune system. Cell Stress Chaperones 2003, 8, 272–286. [Google Scholar] [CrossRef]
  123. Chalmin, F.; Ladoire, S.; Mignot, G.; Vincent, J.; Bruchard, M.; Remy-Martin, J.P.; Boireau, W.; Rouleau, A.; Simon, B.; Lanneau, D.; et al. Membrane-associated HSP72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Investig. 2010, 120, 457–471. [Google Scholar] [CrossRef] [PubMed]
  124. Bausinger, H.; Lipsker, D.; Ziylan, U.; Manié, S.; Briand, J.P.; Cazenave, J.P.; Muller, S.; Haeuw, J.F.; Ravanat, C.; de la Salle, H.; et al. Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur. J. Immunol. 2002, 32, 3708–3713. [Google Scholar] [CrossRef]
  125. Gao, B.; Tsan, M.F. Endotoxin contamination in recombinant human heat shock protein 70 (HSP70) preparation is responsible for the induction of tumor necrosis factor α release by murine macrophages. J. Biol. Chem. 2003, 278, 174–179. [Google Scholar] [CrossRef] [PubMed]
  126. Gao, B.; Tsan, M.F. Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor α from murine macrophages. J. Biol. Chem. 2003, 278, 22523–22529. [Google Scholar] [CrossRef] [PubMed]
  127. Gao, B.; Tsan, M.F. Induction of cytokines by heat shock proteins and endotoxin in murine macrophages. Biochem. Biophys. Res. Commun. 2004, 317, 1149–1154. [Google Scholar] [CrossRef] [PubMed]
  128. Zheng, H.; Nagaraja, G.M.; Kaur, P.; Asea, E.E.; Asea, A. Chaperokine function of recombinant HSP72 produced in insect cells using a baculovirus expression system is retained. J. Biol. Chem. 2010, 285, 349–356. [Google Scholar] [CrossRef] [PubMed]
  129. Zuo, D.; Yu, X.; Guo, C.; Yi, H.; Chen, X.; Conrad, D.H.; Guo, T.L.; Chen, Z.; Fisher, P.B.; Subjeck, J.R.; et al. Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated pathogen sensing and innate immunity. FASEB J. 2012, 26, 1493–1505. [Google Scholar] [CrossRef] [PubMed]
  130. Eustace, B.K.; Sakurai, T.; Stewart, J.K.; Yimlamai, D.; Unger, C.; Zehetmeier, C.; Lain, B.; Torella, C.; Henning, S.W.; Beste, G.; et al. Functional proteomic screens reveal an essential extracellular role for HSP90 α in cancer cell invasiveness. Nat. Cell Biol. 2004, 6, 507–514. [Google Scholar] [CrossRef] [PubMed]
  131. Wang, X.; Song, X.; Zhuo, W.; Fu, Y.; Shi, H.; Liang, Y.; Tong, M.; Chang, G.; Luo, Y. The regulatory mechanism of HSP90α secretion and its function in tumor malignancy. Proc. Natl. Acad. Sci. USA 2009, 106, 21288–21293. [Google Scholar] [CrossRef] [PubMed]
  132. Becker, B.; Multhoff, G.; Farkas, B.; Wild, P.J.; Landthaler, M.; Stolz, W.; Vogt, T. Induction of HSP90 protein expression in malignant melanomas and melanoma metastases. Exp. Dermatol. 2004, 13, 27–32. [Google Scholar] [CrossRef] [PubMed]
  133. Tsutsumi, S.; Neckers, L. Extracellular heat shock protein 90: A role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci. 2007, 98, 1536–1539. [Google Scholar] [CrossRef] [PubMed]
  134. Stellas, D.; Karameris, A.; Patsavoudi, E. Monoclonal antibody 4C5 immunostains human melanomas and inhibits melanoma cell invasion and metastasis. Clin. Cancer Res. 2007, 13, 1831–1838. [Google Scholar] [CrossRef] [PubMed]
  135. Sidera, K.; Patsavoudi, E. Extracellular HSP90: Conquering the cell surface. Cell Cycle 2008, 7, 1564–1568. [Google Scholar] [CrossRef] [PubMed]
  136. Hance, M.W.; Dole, K.; Gopal, U.; Bohonowych, J.E.; Jezierska-Drutel, A.; Neumann, C.A.; Liu, H.; Garraway, I.P.; Isaacs, J.S. Secreted HSP90 Is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J. Biol. Chem. 2012, 287, 37732–37744. [Google Scholar] [CrossRef] [PubMed]
