BIOLOGY OF DISEASES
• Skin diseases
Topics
• Epidermal Stem Cells
• Skin cancer
• Basal cell carcinoma
• Squamous cell car...
• Self-maintenance of stem cell population
• Often pluripotent differentiation potential
Transit amplifying cells
Model of...
• Transfection and viral transduction can be used to manipulate
cells in culture
Stem cells are slowly cycling in vivo
Ste...
• When applied to transgenic or knock-out mice, 2-stage model
gives information on roles of individual proteins in
carcino...
Actinic Keratoses
Squamous Cell Carcinoma
Squamous Cell Carcinoma
Malignant melanoma
Sunburn and melanoma
Melanocytes
Mela...
ECM Turnover - MMPs
• Matrix metalloproteinases are enzymes that cleave components
of ECM
• Over 20 different enzymes with...
Chicken or Egg
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BIOLOGY OF DISEASES

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BIOLOGY OF DISEASES

  1. 1. BIOLOGY OF DISEASES • Skin diseases Topics • Epidermal Stem Cells • Skin cancer • Basal cell carcinoma • Squamous cell carcinoma • Melanoma • Psoriasis Epidermal Stem Cells • Epidermal stem cells are a subpopulation of keratinocytes • Epidermal stem cells give rise to interfollicular epidermis, hair follicles and sebaceous glands • Sweat glands are derived from the epidermis during embryonic development but is is not known whether epidermal stem cells contribute to this differentiation pathway during postnatal life. Properties of Stem Cells • Not terminally differentiated • Can divide without limit (at least for the lifetime) • When a stem cell divides, each daughter cell has a choice: remain as a stem cell or embark on a course that commits to differentiation
  2. 2. • Self-maintenance of stem cell population • Often pluripotent differentiation potential Transit amplifying cells Model of epidermal cell lineages Maintenance of stem cell compartment • Divisional asymmetry • Population asymmetry • Epidermal stem cells form clusters • Locations: upper hair follicle (bulge) and patches of basal keratinocytes at the tips of dermal papillae (between rete ridges) • Stem cell niche Stem cell niche Stem Cell Research • Problem: no definite cell surface marker to distinguish pure populations of epidermal stem cells (compare to haematopoietic stem cells). • Indirect methods utilised Clone forming ability of individual keratinocytes • Only stem cells have unlimited potential for cell divisions. • When keratinocytes are cultured in low density only stem cells give rise to large colonies
  3. 3. • Transfection and viral transduction can be used to manipulate cells in culture Stem cells are slowly cycling in vivo Stem cell fate can be studied in vivo using transgenic mice Biomedical applications for epidermal stem cells • Wound healing • Gene therapy • Implications in carcinogenesis Skin Cancer • Mouse 2-stage skin carcinogenesis => tumour growth can be promoted even 1 year after exposure to carcinogen. • Mutated differentiated cells are shed off from the surface of the skin but mutated stem cells and their stem cell daughters remain in the skin and can acquire further mutational hits 2-stage skin carcinogenesis • Mutations are caused by applying a mutagen ( for example DMBA) to shaved back skin • Tumour growth is promoted by repeated applications of TPA over several weeks • Multiple benign papillomas, some of them convert to malignant carcinomas.
  4. 4. • When applied to transgenic or knock-out mice, 2-stage model gives information on roles of individual proteins in carcinogenesis Skin cancer • Basal Cell Carcinoma and Squamous Cell Carcinoma are of keratinocyte origin • Melanoma originates from melanocytes Ultraviolet light is carcinogenic Sunburn UV light is mutagen DNA-Repair mechanisms protect cells from mutagens • Excision repair mechanism can cut out thymine dimers • Xeroderma Pigmentosum, a rare inherited disease. Affected individual lack excision repair and are extremely prone to skin cancer. Basal Cell Carcinoma Basal Cell Carcinoma • Basal cell carcinoma is hardly ever invasive and can be completely cured by surgery Basal Cell Carcinoma Inherited BCC Naevus
  5. 5. Actinic Keratoses Squamous Cell Carcinoma Squamous Cell Carcinoma Malignant melanoma Sunburn and melanoma Melanocytes Melanoma - staging is important prognostic tool Familial melanoma - mutations in p16 INK tumour suppressor gene Invasion and metastasis • Cytoskeleton • Adhesion • Cell-cell • Cell-matrix • Signalling proteins • Rho family • Tumour microenvironment • Matrix Metalloproteinases
  6. 6. ECM Turnover - MMPs • Matrix metalloproteinases are enzymes that cleave components of ECM • Over 20 different enzymes with differenrt specificities. • Common theme: expressed as an inactive proenzyme • Also other substrates than ECM proteins • TIMPs = tissue inhibitors of MMPs Experimental Therapies for Melanoma • Immunotherapy - Tumour vaccines • Some promising results • Inhibitors of MMPs • Against invasion and angiogenesis • Early results in human trials (many different tumour types) disappointing Psoriasis - a disease of immune cells and keratinocytes Psoriasis has a genetic component
  7. 7. Chicken or Egg

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