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)

Research output: Contribution to journalArticle

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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 languageEnglish
Article number77
Number of pages17
JournalCancers
Volume8
Issue number9
Early online date24 Aug 2016
DOIs
Publication statusPublished - Sep 2016

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HSP90 Heat-Shock Proteins
Prostatic Neoplasms
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Neoplasms
Neoplasm Grading
Cancer-Associated Fibroblasts
HSP70 Heat-Shock Proteins
Tumor Microenvironment
Transforming Growth Factor beta
Extracellular Matrix
Collagen

Keywords

  • Journal article
  • Prostate cancer
  • Cancer associated fibroblast
  • Heat shock protein
  • Contractility

Cite this

Henke, A., Franco, O. E., Stewart, G. D., Riddick, A. C. P., Katz, E., Hayward, S. W., & Thomson, A. A. (2016). Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90. Cancers, 8(9), [77]. https://doi.org/10.3390/cancers8090077
Henke, Alex ; Franco, Omar E. ; Stewart, Grant D. ; Riddick, Antony C. P. ; Katz, Elad ; Hayward, Simon W. ; Thomson, Axel A. / Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90. In: Cancers. 2016 ; Vol. 8, No. 9.
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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.",
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Reduced contractility and motility of prostatic cancer-associated fibroblasts after inhibition of heat shock protein 90. / Henke, Alex; Franco, Omar E.; Stewart, Grant D.; Riddick, Antony C. P.; Katz, Elad; Hayward, Simon W.; Thomson, Axel A. (Lead / Corresponding author).

In: Cancers, Vol. 8, No. 9, 77, 09.2016.

Research output: Contribution to journalArticle

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

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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

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ER -