  137. Li, W.; Li, Y.; Guan, S.; Fan, J.; Cheng, C.F.; Bright, A.M.; Chinn, C.; Chen, M.; Woodley, D.T. Extracellular heat shock protein-90α: Linking hypoxia to skin cell motility and wound healing. EMBO J. 2007, 26, 1221–1233. [Google Scholar] [CrossRef] [PubMed]
  138. Cheng, C.F.; Fan, J.; Fedesco, M.; Guan, S.; Li, Y.; Bandyopadhyay, B.; Bright, A.M.; Yerushalmi, D.; Liang, M.; Chen, M.; et al. Transforming Growth Factor (TGF)—Stimulated secretion of HSP90: Using the receptor LRP-1/CD91 to promote human skin cell migration against a TGF-rich environment during wound healing. Mol. Cell. Biol. 2008, 28, 3344–3358. [Google Scholar] [CrossRef] [PubMed]
  139. Chen, J.S.; Hsu, Y.M.; Chen, C.C.; Chen, L.L.; Lee, C.C.; Huang, T.S. Secreted Heat shock protein 90 induces colorectal cancer cell invasion through CD91/LRP-1 and NF-B-mediated integrin V Expression. J. Biol. Chem. 2010, 285, 25458–25466. [Google Scholar] [CrossRef] [PubMed]
  140. Bausero, M.A.; Page, D.T.; Osinaga, E.; Asea, A. Surface expression of HSP25 and HSP72 differentially regulates tumor growth and metastasis. Tumour Biol. 2004, 25, 243–251. [Google Scholar] [CrossRef] [PubMed]
  141. Zhang, Y.; Liu, R.; Ni, M.; Gill, P.; Lee, A.S. Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP. J. Biol. Chem. 2010, 285, 15065–15075. [Google Scholar] [CrossRef] [PubMed]
  142. Delpino, A.; Castelli, M. The 78 kDa glucose-regulated protein (GRP78/BIP) is expressed on the cell membrane, is released into cell culture medium and is also present in human peripheral circulation. Biosci. Rep. 2002, 22, 407–420. [Google Scholar] [CrossRef] [PubMed]
  143. Mintz, P.J.; Kim, J.; Do, K.A.; Wang, X.; Zinner, R.G.; Cristofanilli, M.; Arap, M.A.; Hong, W.K.; Troncoso, P.; Logothetis, C.J.; et al. Fingerprinting the circulating repertoire of antibodies from cancer patients. Nat. Biotechnol. 2003, 21, 57–63. [Google Scholar] [CrossRef] [PubMed]
  144. Arap, M.A.; Lahdenranta, J.; Mintz, P.J.; Hajitou, A.; Sarkis, A.S.; Arap, W.; Pasqualini, R. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 2004, 6, 275–284. [Google Scholar] [CrossRef] [PubMed]
  145. Guzhova, I.; Kislyakova, K.; Moskaliova, O.; Fridlanskaya, I.; Tytell, M.; Cheetham, M.; Margulis, B. In vitro studies show that HSP70 can be released by glia and that exogenous HSP70 can enhance neuronal stress tolerance. Brain Res. 2001, 914, 66–73. [Google Scholar] [CrossRef]
  146. Popiel, H.A.; Takeuchi, T.; Fujita, H.; Yamamoto, K.; Ito, C.; Yamane, H.; Muramatsu, S.; Toda, T.; Wada, K.; Nagai, Y. HSP40 gene therapy exerts therapeutic effects on polyglutamine disease mice via a non-cell autonomous mechanism. PLoS ONE 2012, 7, e51069. [Google Scholar] [CrossRef] [PubMed]
  147. Rodina, A.; Wang, T.; Yan, P.; Gomes, E.D.; Dunphy, M.P.S.; Pillarsetty, N.; Koren, J.; Gerecitano, J.F.; Taldone, T.; Zong, H.; et al. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 2016, 538, 397–401. [Google Scholar] [CrossRef] [PubMed]
  148. Hajj, G.N.M.; Arantes, C.P.; Dias, M.V.S.; Roffé, M.; Costa-Silva, B.; Lopes, M.H.; Porto-Carreiro, I.; Rabachini, T.; Lima, F.R.; Beraldo, F.H.; et al. The unconventional secretion of stress-inducible protein 1 by a heterogeneous population of extracellular vesicles. Cell. Mol. Life Sci. 2013, 70, 3211–3227. [Google Scholar] [CrossRef] [PubMed]
  149. Dias, M.V.S.; Teixeira, B.L.; Rodrigues, B.R.; Sinigaglia-Coimbra, R.; Porto-Carreiro, I.; Roffé, M.; Hajj, G.N.M.; Martins, V.R. PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy. Autophagy 2016, 12, 2113–2128. [Google Scholar] [CrossRef] [PubMed]
