Cancer II Flashcards
What are the two major categories of tumor suppressor genes?
Proteins that normally restrict cell growth and proliferation
Proteins that maintain integrity of the genome
What are some tumor suppressor proteins that normally restrict cell growth and proliferation
Intracellular proteins that inhibit progression through G1 in the cell cycle (Rb, CKI)
Receptors or components of a signaling pathway that inhibit cell proliferation
Proteins that promote apoptosis
What are some tumor suppressor proteins that maintain integrity of the genome?
Checkpoint control proteins (ATM, ATR-detect DNA damage - stops cell cycle) - Ataxia Telangiectasia
DNA repair enzymes or pathways
What is retinoblastoma?
Inherited eye cancer in children. rare and occurs before age 2
Diagnosed before age 5
Involves Rb - a tumor suppressor that inhibits cell division
What are the two forms of retinoblastoma?
Hereditary (40%-both eyes) and sporadic form(60%-one eye)
Describe hereditary form Rb
Loss of function or deletion of one copy of Rb in every cell
Somatic event occurs and eliminates one good copy and tumor forms. thus a loss of heterozygosity
Describe sporadic form Rb
non-hereditary
two hit hypothesis- first Rb gene obtains mutation then needs second mutation Rb
More rare than hereditary form
What are proto-oncogenes?
Normal gene, usually involved in regulation of cell proliferation that can be converted to a cancer-causing oncogene by a mutation (overactivity mutations)
What are the four functions of cancer genes?
Regulate cell proliferation
Control cell growth
Control division
Control apoptosis
Cdk or cyclin:
A proto-oncogene or a tumor suppressor gene?
Proto-oncogene
Active CKI stops Cdk
Rb binds E2F
CKI or Rb:
A proto-oncogene or a tumor suppressor gene?
Tumor suppressor gene
CKI absent so Cdk always active
Rb inactive and E2F drives S-Cdk activation by making more cyclins
What is the guardian of the genome?
p53: huge tumor suppressor gene Involved in: Cell cycle arrest DNA repair Apoptosis Block of angiogenesis
If you lose p53, what functions will be lost?
- loss of checkpoint control in cell cycle
- loss of cell cycle arrest in response to DNA damage
- loss of apoptosis in response to DNA damage
- loss of DNA repair activities
How is p53 associated with p21 and pro-apoptotic proteins?
p53 upregulates p21
p53 activates expression of pro-apoptotic proteins
Bcl2:
proto-oncogene or tumor suppressor?
proto-oncogene
What is papilloma virus?
Warts and cervical cancer
If tumor integrates with host DNA it interferes with control of cell division in basal cells and a malignant tumor develops
E6 and E7 cause malignancy and they bind to p53 and Rb, respectively
The cells then can replicate in an uncontrolled manner
too much cyclins and no CKI available
For most cancers what is the first step of metastasis?
Local invasion and only a few cancer cells will pass this barrier
-difficult
What is the initial entry into blood or lympathic vessels facilitated by?
Angiogenesis of new blood or lympathic vessels
-most cancer cells have acquire this ability before becoming invasive through mutations in genes that control apoptosis
How are cancer cells colonized at remote sites?
They survive in circulation and exit at remote sites
Some cells die after they enter a foreign tissues, others fail to proliferate, or only form micro-metastasis
Only a few continue to proliferate and colonize
What is one of the most preventable cancers and why?
Colorectal cancer
Colonoscopy reveals early detection
Takes 10 years for tumor progression so there is lots of time to check
Where does colorectal cancer arise?
in the epithelial lining of large intestine
Mutations that disrupt organization signals begin tumor progression for colorectal cancer
What is a small,protruding benign tumor called?
polyp: adenoma
Precursor of colorectal cancer
Cut it off and itss a cure
What are the common mutations in colorectal cancer?
40% have point mutation in K-Ras
60% inactivating mutation of p53
Important loss is APC mutation
what is familial adenomatous polyposis coli?
hereditary colorectal cancer Hundreds of polyps At least one will become malignant Caused by inactivation of tumor suppressor gene APC LOH
What is HPNCC?
hereditary non-polyposis colorectal cancer
Unusual
Most have normal # or near-normal # of chromosomes
Colorectal cancer cells usually have multiple copies of chromosomes
What is chemotherapy
Drugs that treat cancer
Stops cell division - impact on rapidly dividing cells like cancer cells but also stops follicle cells produce hair, stomach-lining cells, blood-producing cells
What is responsible for chronic myelogenous leukemia?
Reciprocal translocation between chromosomes 9 and 22
- philadelphia chromosome
- Bcr-Abl
Describe Bcr-Abl
Abl - tyrosine kinase for cell signaling
N-terminus Bcr makes it hyperactive
Coding sequence of Bcr is fused to Abl when chromosomal translocation occurs
Bcr-Able makes highly active tyrosine kinases and is highly expressed
->CML
What is the treatment for CML?
Gleevec: inhibits tyrosine kinase activity
Causes disappearance of Philadelphia crh in most patients
Gleevec takes place of ATP on Bcr-Abl-substrate not changed: competitive inhibitor
What is combination therapy?
treat patients with drugs simultaneously is an advantage for cancery therapy
fight those rare mutant cells that are resistant to one drug and then go on to proliferate to form new tumor
How can microarray be used to fight cancer?
Gene expression profile of a cancer can be analyzed by microarray to identify disregulated cancer-critical genes
Custom-driven treatments can be selected to target specific disregulated cancer-critical proteins
Presonalized medicine
What therapy has Folkman created?
Anti-angiogenesis therapy
The idea that cancerous tumors require formation of new blood vessels- if prevented, starve tumors
What are tumor suppressor genes?
Genes that generally encode proteins that inhibit cell proliferation
