CANCER Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. (American Cancer Society)
INCIDENCE of CANCER - is a common disease - 1 person in 3 can expect to contract cancer at some stage in their life - 1 person in 5 can expect to die from it - worldwide, 100-350 of every 100,000 people will die of cancer each year - given a global population of about 6.4x10 9 , this implies 6.4 t0 22.4 million people will die this year
TUMOUR CLASSIFICATION BENIGN TUMOURS Develop in any tissue • grow locally • May cause problems by pressure (brain) or obstruction ( colon) • Histologically resemble the tissue of origin • Covering or lining tissues of skin, intestine, bladder etc may produce wart-like outgrowths containing all cell types • In other situations only one cell type may be present- may produce an excess of particular hormone • Benign does not mean ‘completely harmless’ • Do not spread to distant sites
TUMOUR CLASSIFICATION IN SITU TUMOURS Usually develop in the epithelium Usually small • Have altered histological appearance • Loss of normal arrangement of cells • Variations in cell size and shape, increase in nucleus size and staining ( increased DNA ), presence of abnormal chromosomes • Do not invade basement membrane and supporting mesenchyme
TUMOUR CLASSIFICATION CANCERS Fully developed malignant tumours with the specific capacity to invade and destroy the underlying mesenchyme. • Metastasise • Stimulate angiogenesis and development of blood supply • difficult to treat.
Two Broad Classes of Genes are Involved in the Onset of Cancer 1). Proto-oncogenes activated by mutation to become oncogenes,- excessively active in growth promotion. 2). Tumour Suppressor genes normally restrain cell growth- damage to these genes allows inappropriate growth Many of the genes in both classes code for proteins involved in • entry into, and passage through, the cell cycle • cell death by apoptosis • repair of damaged DNA
Chemical Carcinogens - Earliest example 1775 coal tar and skin cancer - Later, 2 – naphthylamine as a bladder carcinogen - Wide chemical diversity and many ( eg polycyclic aromatic hydrocarbons) show great chemical stability. - Now known to be converted to highly reactive compounds by detoxification enzymes in the liver. - Guanine is often converted to methyl guanine, acts like adenine and pairs with thymidine in the copied strand- hence G-C pair is converted to A-T pair as point mutation.
3 ways in which cancer cells become growth signal autonomous. - modulation of growth factor provision - modulation of growth factor receptor activity - modulation of intracellular signalling pathways
Self Sufficiency in Growth Signals ii). Modulation of growth factor receptor activity Many growth factor receptors are protein tyrosine kinases Overexpression allows tumours to respond to low levels of growth factor that would not normally produce a growth response. EGF-R ( the receptor for EGF) and Erb-B ( the receptor for hereglulin ) are upregulated in stomach, brain and breast tumours. HER2/neu is overexpressed in stomach and breast tumours Overexpression of GF receptors may result in ligand –independent signalling.
Self Sufficiency in Growth Signals ii). Modulation of growth factor receptor activity (cont) Receptors may become structurally altered- ligand independent as a result. Truncated versions of the EGF receptor lacking the cytoplasmic domain are constitutively active Alteration of integrins expression (ECM receptors) to those favouring growth. Ligand activated GF receptors and pro-growth integrins attached to ECM often activate the SOS-Ras-Raf-MAP Kinase pathway.