  150. Lopes, M.H.; Santos, T.G.; Rodrigues, B.R.; Queiroz-Hazarbassanov, N.; Cunha, I.W.; Wasilewska-Sampaio, A.P.; Costa-Silva, B.; Marchi, F.A.; Bleggi-Torres, L.F.; Sanematsu, P.I.; et al. Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene 2015, 34, 3305–3314. [Google Scholar] [CrossRef] [PubMed]
  151. Ghosh, S.; Shinogle, H.E.; Garg, G.; Vielhauer, G.A.; Holzbeierlein, J.M.; Dobrowsky, R.T.; Blagg, B.S.J. HSP90 C-terminal inhibitors exhibit antimigratory activity by disrupting the HSP90α/Aha1 complex in PC3-MM2 cells. ACS Chem. Biol. 2015, 10, 577–590. [Google Scholar] [CrossRef] [PubMed]
  152. El Hamidieh, A.; Grammatikakis, N.; Patsavoudi, E. Cell surface Cdc37 participates in extracellular HSP90 mediated cancer cell invasion. PLoS ONE 2012, 7, e42722. [Google Scholar] [CrossRef] [PubMed]
  153. Tatebe, H.; Shiozaki, K. Identification of Cdc37 as a novel regulator of the stress-responsive mitogen-activated protein kinase. Mol. Cell. Biol. 2003, 23, 5132–5142. [Google Scholar] [CrossRef] [PubMed]
  154. Sõti, C.; Nagy, E.; Giricz, Z.; Vígh, L.; Csermely, P.; Ferdinandy, P. Heat shock proteins as emerging therapeutic targets. Br. J. Pharmacol. 2005, 146, 769–780. [Google Scholar] [CrossRef] [PubMed]
  155. Nahleh, Z.; Tfayli, A.; Najm, A.; El Sayed, A.; Nahle, Z. Heat shock proteins in cancer: Targeting the “chaperones”. Future Med. Chem. 2012, 4, 927–935. [Google Scholar] [CrossRef] [PubMed]
  156. Isaacs, J.S. HSP90 as a “Chaperone” of the epigenome: Insights and opportunities for cancer therapy. Adv. Cancer Res. 2016, 129, 107–140. [Google Scholar] [PubMed]
  157. Garg, G.; Khandelwal, A.; Blagg, B.S.J. Anticancer inhibitors of HSP90 function: Beyond the usual suspects. Adv. Cancer Res. 2016, 129, 51–88. [Google Scholar] [PubMed]
  158. Calderwood, S.K.; Gong, J. Heat shock proteins promote cancer: It’s a protection racket. Trends Biochem. Sci. 2016, 41, 311–323. [Google Scholar] [CrossRef] [PubMed]
  159. Cho, J.; Lee, Y.S.; Kim, S.H.; Ko, J.K.; Kim, C.W. MHC independent anti-tumor immune responses induced by HSP70-enriched exosomes generate tumor regression in murine models. Cancer Lett. 2009, 275, 256–265. [Google Scholar] [CrossRef] [PubMed]
  160. Gastpar, R.; Gehrmann, M.; Bausero, M.A.; Asea, A.; Gross, C.; Schroeder, J.A.; Multhoff, G. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 2005, 65, 5238–5247. [Google Scholar] [CrossRef] [PubMed]
  161. Chen, T.; Guo, J.; Yang, M.; Zhu, X.; Cao, X. Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. J. Immunol. 2011, 186, 2219–2228. [Google Scholar] [CrossRef] [PubMed]
  162. Wang, M.H.; Grossmann, M.E.; Young, C.Y.F. Forced expression of heat-shock protein 70 increases the secretion of HSP70 and provides protection against tumour growth. Br. J. Cancer 2004, 90, 926–931. [Google Scholar] [CrossRef] [PubMed]
  163. Chen, W.; Wang, J.; Shao, C.; Liu, S.; Yu, Y.; Wang, Q.; Cao, X. Efficient induction of antitumor T cell immunity by exosomes derived from heat-shocked lymphoma cells. Eur. J. Immunol. 2006, 36, 1598–1607. [Google Scholar] [CrossRef] [PubMed]
  164. Shevtsov, M.; Multhoff, G. Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Front. Immunol. 2016, 7, 171. [Google Scholar] [CrossRef] [PubMed]
  165. Castelli, C.; Rivoltini, L.; Rini, F.; Belli, F.; Testori, A.; Maio, M.; Mazzaferro, V.; Coppa, J.; Srivastava, P.K.; Parmiani, G. Heat shock proteins: Biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol. Immunother. 2004, 53, 227–233. [Google Scholar] [CrossRef] [PubMed]
