Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity

Dodd, Keela; Nance, Stephanie; Quezada, Melanie; Janke, Laura J.; Morrison, Jeffrey; Williams, Richard; Beere, Helen M.

doi:10.1038/onc.2014.63

Cited by 27 publications

(17 citation statements)

References 39 publications

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“…The role of Hsp70 in regulation of OIS was further corroborated by a recent publication that did not find significant effects of Hsp70 knockout on either survival or tumor emergence in a model that combined Ras and E6 oncogenes 58 . In fact, E6 downregulates p53 and effectively reduces expression of its downstream target p21 59 .…”

Section: Hsp70 Is Critical For Cancer Developmentmentioning

confidence: 66%

Hsp70 in cancer: back to the future

2014

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Mechanistic studies from cell culture and animal models have revealed critical roles for the heat shock protein Hsp70 in cancer initiation and progression. Surprisingly, many effects of Hsp70 on cancer have not been related to its chaperone activity, but rather to its role(s) in regulating cell signaling. A major factor that directs Hsp70 signaling activity appears to be the co-chaperone Bag3. Here, we review these recent breakthroughs, and how these discoveries drive drug development efforts.

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Section: Hsp70 Is Critical For Cancer Developmentmentioning

confidence: 66%

Hsp70 in cancer: back to the future

2014

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“…HSPs are over-expressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death and recognition by the immune system [51, 52]. Our results show that HSP70, but not HSP40 or 60, is specifically involved in glioma progression, although its expression does not appear informative for diagnostic purposes.…”

Section: Discussionmentioning

confidence: 77%

Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization

Zhang

Sun

et al. 2016

Oncotarget

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Macrophages enhance glioma development and progression by shaping the tumor microenvironment. Class A1 scavenger receptor (SR-A1), a pattern recognition receptor primarily expressed in macrophages, is up-regulated in many human solid tumors. We found that SR-A1 expression in 136 human gliomas was positively correlated with tumor grade (P<0.01), but not prognosis or tumor recurrence. SR-A1-expressing macrophages originated primarily from circulating monocytes attracted to tumor tissue, and were almost twice as numerous as resident microglia in glioma tissues (P<0.001). The effects of SR-A1 on glioma proliferation and invasion were assessed in vivo using an SR-A1-deficient murine orthotopic glioma model. SR-A1 deletion promoted M2-like tumor-associated macrophage (TAM) polarization in mice by activating STAT3 and STAT6, which resulted in robust orthotopic glioma proliferation and angiogenesis. Finally, we found that HSP70 might be an endogenous ligand that activates SR-A1-dependent anti-tumorigenic pathways in gliomas, although its expression does not appear informative for diagnostic purposes. Our findings demonstrate a relationship between TAMs, SR-A1 expression and glioma growth and provide new insights into the pathogenic role of TAMs in glioma.

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“…allografts of B16 melanoma and E0771 breast tumor. On the other hand, in the PyMT model breast tumors emerged in Hsp70KO (though grew slower than in WT), and similarly in the model of Ras-transformed fibroblasts tumors emerged and grew (22), suggesting that in these models the requirement for TAM is less strict.…”

Section: Resultsmentioning

confidence: 97%

Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells

et al. 2016

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The stress-induced chaperone protein Hsp70 enables the initiation and progression of many cancers, making it an appealing therapeutic target for development. Here we show that cancer cells resistant to Hsp70 inhibitors in vitro remain sensitive to them in vivo, revealing the pathogenic significance of Hsp70 in tumor stromal cells rather than tumor cells as widely presumed. Using transgenic mouse models of cancer, we found that expression of Hsp70 in host stromal cells was essential to support tumor growth. Furthermore, genetic ablation or pharmacological inhibition of Hsp70 suppressed tumor infiltration by macrophages needed to enable tumor growth. Overall, our results illustrate how Hsp70 inhibitors mediate the anti-cancer effects by targeting both tumor cells and tumor stromal cells, with implications for the broad use of these inhibitors as tools to ablate tumor-associated macrophages that enable malignant progression.

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Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity

Cited by 27 publications

References 39 publications

Hsp70 in cancer: back to the future

Hsp70 in cancer: back to the future

Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization

Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells

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