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Lecture 5
What is Cancer?
Introduction
Well known to ancient Egyptians and to succeeding civilizations
Affected a small number of people
Once infectious disease was controlled due to public health improvements and improved medical care, cancer became more common 1 in 3 people will develop cancer
1 in 4 males will die of it 1 in 5 females will die of it
Cancer is a disorder of cells and it usually appears as a tumour made up of a mass of cells, but this is the end point
A whole series of changes have occurred to lead to this disorder Occurs typically at an older age
Normal Tissue
Epithelium Stem Cells Basement Membrane Tissue specific cells
Mesenchyme
Not all adult cells can proliferate Special reserve cells retain proliferation potenitial
Embryonic stem cells can make any cell in the body Although, many stem cells are committed and have limited potential. i.e. can produce all the intestinal epithelial cells. Proliferation requires the cell cycle
G0,G1,S,G2, and M phase
Draw on board
Pathways that control colorectal tumorigenesis. Mutations in the APC/b-catenin pathway initiate the neoplastic process, resulting in small benign tumors (adenomas). These tumors progress, becoming larger and more dangerous, as mutations in other growth-controlling pathway genes (such as K-Ras, B-RAF, PIK3CA, or p53) accumulate. The process is accelerated by mutations in stability genes. The top line indicates potential clinical applications of knowledge of these pathways.
Hallmarks of Cancer
Summarized by Hanahan and Weinberg (2000) Cell Six changes for cancer found in most, if not all, cancers
Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replicative capacity Sustained angiogenesis Tissue invasion and metastasis
Causes of Cancer
DNA Mutations
Radiation other environmental (tobacco, alcohol, radon, asbestos, etc) Random somatic mutations Inherited germ line mutations
Genetic predisposition Rb, p53, APC, CDKN2A, BRCA1, BRCA2 Will discuss these later in a pathway context
Infectious agents
Viral
HPV cervical cancer Hepatitis liver cancer
Vaccines have been developed and are extremely effective not available
Bacterial
H. pylori stomach cancer
There are probably other breast cancer genes and many cancers are random
Proto-oncogenes are the normal genes Over 100 oncogenes have been identified
Retroviral transduction
Transduction of normal cellular genes by transduction
Over-expression, mutant genes
Mutations
Ras activating mutations in codons 12, 13, and 61
Overexpression
Gene amplification
Tyrosine-Kinase Receptors
haploinsufficiency
TSG
Classic RB gene
Germline mutations in RB and one acquired somatic mutation
Leads to retinoblastoma
P53
50-75% of all cancers have a p53 mutation
Loss of both or dominant negative
Evasion of Apoptosis
Receptors transmit death signals
FAS and FAS receptor TNF and TNFR1 Decoy receptor that dont signal can promote survival
Hayflick limit ~ 50-80 doublings Reach replicative senescence Inactivating pRb/p53 extends lifespan ~30 doublings
Cells reach crisis due to continued chromosome shortening Chr fussions, genetic loss, and cell death