  166. Pilla, L.; Patuzzo, R.; Rivoltini, L.; Maio, M.; Pennacchioli, E.; Lamaj, E.; Maurichi, A.; Massarut, S.; Marchianò, A.; Santantonio, C.; et al. A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-α in metastatic melanoma patients. Cancer Immunol. Immunother. 2006, 55, 958–968. [Google Scholar] [CrossRef] [PubMed]
  167. Mazzaferro, V.; Coppa, J.; Carrabba, M.G.; Rivoltini, L.; Schiavo, M.; Regalia, E.; Mariani, L.; Camerini, T.; Marchianò, A.; Andreola, S.; et al. Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin. Cancer Res. 2003, 9, 3235–3245. [Google Scholar] [PubMed]
  168. Wood, C.; Srivastava, P.; Bukowski, R.; Lacombe, L.; Gorelov, A.I.; Gorelov, S.; Mulders, P.; Zielinski, H.; Hoos, A.; Teofilovici, F.; et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: A multicentre, open-label, randomised phase III trial. Lancet 2008, 372, 145–154. [Google Scholar] [CrossRef]
  169. Bloch, O.; Crane, C.A.; Fuks, Y.; Kaur, R.; Aghi, M.K.; Berger, M.S.; Butowski, N.A.; Chang, S.M.; Clarke, J.L.; McDermott, M.W.; et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: A phase II, single-arm trial. Neuro Oncol. 2014, 16, 274–279. [Google Scholar] [CrossRef] [PubMed]
  170. Janetzki, S.; Palla, D.; Rosenhauer, V.; Lochs, H.; Lewis, J.J.; Srivastava, P.K. Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: A pilot study. Int. J. Cancer 2000, 88, 232–238. [Google Scholar] [CrossRef]
  171. Testori, A.; Richards, J.; Whitman, E.; Mann, G.B.; Lutzky, J.; Camacho, L.; Parmiani, G.; Tosti, G.; Kirkwood, J.M.; Hoos, A.; et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician’s choice of treatment for stage IV melanoma: The C-100–21 Study Group. J. Clin. Oncol. 2008, 26, 955–962. [Google Scholar] [CrossRef] [PubMed]
  172. Clinical Trials. Available online: https://clinicaltrials.gov/ (accessed on 1 February 2017).
  173. Krause, S.W.; Gastpar, R.; Andreesen, R.; Gross, C.; Ullrich, H.; Thonigs, G.; Pfister, K.; Multhoff, G. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: A clinical phase I trial. Clin. Cancer Res. 2004, 10, 3699–3707. [Google Scholar] [CrossRef] [PubMed]
  174. Li, Z.; Qiao, Y.; Liu, B.; Laska, E.J.; Chakravarthi, P.; Kulko, J.M.; Bona, R.D.; Fang, M.; Hegde, U.; Moyo, V.; et al. Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia. Clin. Cancer Res. 2005, 11, 4460–4468. [Google Scholar] [CrossRef] [PubMed]
Ijms 18 00946 g001 550
Figure 1. Functions of extracellular HSPs in cancer. Secreted HSPs whose functions were described as (A) anti-tumor immunomodulation; (B) pro-tumor immunomodulation; (C) cell proliferation; (D) angiogenesis; (E) cell invasion. APC, antigen presenting cell; DC, dendritic cell.
Figure 1. Functions of extracellular HSPs in cancer. Secreted HSPs whose functions were described as (A) anti-tumor immunomodulation; (B) pro-tumor immunomodulation; (C) cell proliferation; (D) angiogenesis; (E) cell invasion. APC, antigen presenting cell; DC, dendritic cell.
Ijms 18 00946 g001
Table
Table 1. Secreted HSPs considered in this review.
Table 1. Secreted HSPs considered in this review.
FamilyHUGO SymbolSynonymsIntracellular Function (Gene Cards)Extracellular Role
HSP70HYOU1HSP12A, Grp170Endoplasmic reticulum (ER)-associated protein involved in stress responses promoted by hypoxiaMediates cross-presentation in macrophages [6]; enhances immunogenicity [7,8]; potentiates TLR9 activation [9]
