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The role of senescent fibroblasts in oral cancer and disease

Associated Centre/s: Clinical and Diagnostic Oral Sciences

Associated Research: Oral Cancer

Research Programme Funder: NC3R

Fluorescent staining of a senescent OSMF fibroblast expressing the cell cycle inhibitor p16INK4A (green) and counterstained with the nuclear DNA stain Dapi (blue).
Fluorescent staining of a senescent OSMF fibroblast expressing the cell cycle inhibitor p16INK4A (green) and counterstained with the nuclear DNA stain Dapi (blue).

The aims of Professor Parkinson’s group are to investigate the role of senescent fibroblasts in the development and progression of oral squamous cell carcinoma (SCC) and to exploit the detection of senescent fibroblasts in early diagnosis using non-invasive approaches.  We have shown previously that senescent fibroblasts accumulate in the cancer-prone condition oral sub-mucous fibrosis (OSMF) and are present in large numbers in the cancer-associated fibroblast population of SCC.

The senescent cells may be a natural defence against fibrosis and are induced by reactive oxygen species that cause irreparable DNA double strand breaks (Pitiyage et al J. Pathol. 2011). Our current research is focused around determining whether senescent fibroblasts aid tumour promotion and progression (Hassona –manuscript in revision) and the mechanism by which senescence occurs in the cancer-associated mesenchyme and in fibrosis.

Other evidence from extensive microarray analysis suggests that the senescent fibroblasts in the cancer microenvironment are associated with poor prognosis (Thurlow et al J. Cli. Oncol. 2010; Lim et al J.Pathol 2011).  Our other work has attempted to identify novel metabolites that accumulate in the conditioned medium of senescent oral fibroblasts and those induced to senesce by irreparable DNA double strand breaks.

Several novel molecules have been identified and are being investigated for their functional significance and diagnostic potential. Some of these molecules are associated with the presence of irreparable DNA double strand breaks, which we have established are present in the senescent fibroblasts of oral submucous fibrosis (Pitiyage et al J.Pathol., 2011). Others are elevated in replicative senescence and a few are associated with both replicative and strand break-induced senescence.

Research Lead: Prof Ken Parkinson
Post Doctoral Scientist: Alice DeCastro
PhD Student: Emma James
Visitors: Professor Stephen Prime, Dr. Gayani Pitiyage; Dr. Zacharoula Nikolakopoulou

Research

Immunperoxidase staining of p16INK4A in OSMF tissue showing extensive expression of p16INK4A in both the oral epithelium and the oral mesenchyme (arrows).
Immunperoxidase staining of p16INK4A in OSMF tissue showing extensive expression of p16INK4A in both the oral epithelium and the oral mesenchyme (arrows)

The mechanism of action of fibroblast senescence in fibrosis and cancer.

We have previously established that fibroblast senescence in both OSMF and SCC involves TGF-β and reactive oxygen species (ROS) but the manner by which TGF-β generates ROS in these cells is not clear.  Our research will focus on the pathways known to be associated with ROS-induced senescence and we will attempt to rescue the senescent phenotype by manipulating these pathways in vitro. In particular, we will test the link between TGF-β, the cysteine-rich proteins (CCNs) and ROS generation and test for the presence of CCN proteins in OSMF and SCC samples.

The role of fibroblast senescence in tumour development and progression (with Professors Stephen Prime and Kim Piper)

It is well known that OSMF and fibrosis in general is predisposed to cancer and there is now much evidence that cancer-associated fibroblasts (CAFs) and senescent fibroblasts can promote various aspects of cancer development and progression, including the selective growth of pre-neoplastic keratinocytes and the invasion of established SCC cells. However, as senescence has been shown to ameliorate fibrosis in vivo (Jun and Lau Nat Cell Biol. 2010; 12:676-85) and to generate MMPs in vitro (Pitiyage et al J. Pathol 2011), it is unclear whether fibroblast activation or the associated senescence is responsible for the reported links with progression and poor prognosis (Thurlow et al J. Clin. Oncol. 2010; Lim et al J.Pathol 2011; Marsh et al J Pathol. 2011; 223:470-81).

