Progression of genotype-specific oral cancer leads to senescience of cancer associated fibroblasts and is mediated by oxidative stress and TGF-B
Progression of genotype-specific oral cancer leads to senescience of cancer associated fibroblasts and is mediated by oxidative stress and TGF-B
Keratinocyte senescence acts as a barrier to tumor progression but appears to be lost in late pre-malignancy to yield genetically unstable oral squamous cell carcinomas (GU-OSCC); a subset of OSCC possessing wild-type p53 and are genetically stable (GS-OSCC). In this study, fibroblasts from GU-OSCC were senescent relative to fibroblasts from GS-OSCC, epithelial dysplastic tissues or normal oral mucosa, as demonstrated by increased senescence-associated ?-galactosidase (SA ?-Gal) activity and overexpression of p16(INK4A). Keratinocytes from GU-OSCC produced high levels of reactive oxygen species (ROS) and this was associated with an increase in the production of transforming growth factor-?1 (TGF-?1) and TGF-?2 in stromal fibroblasts. Treatment of normal fibroblasts with keratinocyte conditioned media (CM) from GU-OSCC, but not GS-OSCC or dysplastic keratinocytes with dysfunctional p53, induced fibroblast senescence. This phenomenon was inhibited by antioxidants and anti-TGF-? antibodies. Fibroblast activation by TGF-?1 preceded cellular senescence and was associated with increased ROS levels; antioxidants inhibited this reaction. Senescent fibroblasts derived from GU-OSCC or normal fibroblasts treated with CM from GU-OSCC or hydrogen peroxide, but not non-senescent fibroblasts derived from GS-OSCC, promoted invasion of keratinocytes in vitro. Epithelial invasion was stimulated by fibroblast activation and amplified further by fibroblast senescence. The data demonstrate that malignant keratinocytes from GU-OSCC, but not their pre-malignant counterparts, produce high levels of ROS, which, in turn, increase TGF-?1 expression and induce fibroblast activation and senescence in a p5-independent manner. Fibroblasts from GU-OSCC were particularly susceptible to oxidative DNA damage because of high levels of ROS production, downregulation of antioxidant genes and upregulation of pro-oxidant genes. The results demonstrate the functional diversity of cancer-associated fibroblasts and show that malignant keratinocytes from GU-OSCC reinforce their malignant behavior by inducing fibroblast activation and senescence through ROS and TGF-?-dependent mechanisms
1286-1295
Hassona, Y.
88050543-9c17-400a-a722-a90c8e02aa46
Cirillo, N.
aee162ed-ce3d-419c-a6b5-08d3e62424ec
Lim, K.P.
a2c432b9-0ba4-428c-8855-de3d5aad230d
Herman, A.
1bea745b-7a2f-4c8f-bf66-f974f76e6855
Mellone, M.
10dff24e-086d-491e-8be4-db96327847c7
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Pitiyage, G.
6477777b-fd43-42c8-8b30-44050c10040b
Parkinson, E.K.
ca386b59-0308-468e-b58d-336d850c356c
January 2013
Hassona, Y.
88050543-9c17-400a-a722-a90c8e02aa46
Cirillo, N.
aee162ed-ce3d-419c-a6b5-08d3e62424ec
Lim, K.P.
a2c432b9-0ba4-428c-8855-de3d5aad230d
Herman, A.
1bea745b-7a2f-4c8f-bf66-f974f76e6855
Mellone, M.
10dff24e-086d-491e-8be4-db96327847c7
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Pitiyage, G.
6477777b-fd43-42c8-8b30-44050c10040b
Parkinson, E.K.
ca386b59-0308-468e-b58d-336d850c356c
Hassona, Y., Cirillo, N., Lim, K.P., Herman, A., Mellone, M., Thomas, Gareth J., Pitiyage, G. and Parkinson, E.K.
(2013)
Progression of genotype-specific oral cancer leads to senescience of cancer associated fibroblasts and is mediated by oxidative stress and TGF-B.
Carcinogenesis, 34 (6), .
(doi:10.1093/carcin/bgt035).
(PMID:23358854)
Abstract
Keratinocyte senescence acts as a barrier to tumor progression but appears to be lost in late pre-malignancy to yield genetically unstable oral squamous cell carcinomas (GU-OSCC); a subset of OSCC possessing wild-type p53 and are genetically stable (GS-OSCC). In this study, fibroblasts from GU-OSCC were senescent relative to fibroblasts from GS-OSCC, epithelial dysplastic tissues or normal oral mucosa, as demonstrated by increased senescence-associated ?-galactosidase (SA ?-Gal) activity and overexpression of p16(INK4A). Keratinocytes from GU-OSCC produced high levels of reactive oxygen species (ROS) and this was associated with an increase in the production of transforming growth factor-?1 (TGF-?1) and TGF-?2 in stromal fibroblasts. Treatment of normal fibroblasts with keratinocyte conditioned media (CM) from GU-OSCC, but not GS-OSCC or dysplastic keratinocytes with dysfunctional p53, induced fibroblast senescence. This phenomenon was inhibited by antioxidants and anti-TGF-? antibodies. Fibroblast activation by TGF-?1 preceded cellular senescence and was associated with increased ROS levels; antioxidants inhibited this reaction. Senescent fibroblasts derived from GU-OSCC or normal fibroblasts treated with CM from GU-OSCC or hydrogen peroxide, but not non-senescent fibroblasts derived from GS-OSCC, promoted invasion of keratinocytes in vitro. Epithelial invasion was stimulated by fibroblast activation and amplified further by fibroblast senescence. The data demonstrate that malignant keratinocytes from GU-OSCC, but not their pre-malignant counterparts, produce high levels of ROS, which, in turn, increase TGF-?1 expression and induce fibroblast activation and senescence in a p5-independent manner. Fibroblasts from GU-OSCC were particularly susceptible to oxidative DNA damage because of high levels of ROS production, downregulation of antioxidant genes and upregulation of pro-oxidant genes. The results demonstrate the functional diversity of cancer-associated fibroblasts and show that malignant keratinocytes from GU-OSCC reinforce their malignant behavior by inducing fibroblast activation and senescence through ROS and TGF-?-dependent mechanisms
This record has no associated files available for download.
More information
Published date: January 2013
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 359556
URI: http://eprints.soton.ac.uk/id/eprint/359556
ISSN: 0143-3334
PURE UUID: 42ce9a26-7112-4b86-8535-a22ba301975f
Catalogue record
Date deposited: 04 Nov 2013 14:15
Last modified: 14 Mar 2024 15:24
Export record
Altmetrics
Contributors
Author:
Y. Hassona
Author:
N. Cirillo
Author:
K.P. Lim
Author:
A. Herman
Author:
M. Mellone
Author:
G. Pitiyage
Author:
E.K. Parkinson
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics