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Defining and Targeting Differentiation of Non-Melanoma Skin Cancer

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Defining and Targeting Differentiation of Non-melanoma Skin Cancer Dr Antisar Benketah Supervisors Dr Girish Patel Prof Simon Reed Submitted to in partial fulfilment of the requirements for the degree of Doctor of Medicine Department of Dermatology School of Medicine Cardiff University June - 2014 Declaration This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of Doctor of Medicine (MD) Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access previously approved by the Graduate Development Committee. Signed ………………………………………… (candidate) Date …………………… 1 Abstract Human cancer stem cells are proposed to play a critical role in tumour initiation and maintenance by their exclusive ability to regenerate the tumour. Thus cancer stem cells share many of the properties of normal stem cell including self-renewal and ability to give rise to progeny which undergo tissue-specific differentiation. Thus we hypothesised that by determining the normal patterns of tissue differentiation within cancer we could identify tumour type specific factors that promote differentiation, for therapeutic development. Therefore the aim of this study is to define patterns of human hair follicle differentiation in human basal cell carcinoma (BCC) in order to elucidate potential drug-able targets that can promote tumour specific differentiation. To test this hypothesis we analysed 20 different hair follicle specific differentiation markers, which define distinct layers within the normal adult hair, in six different human BCC samples using RT-PCR with normal hair follicle tissue as control. For the 12 specific keratin genes expressed in the BCC, we analysed expression by immunofluorescence on 20 different BCC samples, using hair follicle samples as positive controls. Our findings suggest that human BCC demonstrates both inward and upward differentiation patterns similar to the hair follicle, with expression of: outer root sheath (K5,14,16,and k17), companion layer (K75), inner root sheath (K26,27,28,71,72,and k74), and cuticle (K32,35,82,and k85); but not hair shaft (K31) markers. Consistent with these findings we observed the mutually exclusive relationship between expression of the early differentiation marker K19 and cell proliferation in the hair follicle and BCC. Similarly, expression of the outer root sheath keratins coincided with nuclear translocation of both GLI1 and NFIL-6, suggesting that BCC also share normal hair follicle tissue regulatory pathways. To further test the hypothesis that normal tissue factors observed in the hair follicle regulate BCC differentiation we have developed an in vitro BCC assay. Using this tissue culture model we hypothesised that BCC’s are stuck in the telogen part of the hair follicle cycle, resulting from autocrine expression of bone morphogenic proteins 2 and 4. Inhibition of BMP signalling by addition of noggin as well as addition of TGF-β to BCC colonies in tissue culture led to further induction of inner root sheath, cuticle and medulla keratins. In summary we have shown that BCC exhibit hair follicle differentiation, which is similarly regulated, but is stuck in telogen arrest and can be rescued by addition of noggin and TGF- β2. 2 List of Presentation and Publication Arising From This Work Publications A. Original papers Colmont CS, BenKetah A, Errington RJ, et al. (2014) Human basal cell carcinoma tumor-initiating cells are resistant to etoposide. J Invest Dermatol 134:867-70. Colmont CS, Benketah A, Reed SH, et al. (2013). CD200-expressing human basal cell carcinoma cells initiate tumor growth. Proc Natl Acad Sci U S A 110:1434-9. B. Abstracts (Oral and Posters Presentation) A.BenKetah, P. Bowden, S. Reed and G. Patel. Human basal cell carcinoma demonstrates telogen arrest British Journal of Dermatology (2014) 170, ppe6–e18. (Oral presentation at BSID Meeting, Newcastle, 7-9 April, 2014). A BenKetah, SH Reed, PE Bowden and GK Patel. Defining and targeting differentiation pathways in non-melanoma skin cancer. Carcinogenesis and Cancer Genetics. Journal of Investigative Dermatology (2013); 133 (P 439), (Poster ). A. Benketah, G. Patel, S. Reed and P. Bowden . Human Basal Cell Carcinoma Differentiate Along Normal Hair Follicle Lineages. European Cancer Stem Cell Research day, Cardiff 26 January 2012 ; (Secured the best poster presentation ) A. Benketah, G. Patel, S. Reed and P. Bowden. Defining and targeting differentiation pathways in basal cell carcinoma. Br.J.Dermatol 2011 Jul;165 Suppl 1: pp 82-92 (PD19). (Poster presentation at the 91st British Association of Dermatologists) A Benketah, Girish Patel, Paul Bowden. Defining and targeting differentiation pathways in basal cell carcinoma. Journal of Investigative Dermatology (2011), Volume 131 (p152), (poster presentation at 41st Annual Meeting of the European Society for Dermatological Research (ESDR), Barcelona, Spain; 7-10 September 2011. A. Benketah, G. Patel, S. Reed and P. Bowden. Defining and targeting differentiation pathways in non-melanoma skin cancer. (Poster presentation) at the 25th Annual Postgraduate Research Day, School of Medicine, Cardiff University; 19th November 2010. 3 Dedication To my sweetest most dedicated and truly beloved husband for his time, assistance and patience, to my parents for their love, support and prays, and to my lovely kids for keeping me joyful. 4 Acknowledgements Firstly, I would like to thank Almighty God for giving me the strength to carry on with pleasure. I wish to express my deepest gratitude to my joint supervisors, Dr Girish Patel and Prof Simon Reed for their support and encouragement throughout the project and a special thanks to Dr Paul Bowden for his support, and guidance. I owe my utmost gratitude to my supervisor Dr Girish Patel for considering me worthy of this opportunity and for his constant advice, patience and motivation. I gratefully thank the Libyan Government for funding the project, and giving me this scholarship to accomplish my post-graduate studies in the UK I wish to express my sincere thanks to all friends in the Department of Dermatology for their support, also would like to give a special thank you to Tammy Ester, Fiona Ruge and Chantel Colmont for their technical help throughout my MD project. I am most grateful to my parents for having constant faith and love. I cannot thank my Father enough for supporting me throughout the project. I would like to express a special word of thanks to my friends Dena, Ibtesam, Randa, Amina, Shada , Rania , Afnan, and Katija who made my stay in Cardiff enjoyable. I would like also to acknowledge the PGR Office team for their advice, and help. And, last but not least I would like to thank the patients who provided the biopsies and without whose cooperation and time this project would not have been possible. 5 Abbreviation Ab Antibody APRT Adenine phosphoribosyltransferase APM Arrector Pili Muscle ATP Adenosine triphosphate BCC Basal Cell Carcinoma Bcl-2 B-cell CLL/lymphoma 2 BCN Basal cell nevus syndrome BPE Bovine pituitary extract BSA Bovine serum albumin BMP Bone morphogenic protein BMPr Bone morphogenic protein receptor BMPihh Bone morphogenic protein inhibitor cDNA Complementary deoxyribonucleic acid CL Companion Layer ORS Outer root sheath layer DAB 3,3’-diaminobenzidine DAPI 4’,6-diamidino-2-phenylindole dH2O Distilled sterile water DHH Desert Hedgehog Disp Dispatched DNA Deoxyribonucleic acid dNTP Deoxyribonucleotide triphosphate PBS phosphate buffered saline DPX Di-N-Butyle Phthalate in Xylene dsDNA Double stranded deoxyribonucleic acid EDTA Ethylenediaminetetraacetic acid EGF Epidermal Growth Factor EGFR Epidermal Growth Factor Receptor EGFr Epidermal growth factor receptor END2 Endothelin 2 FBS Foetal Bovine serum GAPDH Glyceraldehyde3- Phosphate Dehdrogenase GFP Green Fluorescent Protein 6 GLI1 GLIoma-associated oncogenes homologue 1 GLI2 GLIoma-associated oncogenes homologue 2 GLI3 GLIoma-associated oncogenes homologue 3 GLIA/GLIact GLI activated GLIR GLI repressor form Grk2 G protein–coupled receptor kinase 2 GSK3β Glycogen synthase kinase 3 beta HaCaT Keratinocyte cell line HCA2 Fibroblast cell line HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HH Hedgehog HDAC Histone deacetylase inhibitors HS Hair shaft IgG Immunoglobulin IHC Immunohistochemistry IHH Indian Hedgehog IRS Inner root sheath JAG-2 Jagged 2 JUN Forms the AP-1 early response transcription factor KAPs Keratin-associated proteins KDa KiloDalton KHG Keratohyalin granules KIT Keratinocyte (melanocytes) KRT Keratins KV Kilo volt mRNA Messenger ribonucleic acid NF-ᶄB Nuclear Factor Kappa-light chain enhancer of activated B-cells ORS Outer root sheath P53 Protein 53 PBS Phosphate buffered saline PCR
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