Our recent data has indicated that fibroblast activation alone, as assessed by the presence of alpha smooth muscle actin (Marsh et al J Pathol. 2011; 223:470-81), is insufficient to induce SCC invasion but the onset of senescence leads to a much more powerful phenotype (Hassona et al –manuscript in revision). We will investigate this further by depleting the senescent fibroblasts from CAF and OSMF populations using a recently developed panning technique (Pitiyage et al J.Pathol. 2011) and testing the resulting populations for their ability to promote pre-neoplastic keratinocyte growth and SCC invasion.

In parallel, we will test archival samples of dysplasia and SCC for the presence and number of senescent fibroblasts using newly established techniques and will test whether the number of senescent fibroblast correlates with tumour progression or patient outcome.

The identification of secreted biomarkers of senescent fibroblasts

In collaboration with a service provider we have identified novel metabolites that accumulate in the conditioned medium of senescent oral fibroblasts and those induced to senesce by irreparable DNA double strand breaks. Some of these molecules are associated with the presence of irreparable DNA double strand breaks, which we have established are present in the senescent fibroblasts of oral submucous fibrosis (Pitiyage et al J.Pathol., 2011). Others are elevated in replicative senescence and a few are associated with both replicative and strand break-induced senescence. We are continuing to assess the most interesting molecules as candidates in the diagnosis of diseases such as OSMF and SCC where senescent fibroblasts are established to play a role.

Key Publications

Thurlow, J.K., Peña Murillo, C.L., Hunter, K.D., Buffa, F.M. Patiar, S., Betts,G., West, C.M.L., Harris, A.L., Parkinson, E.K., Harrison,P.R., Ozanne, B.W., Partridge, M. and Kalna, G.Spectral clustering of microarray data elucidates the roles of microenvironment remodelling and immune responses in survival of head and neck squamous cell carcinoma. J. Clin.Oncol. (2010) 28:2881-8.

Pitiyage G.N., Slijepcevic P., GabraniA., Chianea Y.G., Lim K.P., Prime S.S., Tilakaratne W.M., Fortune F. and  Parkinson E.K. Senescent Mesenchymal Cells Accumulate in Human Fibrosis by a Telomere-Independent Mechanism and Ameliorate Fibrosis through Matrix Metalloproteinases  J.Pathol. (2011) 223:604-17.

Lim, K.P., Cirillo, N., Hassona, Y., Wei W., Thurlow, J.K.,Cheong, S.C., Pitiyage, G. Parkinson, E.K. and Prime, S.S. Fibroblast gene expression profile reflects the stage of tumor progression in oral squamous cell carcinoma. J.Pathol. (2011) 223:459-69.

McCaul, J., Gordon, K., Clark, L.J. and Parkinson, E.K. Telomerase inhibition and the future management of head-and-neck cancer.  Lancet Oncology (2002) 3: 280-288.

Hunter, K., Parkinson E.K and Harrison P.R.  Profiling early head and neck cancer. Nature Reviews in Cancer (2005) 5: 127-135.

Parkinson, E.K. Senescence as a modulator of oral squamous cell carcinoma development. Oral Oncol. 2010 46: 840-53.

Contact

Professor Ken Parkinson
Professor of Head & Neck Cancer

e.k.parkinson@qmul.ac.uk
+44 20 7882 7185

Research Centre for Clinical & Diagnostic Oral Sciences
Blizard Building
Barts & The London
Queen Mary's School of Medicine & Dentistry
4 Newark Street
London E1 2AT
UK

Staff

  • Professor Kim Piper - Consultant Oral Pathologist and Hon Professor, Senior Tutor for Dental Admissions
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