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Published by: 3d3 on Nov 29, 2010
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Exploring Your Genome
Week 13: Genomes & Health III: Cancer Lecture 2 Part1: The Hallmarks of Cancer 
Hallmarks of Cancer 
In 2000, two preeminent cancer biologyresearchers published a paper that outlined thehallmarks of a cancer cell
Most cancers have all or some of thesecharacteristics
These characteristics are now cited in the field asthe defining traits of cancer cells
Hallmarks of Cancer 
1.Uncontrollable growth2.Evading Death3.Processing nutrients4.Becoming immortal5.Invading tissues6.Avoiding detection by the immune system7.Promoting genomic instability
1. Uncontrollable Growth
Cancer cells grow even in the absence of growth signals
Even without growth factors to initiate the cellcycle and mitosis, cancer cells will go rightthrough that checkpoint
Cancer cells are insensitive to growthinhibitory signals
Most normal cells require an externalgrowth signal to stimulate division
Cancer cells make their own external growthfactors
Cancer cells stimulate their division byactivating their signal pathways without anexternal signal
25 - 50% of all cancer types have a mutationin the Ras proto-oncogene that turns on asignal that tells the cell to divide
Ras Family of Oncogenes
Mutations in Ras cause the protein to become locked in itsactivated form - always signaling to initiate cell growth anddivision
Insensitivity to growth inhibitors
pRB - retinoblastoma protein
tumor suppressor protein that inhibits progressionthrough the cell cycle
Mutations in Rb prevent Rb protein from inhibiting thegrowth cycle: Mutant Rb meansa loss of function
It takes two mutant Rbs to knock out its function
Rb is a classictumor suppressor gene
Rare childhood cancer of the eye that occurs in hereditaryand spontaneous forms
Now, 90% of children with Rb are cured
In families of Rb survivors, their children have 50% chanceof developing the cancer 
In Rb patients, doctors noticed that they were missing aportion of Chr. 13
Later, the Rb gene was identified on Chr. 13
Two “hits” to the Rb gene are needed to deactivate it
First tumor suppressor gene to be identified
Tumor Suppressor Gene (TSG)
A “hit” is a point mutationor a deletion that takesout the function of thegeneBecause the mutated Rbis recessive to wild type,it takes two hits to lead toloss of Rb functionIf a baby is born with aninherited hit in their Rbgene, then they are half way to the two hitsIn 90% of babies bornwith one hit, the other Rbcopy develops a hit in acell and leads to a tumor 
Inherited types of cancer are usually dueto inheriting one defective copy of a TSG
The mutations in the TSGs, like Rb, arerecessivebecauseit takes two copies to knock out function
However, the
cancer risk 
acts like a dominant trait. If youinherit one recessive allele of a TSG, then you are verylikely to acquire the second mutation in your cells and youhave a very high risk of developing cancer 
Although you may only inherit one recessive allele, it actslike a dominant trait
Familial Adenomatosis Polyposis (FAP) is a colon cancer syndrome caused by inherited mutations in the APC gene
Hereditary Cancers
BRCA1 and 2
1 of 8 women in US will develop breast cancer 
10% of all breast cancers can be traced to a hereditarypredisposition: inherited mutations in either BRCA1 or BRCA2
If you inherit one copy of BRCA with a mutation, you aremore likely to develop cancer because you may acquire amutation in the second copy
BRCA genes do not open the gates for cell proliferation butthey are involved in DNA repair - mutations in these geneshamper DNA repair and result in additional mutations inother genes
2. Evading Death
Cancer cells evade programmed celldeath, or apoptosis
Apoptosis is a common and normalevent in multicellular organisms -when cells age or become sick, theyinitiate programmed cell death for the health of the tissue
P53 is the gatekeeper for apoptosis
p53 triggers apoptosis inresponse to DNA damageand other signalsMany cancer cells evadeapoptosis by disabling p53p53 is a TSG and is mutatedin several different tumor typesp53 may be the moststudied human proteinIt interacts with MANYcellular components
Apoptosis is a complex event and manyfactors participate in the apoptosis signal
3. Obtaining Nutrients
A growing mass of cancer cells needsoxygen and nutrients to thrive
Cancer cells “induce” blood vessel growthto deliver nutrients to the tumor 
The process of recruiting blood vessels andinducing their growth isAngiogenesis
Establishing its own blood supply is acritical step in tumor development
Angiogenesis is the growthof new blood vessels andoccurs during normaldevelopment and in woundrepair Angiogenesis is induced byVascular Endothelial GrowthFactor (VEGF)this is released bythe tumor to stimulate the growthof nearby endothelial bloodvessels.

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