Lecture5 Edwards Cancer

8/3/2019 Lecture5 Edwards Cancer

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Introduction to Cancer

Lecture 5

Jeremy Edwards

University of New Mexico Health Sciences Center


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What is Cancer?


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Introduction Well known to ancient Egyptians and to succeeding

civilizations Affected a small number of people

Once infectious disease was controlled due to publichealth improvements and improved medical care, cancerbecame 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 endpoint A whole series of changes have occurred to lead to this disorder Occurs typically at an older age


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Normal Tissue

Stem Cells

Basement

Membrane

Epithelium

Mesenchyme

Nerve FibersCollagen

FibroblastBlood Vessels

etc

Tissue specific

cells


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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 havelimited potential. i.e. can produce all the intestinalepithelial cells.

Proliferation requires the cell cycle G0,G1,S,G2, and M phase

Draw on board


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Tumour Growth or neoplasia

Pathways that control colorectal tumorigenesis. Mutations in the

APC/b-cateninpathway initiate the neoplastic process, resulting insmall 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 applicationsof knowledge of these pathways.


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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


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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


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Inherited cancers account for asmall percentage of many cancers

Breast cancer

~3% cases between 36 and 45 years of agehave 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


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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 tocancer 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


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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


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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


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TSG

Classic RB gene

Germline mutations in RB and one acquiredsomatic mutation

Leads to retinoblastoma

80% of small cell lung cancers have an RBmutation

P53

50-75% of all cancers have a p53 mutation

Loss of both or dominant negative


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Apoptosis:Hallmark #3: Evasion of Apoptosis

Apoptosis is programmed cell death

Damaged cells are effectively removed bythis mechanism

Also, this is a mechanism by which cellsthat have an oncogenic mutations areremoved

Apoptosis is a critical defense against cancer


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Evasion of Apoptosis Receptors transmit death signals

FAS and FAS receptor

TNF and TNFR1

Decoy receptor that dont signal can promotesurvival

Intracellular proteins that monitor DNA

damage p53


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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 (hexamerrepeats - 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


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Hallmark #4:

Acquisition of limitless proliferative capacity


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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 cellproliferation and growth of blood vessels.


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Hallmark #6:

Tissue invasion and metastasis

Little is known about these genes


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Lecture5 Edwards Cancer

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