Introduction to Cancer

Lecture 5

Jeremy Edwards University of New Mexico Health Sciences Center

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

Nerve Fibers Collagen Fibroblast Blood Vessels etc

Growth control in normal tissue

Control of cell growth has been extensively studied
Growth means size increase and proliferation

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

Tumour Growth or neoplasia

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

Inherited cancers account for a small percentage of many cancers

Breast cancer
~3% cases between 36 and 45 years of age have a BRCA1 mutation ~3% cases between 36 and 45 years of age have a BRCA2 mutation
1/500 people have a BRCA1 mutation

There are probably other breast cancer genes and many cancers are random

Oncogenes Hallmark #1:

Self-sufficiency in growth signals
Originally coined as a genetic term to describe any gene capable of causing cancer. But, later tumor suppressor loss of function genes that can cause cancer Oncogenes refers to genes that contribute to cancer in a gain-of-function manner
And are dominate at the cellular level.

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

Translocations and re-arrangements

Autocrine signaling, transcription factors

Tumour suppressor genes:

Hallmark #2: Insensitvity to negative signals TSGs are altered by inactivating mutations and this can lead to cancer
Point mutations Delete regions of chromosomes LOH Altered methylation of the promotor epigenetics Knudsons two hit model
Dominant negative
p53

haploinsufficiency

TSG
Classic RB gene
Germline mutations in RB and one acquired somatic mutation
Leads to retinoblastoma

80% of small cell lung cancers have an RB mutation

P53
50-75% of all cancers have a p53 mutation
Loss of both or dominant negative

Apoptosis: Hallmark #3: Evasion of Apoptosis

Apoptosis is programmed cell death Damaged cells are effectively removed by this mechanism Also, this is a mechanism by which cells that have an oncogenic mutations are removed
Apoptosis is a critical defense against cancer

Evasion of Apoptosis
Receptors transmit death signals
FAS and FAS receptor TNF and TNFR1 Decoy receptor that dont signal can promote survival

Intracellular proteins that monitor DNA damage

p53

Hallmark #4: Acquisition of limitless proliferative capacity

Cells have a finite life and ability to replicate
Due to chromosome shortening Ends of chromosome are called telomeres (hexamer repeats - TTAGGG)

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

Rare mutations lead to immortalization

Activation of telomerase

Hallmark #4: Acquisition of limitless proliferative capacity

Hallmark #5: Angiogenesis

All tumours require a blood supply if they are to grow to a significant size VEGF and FGF1 and FGF2 are activated in tumours and signal endothelial cell proliferation and growth of blood vessels.

Hallmark #6: Tissue invasion and metastasis

Little is known about these genes