Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90

Alex Henke; Omar E. Franco; Grant D. Stewart; Antony C. P. Riddick; Elad Katz; Simon W. Hayward; Axel A. Thomson

doi:10.3390/cancers8090077

Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90

Alex Henke, Omar E. Franco, Grant D. Stewart, Antony C. P. Riddick, Elad Katz, Simon W. Hayward, Axel A. Thomson (Lead / Corresponding author)

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Abstract

BACKGROUND: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix;

METHODS: We isolated CAF from prostate cancer patients of Gleason Score 6-10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay;

RESULTS: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF;

CONCLUSIONS: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.

Original language	English
Article number	77
Number of pages	17
Journal	Cancers
Volume	8
Issue number	9
Early online date	24 Aug 2016
DOIs	https://doi.org/10.3390/cancers8090077
Publication status	Published - Sept 2016

Keywords

Journal article
Prostate cancer
Cancer associated fibroblast
Heat shock protein
Contractility

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10.3390/cancers8090077Licence: CC BY

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© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 2.8 MBLicence: CC BY

Cite this

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title = "Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90",

abstract = "BACKGROUND: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix;METHODS: We isolated CAF from prostate cancer patients of Gleason Score 6-10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay;RESULTS: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF;CONCLUSIONS: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.",

keywords = "Journal article, Prostate cancer, Cancer associated fibroblast, Heat shock protein, Contractility",

author = "Alex Henke and Franco, {Omar E.} and Stewart, {Grant D.} and Riddick, {Antony C. P.} and Elad Katz and Hayward, {Simon W.} and Thomson, {Axel A.}",

year = "2016",

month = sep,

doi = "10.3390/cancers8090077",

language = "English",

volume = "8",

journal = "Cancers",

issn = "2072-6694",

publisher = "MDPI",

number = "9",

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TY - JOUR

T1 - Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90

AU - Henke, Alex

AU - Franco, Omar E.

AU - Stewart, Grant D.

AU - Riddick, Antony C. P.

AU - Katz, Elad

AU - Hayward, Simon W.

AU - Thomson, Axel A.

PY - 2016/9

Y1 - 2016/9

N2 - BACKGROUND: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix;METHODS: We isolated CAF from prostate cancer patients of Gleason Score 6-10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay;RESULTS: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF;CONCLUSIONS: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.

AB - BACKGROUND: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix;METHODS: We isolated CAF from prostate cancer patients of Gleason Score 6-10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay;RESULTS: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF;CONCLUSIONS: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.

KW - Journal article

KW - Prostate cancer

KW - Cancer associated fibroblast

KW - Heat shock protein

KW - Contractility

U2 - 10.3390/cancers8090077

DO - 10.3390/cancers8090077

M3 - Article

C2 - 27563925

SN - 2072-6694

VL - 8

JO - Cancers

JF - Cancers

IS - 9

M1 - 77

ER -

Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90

Abstract

Keywords

UN SDGs

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