Forced expression of heat-shock protein 70 increases the secretion of Hsp70 and provides protection against tumour growth

Wang, M. H.; Großmann, Matthias; Young, Charles Y.F.

doi:10.1038/sj.bjc.6601583

Cited by 54 publications

(39 citation statements)

References 36 publications

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“…Moreover, facilitation of surface localization or release of Hsp70 has been shown to correlate with increased immunogenicity of several tumor cell types tested in mice or at in vitro conditions [19,[47][48][49][50] These observations together with our findings indicate that Hsp70 overexpression in B16 cells could generate an excellent immune activating milieu through an elevated level of surface and released Hsp70. Furthermore, we showed that B16 melanoma cells chronically expressing excess Hsp70 lost their ability to release Hsp70 through active transport mechanisms.…”

Section: Discussionsupporting

confidence: 67%

Lysosomal Rerouting of Hsp70 Trafficking as a Potential Immune Activating Tool for Targeting Melanoma

Juhász¹,

Thuenauer²,

Spachinger³

et al. 2012

CPD

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Tumor specific cell surface localization and release of the stress inducible heat shock protein 70 (Hsp70) stimulate the immune system against cancer cells. A key immune stimulatory function of tumor-derived Hsp70 has been exemplified with the murine melanoma cell model, B16 overexpressing exogenous Hsp70. Despite the therapeutic potential mechanism of Hsp70 transport to the surface and release remained poorly understood. We investigated principles of Hsp70 trafficking in B16 melanoma cells with low and high level of Hsp70. In cells with low level of Hsp70 apparent trafficking of Hsp70 was mediated by endosomes. Excess Hsp70 triggered a series of changes such as a switch of Hsp70 trafficking from endosomes to lysosomes and a concomitant accumulation of Hsp70 in lysosomes. Moreover, lysosomal rerouting resulted in an elevated concentration of surface Hsp70 and enabled active release of Hsp70. In fact, hyperthermia, a clinically applicable approach triggered immediate active lysosomal release of soluble Hsp70 from cells with excess Hsp70. Furthermore, excess Hsp70 enabled targeting of internalized surface Hsp70 to lysosomes, allowing in turn heat-induced secretion of surface Hsp70. Altogether, we show that excess Hsp70 expressed in B16 melanoma cells diverts Hsp70 trafficking from endosomes to lysosomes, thereby supporting its surface localization and lysosomal release. Controlled excess-induced lysosomal rerouting and secretion of Hsp70 is proposed as a promising tool to stimulate anti-tumor immunity targeting melanoma.

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Section: Discussionsupporting

confidence: 67%

Lysosomal Rerouting of Hsp70 Trafficking as a Potential Immune Activating Tool for Targeting Melanoma

Juhász¹,

Thuenauer²,

Spachinger³

et al. 2012

CPD

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“…However, a recent proteomic analysis of human prostasomes revealed the presence of heat shock proteins in prostatic secretion (Utleg et al 2003). In addition, heat-shock protein 70 has been reported to be secreted from a variety of prostatic cell lines, and to show growth-inhibitory activity (Jones et al 2004, Wang et al 2004. Secreted mouse GRP78 may have a similar activity.…”

Section: Discussionmentioning

confidence: 99%

Identification of prostatic-secreted proteins in mice by mass spectrometric analysis and evaluation of lobe-specific and androgen-dependent mRNA expression

Fujimoto¹,

Akimoto²,

Suzuki³

et al. 2006

Journal of Endocrinology

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Rats and guinea pigs have frequently been used to study the development of the prostate and the mechanism of androgen action, but the mouse prostate has also become an attractive model for prostate research, because an enormous range of genetically altered mice is now available. However, the secretion of proteins in the mouse prostate has not yet been thoroughly investigated. In the present study, major secreted proteins from the ventral prostate (VP), dorsolateral prostate (DLP), and anterior prostate (AP) of mice were identified by means of 2D-gel electrophoresis followed by MALDI-TOF mass spectrometric analysis. A quantitative reverse transcriptase-PCR method was further employed to examine the androgen-dependent transcriptional regulation of the identified proteins. Proteome analysis revealed that the VP secretes spermine-binding protein, serine protease inhibitor Kazal type-3, and a 91 kDa hypothetical scavenger receptor (AK035662). DLP and AP secrete a protein similar to immunoglobulin-binding protein, immunoglobulin-binding protein-like protein, and one of the experimental autoimmune prostatitis antigen proteins (EAPA2). Peroxiredoxin-6, glucoseregulated protein 78, zinc-a2-glycoprotein, and phospholipase Ca are also secreted. Castration of animals led to a decrease in the mRNAs of these secreted proteins, although the extents of changes varied greatly among different lobes. We present here an outlined view of mouse prostate secretion, which should contribute to an understanding of the biological functions of the prostate gland, as well as the androgen dependency of prostate secretion.

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“…Preclinical vaccine models featuring surface HSP expression, whether driven by transfected genetic constructs (Zheng et al, 2001;Chen et al, 2002) or by the propensity of a given cell line to surface localize HSPs (Wang et al, 2004) were capable of generating antitumor immune responses. Other strategies used secretable chaperones and HSPs (again, artificially constructed or "naturally occurring" in certain tissue culture cells), successfully immunizing animals against tumor challenge (Yamazaki et al, 1999;X.…”

Section: Discussionmentioning

confidence: 99%

The Heat Shock Response and Chaperones/Heat Shock Proteins in Brain Tumors: Surface Expression, Release, and Possible Immune Consequences

Graner¹,

Cumming²,

Bigner³

2007

J. Neurosci.

134

151

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The heat shock response is a highly conserved "stress response" mechanism used by cells to protect themselves from potentially damaging insults. It often involves the upregulated expression of chaperone and heat shock proteins (HSPs) to prevent damage and aggregation at the proteome level. Like most cancers, brain tumor cells often overexpress chaperones/HSPs, probably because of the stressful atmosphere in which tumors reside, but also because of the benefits of HSP cytoprotection. However, the cellular dynamics and localization of HSPs in either stressed or unstressed conditions has not been studied extensively in brain tumor cells. We have examined the changes in HSP expression and in cell surface/extracellular localization of selected brain tumor cell lines under heat shock or normal environments. We herein report that brain tumor cell lines have considerable heat shock responses or already high constitutive HSP levels; that those cells express various HSPs, chaperones, and at least one cochaperone on their cell surfaces; and that HSPs may be released into the extracellular environment, possibly as exosome vesicular content. In studies with a murine astrocytoma cell line, heat shock dramatically reduces tumorigenicity, possibly by an immune mechanism. Additional evidence indicative of an HSP-driven immune response comes from immunization studies using tumor-derived chaperone protein vaccines, which lead to antigen-specific immune responses and reduced tumor burden in treated mice. The heat shock response and HSPs in brain tumor cells may represent an area of vulnerability in our attempts to treat these recalcitrant and deadly tumors.

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Forced expression of heat-shock protein 70 increases the secretion of Hsp70 and provides protection against tumour growth

Cited by 54 publications

References 36 publications

Lysosomal Rerouting of Hsp70 Trafficking as a Potential Immune Activating Tool for Targeting Melanoma

Lysosomal Rerouting of Hsp70 Trafficking as a Potential Immune Activating Tool for Targeting Melanoma

Identification of prostatic-secreted proteins in mice by mass spectrometric analysis and evaluation of lobe-specific and androgen-dependent mRNA expression

The Heat Shock Response and Chaperones/Heat Shock Proteins in Brain Tumors: Surface Expression, Release, and Possible Immune Consequences

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