Evolution, Cancer & Aging: Evolution, Cancer & Aging


Cancer: Cancer One third of population suffer from some form of cancer 20% of all deaths are cancer related In developed countries cancer care represents about 10% of total costs


Cancer types: Cancer types Sarcomas (in which tumor arises in mesenchymal tissue) Carcinomas (in which tumors arise in epithelial tissues) Hematopoeitic & lymphoid malignancies


What is cancer ?: What is cancer ? A lineage of cells in which normal genetic control of cell proliferation and cell death have been disrupted


Genetic causes of cancer: Genetic causes of cancer Mutations to oncogenes (signalling pathways influencing death and proliferation, Ras, Bcl-2) Mutations to DNA repair genes (mismatch repair etc) Mutations to tumor suppresor genes (>50% P53, p16)


What are oncogenes: What are oncogenes Genes involved in cell growth and development (growth factors, growth factor receptors etc) When mutated are often called protooncogenes Often related to viral oncogenes (e.g. src oncogene in retroviruses) Often highly conserved (e.g. ras found in both humans and yeast Mutations have a dominant phenotype and many are often required Mutations can be both point (bladder carcinoma) and chromosomal translocation (chronic leukemia)


What are Tumor suppresors?: What are Tumor suppresors? Genes whose products block abnormal growth Mutations are recessive - both alleles must be lost for loss of function The “two hit” model of cancer progression (Knudson 1971) explains both hereditary and sporadic cases. In hereditary case 1 mutation is in germ line and 2nd in soma. E.g retinoblastoma Loss of TS genes often leads to several different types of cancer (50% of cancers have lost P53) TS genes are redundant until some other form of genetic damage arises.


Tumor Progression by Clonal Evolution: Tumor Progression by Clonal Evolution Cancer cells are at a short term growth advantage over wild type cells Thus selection should lead to a preponderance of cancer cells over healthy cells As more mutations accumulate in cancer cells, the greater the competitive edge However, at the whole body level there is a cost In other words cancer evolves towards higher virulence within the body


Tumor Progression by Clonal Evolution - the case of colorectal cancer: Tumor Progression by Clonal Evolution - the case of colorectal cancer Normal cell Increased growth Adenoma II Adenoma I Adenoma III Carcinoma Metastasis 5q mutation RAS mutation P53 mutation Chromosomal loss


Somatic Evolution: Somatic Evolution


Health & Disease: Health & Disease Health is not the absence of tumors but the control of tumors


Evolution Therapy: Evolution Therapy


Effectivetherapy: Effective therapy


Destructivetherapy: Destructive therapy


Slide17: Instability driven progression


Mendelian Cancers: Mendelian Cancers 50 Mendelian disorders associated with high cancer risk In these cases there are multiple primary tumors, unlike sporadic Retinoblastoma (1/20000). Mutation to RB1 (13q) through germline. Each eye must then accumulate somatic mutation. RB1 mutations leads to loss of heterozygosity - homozygosity observed around region of gene


Mendelian Cancers: Mendelian Cancers Wilms Tumor - Embryonic kidney tumor (11p13) Familial Polyposis Coli - 1/10000, autosomal dominant mutation in 5q Neurofibromatosis type 1 - mutation to chromosome 17q11.2 in NF1 gene that regulates ras. Familial Breast Cancer (10% of women). 2-5% of cases associated with susceptibility gene 17q. Burkitt Lymphoma - B cell tumor of jaw. Common in equatorial Africa. Chromosome translocation.


Mutational Mechanisms: Mutational Mechanisms Point mutations Microsatellites Chromosomal instability


The evolutionary lie about cancer: The evolutionary lie about cancer “Cancer is a late onset disease and hence genes will not evolve to counteract cancer as incidence is largely at post-reproductive age”


Why do we age?: Why do we age? The "prolongation of life is the most noble of all medical pursuits, for if any such thing be found out [it] would be the greatest of earthly donations". Francis Bacon


Theories of Aging: Theories of Aging Non adaptive theories: DNA damage, Free radicals, Waste products, radiation, pathogens, Stress Mutation accumulation theory: selection is strongest on early phenotypes. Telomerase loss Antagonistic pleiotropy theory: accumulate mutations with opposing effects Disposable Soma Theory: Finite resources to invest in different cell types (Germ line versus Soma)


Fundamental Theory of Aging: Fundamental Theory of Aging Maintenance and repair of Somatic tissues declines with age Medawar (1952) deleterious mutations influencing late ages can accumlate Williams (1957) Early and late effects are often opposed - antagonistic pleiotropy. Rose & Charlesworth (1981) selection experiments in which offspring of old parents are reared and others culled. Found that fecundity and longevity of old females increased


Life History Tradeoffs: Life History Tradeoffs Early reproduction is correlated with lowered subsequent reproduction Early reproduction is associated with smaller adult body size High extrinsic mortality leads to earlier reproduction but less competitive adults


Diseases of Aging: Diseases of Aging Arteriosclerosis - most common cause of death & disability in elderly. Associated with chronic and progressive degeneration of arteries, with attendant thickening and loss of elasticity Coronary arteries - Myocardial infarction, cardiac failure Cerebral circulation - stroke, ischemia Aorta - Aneurysms Peripheral arterial circulation - gangrene


Alzheimer’s Disease: Alzheimer’s Disease Neurodegenerative disease causing progressive memory & language loss Associated with deposition of amyloid protein in CNS and neurofibrillary tangles (NFTs). NFTs associated with mutations to Tau proteins that stabilise microtubules. Mutations to PS-1 and PS-2 (presenelin genes) give rise to early onset disease. Mutation to apolipoprotein E gives rise to late onset.


More Age related disorders: More Age related disorders Huntington Parkinson Prion diseases Macular degeneration Mitochondrial disease Progeroid disorders - Werner syndrome


Aging in lower metazoans: Aging in lower metazoans Most theories of aging require a distinction between germ line and soma Evidence from the Hydrozoans suggest that they do not age Mechanisms to maintain integrity of telomerase expression seem important


Aging in Yeast: Aging in Yeast During a yeast life cycle, extrachromosomal ribosomal DNA circles, or ERCs, form by excision from DNA . ERCs replicate until the cell becomes overwhelmed and dies. Aging in yeast cells is started by the formation of the first coiled-up ERC. ERCs accumulate exponentially in the mother cell because ERCs have replicative potential The SIR2 gene implicated in longevity in yeast. Plays a role in transcriptional silencing Caloric restriction (e.g. reducing sugar in yeast diet) increases longevity via SIR2.


References: References McVey, M., Kaeberlein, M., Tissenbaum, H. A. and Guarente, L. The Short Life Span of Saccharomyces cerevisiae sgs1 and srs2 Mutants Is a Composite of Normal Aging Processes and Mitotic Arrest Due to Defective Recombination. Genetics 157(4), 1531-1542 (2001) Lithgow GJ, Kirkwood TB. Mechanisms and evolution of aging. Science 1996 Jul 5;273(5271):