Self Sufficiency in Growth Signals iii). Modulation of intracellular signalling pathways Frequently involves the SOS-Ras –Raf- MAPK cascade About 25% of human tumours have a mutated Ras protein. (90% pancreas, 50% colon, 30% lung -- the first oncogene discovered in human tumours)) --- mitogenic signals are transmitted without any upstream activation of the pathway Ras also interacts with PI3 kinase This enables growth signals to simultaneously generate survival signals ie. Signals which protect against apoptosis
Insensitivity to Antigrowth Signals Tumours have developed several ways to block TGFß action • Expression of TGFß receptor is down regulated • The receptor is mutated to a less active form • Intra-cellular signalling is disrupted by- • Mutation of Smad • Loss of p15 • Mutation of CDK4 to be less p15 sensitive • Mutation of Rb
Insensitivity to Antigrowth Signals Tumours have developed several ways to block TGFß acting through Rb In some DNA – virus induced tumours ( cervical carcinomas) Rb is inactivated by being complexed with a viral protein . In human cervical tumours this is the E7 protein of human papilloma virus
Insensitivity to Antigrowth Signals Cancer cells can also • Turn off the expression of cell adhesion molecules that transmit antigrowth signals • These probably act through Rb also
Insensitivity to Antigrowth Signals Some tumours have developed mechanisms for differentiation One such mechanism involves the c-myc oncogene
Evasion of Apoptosis Hormone dependent tumours undergo massive apoptosis if the hormones were removed . Suggested that increased cell growth and apoptosis occurred at the same time Apoptosis may be switched on by oncogene overexpression Elimination of cells with activated oncogenes by apoptosis may be the primary means by which mutant cells are continually removed from the body’s tissues. For a tumour to progress it has to inactivate the apoptopic machinery
Evasion of Apoptosis In 50% of lymphomas, there is a mutation in c-myc and a mutation in bcl-2 Further evidence for a myc-bcl-2 interaction Fibroblasts overexpressing myc grown in culture In low serum the c-myc expressing cells show high apoptosis Increased apoptosis could be abolished by • Addition of survival factors such as IGF-1 to the medium • Overexpression of Bcl-2 or Bcl-XL • Disruption of the FAS pathway
Evasion of Apoptosis In transgenic mice, • Inactivation of Rb ( expected to increase cell proliferation) produced slow growing microscopic tumours with a high rate of apoptosis • Additional inactivation of p53( a key mediator of apoptosis) in the same cells produced rapidly growing tumours • Mutation of p53 and the presence of a mutated p53 protein is extremely common in human tumours ( greater than 50%) Some lung and colon cancers produce a decoy non- signalling receptor for the FAS ligand
Limitless Replicative Potential Why should tumour cells need to become ‘immortalised’? Normal human cell types have the capacity for 60–70 doublings. This should enable clones of tumor cells to expand to numbers that vastly exceed the number of cells in the human body. There seems to be no sense in the idea that the tumour cells have to become immortal in order for malignant tumour growth to occur But…… During tumour development there is widespread apoptosis along side the increased cell division. The number of cells in a tumour greatly under represents the cell divisions required to produce it. Thus the generational limit of normal somatic cells may be a barrier to cancer development.
Limitless Replicative Potential Telomeres Telomeres are simple-sequence DNA repeats found at the end of chromosomes Human telomeres contain 250-1500 copies (6-12 kb) of the sequence TTAGGG At each cell division, 50–100 bp of telomeric DNA are lost from the ends of every chromosome DNA polymerases are unable to completely replicate the 3 ′ ends. Progressive shortening of the telomeres occurs with each division. Eventually the telomeres lose the ability to protect the ends of the chromosomes This results in end to end chromosomal fusion and the death of the affected cell.
Limitless Replicative Potential Telomeres …………..and Telomerase Telomere maintenance occurs in just about all malignant cells The majority (85%–90%) upregulated expression of an enzyme called telomerase This adds hexanucleotide repeats onto the ends of telomeric DNA. The telomeres are thus kept at a length above a critical threshold which allows for unlimited multiplication of descendant cells.
Sustained Angiogenesis Normal Cells and Tissues Cells in a tissue need to be within 100 μ of a capillary blood vessel This closeness is achieved during organ development and once a tissue is formed, the growth of new blood vessels—the process of angiogenesis—is transitory and carefully regulated. Cancer Cells Cancer cells initially lack angiogenic capacity this limits initial expansion of the tumour. To develop to a clinically detectable size the tumours usually develop angiogenic ability.
Sustained Angiogenesis Cancer Cells A cancer cell mass of about 2 millimeters emits signals that recruit surrounding connective tissue and vascular cells to the tumor and induce them to grow into blood vessels. The blood supply to the tumour provides nutrients and oxygen, and provides a route to the rest of the body, ie. A route to metastasis.
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