HSPH1HSP110Prevents the aggregation of denatured proteins, inhibits HSPA8/HSC70Binds to scavenger receptors on macrophages and mediates cross-presentation [6]; affects macrophage polarization [10]
HSPA8HSC71, HSP73, HSC70Facilitates peptide folding; ATPase in clathrin-coated vesicle disassemblyInhibits cell proliferation [11]; dual role in inflammatory response [12,13]
HSPA1AHSP70, HSP72Stabilizes proteins and prevents aggregation; mediates protein folding; involved in the ubiquitin-proteasome pathwayInduces antitumor immune responses [12]
HSPA5GRP78, BiPInvolved in the folding and assembly of proteins in the ERResistance to antiangiogenic agents [14]
HSPA9GRP75Localized to the mitochondria, ER, and plasma membrane. Role in cell proliferation and stress responseInteracts to adhesion molecule podoplanin and regulates cell growth and metastasis in oral squamous cell carcinoma [15]
ChaperoninHSPD1HSP60Folding and assembly of newly imported proteins in the mitochondriaTissue regeneration 15[16]; Modulates innate and adaptive immune system 16[17]; Induction of cytokine release [18]
HSPCHSP90AA1HSP90, HSP90αPromotes maturation and structural maintenance of target proteins involved in cell cycle control and signal transductionIncreased in cell mobility and cancer invasiveness; Increase cytokine production, STAT3 activation and MMP9 expression in prostate tumor [19]; Protection against hypoxia via LRP1 [20]
HSP90B1GRP94, GP96Molecular chaperone that functions in the processing and transport of secreted proteinsAntigen-presenting activity [21]
DNAJDNAJB1HSP40Interacts with HSP70 and stimulates ATPase activityBinds misfolded protein and inhibits protein aggregation, alleviating toxicity [22]
HSPBHSPB1HSP27, Hsp25Involved in stress resistance and actin organizationInduces macrophage differentiation to M2 [23]; interacts with plasma membrane proteins, altering cell signaling [24]
HSPB6HSP20Heat shock protein that likely plays a role in smooth muscle relaxationInduces proliferation, migration and tube formation in endothelial cells [25]; Regulator of platelets functions [26]
CRYABHSPB5, αB-crystallinHold client proteins in large soluble aggregates; autokinase activity; participation in intracellular architectureIncreased levels associated with photoreceptor neurons death in age-related macular degeneration [27,28]; potential circulating biomarker to predict response to chemotherapy [29]
MMP9, matrix metalloprotase 9; LRP1, Low density lipoprotein receptor-related protein 1; STAT3, Signal transducer and activator of transcription 3; TLR9, Toll-like receptor 9.

Share and Cite

MDPI and ACS Style

Santos, T.G.; Martins, V.R.; Hajj, G.N.M. Unconventional Secretion of Heat Shock Proteins in Cancer. Int. J. Mol. Sci. 2017, 18, 946. https://doi.org/10.3390/ijms18050946

AMA Style

Santos TG, Martins VR, Hajj GNM. Unconventional Secretion of Heat Shock Proteins in Cancer. International Journal of Molecular Sciences. 2017; 18(5):946. https://doi.org/10.3390/ijms18050946

Chicago/Turabian Style

Santos, Tiago Góss, Vilma Regina Martins, and Glaucia Noeli Maroso Hajj. 2017. "Unconventional Secretion of Heat Shock Proteins in Cancer" International Journal of Molecular Sciences 18, no. 5: 946. https://doi.org/10.3390/ijms18050946

APA Style

Santos, T. G., Martins, V. R., & Hajj, G. N. M. (2017). Unconventional Secretion of Heat Shock Proteins in Cancer. International Journal of Molecular Sciences, 18(5), 946. https://doi.org/10.3390/ijms18050946

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop