EXAM 3 - Session 22: Cancer as a Cellular Disease Flashcards
Define cancer.
Cancer is a multistage pathology driven by progressive acquisition of deleterious mutations leading to uncontrolled replication
* possibly progressing to invasion of local tissue and metastasis.
Describe the three cancer stages.
- initiation - contained benign
- promotion - malignant (can be +/- invasion)
- progression - heterogeneity, metastasis
Describe initiation - contained benign cancer growth.
FIRST STAGE
small benign overgrowth of cells from mutational event
* initiators = mutagens cause permanent change to genome (2 mutations required)
* contained
* non-cancerous
* initiator examples: UV light, some hydrocarbons, cigarette smoke
Describe promotion - malignant (+/- invasion) of cancerous cells.
SECOND STAGE
promoting events/factors –> lead to DNA mutations accumulating
* likely to be prolonged/repetitive - not always permanent
* not always directly mutagenic –> but can increase CC –> more DNA replication errors
* promoters: some environmental toxins, excess growth factors. some viral proteins (HPV protein inactivates p53 function)
Describe progression - heterogeneity, metastasis of cancerous cells
Formation of more mutations
* metastatic cells enter the blood stream and can relocate to other areas of the body
Explain why sequence and relative timing of 1st versus 2nd stage is important.
The progression of cancer is dependent on when tumor initatiors and promoters are exposed to the cell.
Based on this timeline, what is the outcome?
No cancer
Based on this timeline, what is the outcome?
Cancer
Based on this timeline, what is the outcome?
Cancer
* small time gap between initiator and promotor
Based on this timeline, what is the outcome?
Cancer unlikely
* longer time gap between initiator and promoter events
* unlikely because the initiation event/gene must be present during the WHOLe gap and reach the promotion event to result in cancer
Based on this timeline, what is the outcome?
Cancer unlikely
Based on this timeline, what is the outcome?
Cancer unlikely
* stimulating CC
* not mutagenic - there isn’t a mutagenic gene for the promoter to replicate
Based on this timeline, what is the outcome?
+/- cancer
Based on this timeline, what is the outcome?
Cancer
* initiating events that proceed the first initiation event will act as promoters
* initiating events are mutagenic
Describe the “Hayflick limit”
Normal cells do not divide indefinitely
Replicative senescence - loss of power for growth/replication
* metabolic activity but NO mitotic activity
* permanently out of the cell cycle
* distinct frmo G0 stage
Possible causes:
* end-replication problem (telomere decrease)
* single-stranded DNA breaks (topoisomerase re-ligation failure)
Describe the assocation between cancer stem cells and the Hayflick limit.
Cancer cells escape senescence
* initiation and promotion events in multistage carcinogenesis
* MDM2 overexpression preventing cell cycle braking caused by p53
List some possible ways to escape senescence.
- inactivation of other tumor supressors like Rb
- ALT - alternative lengthening of telomeres
- expression of activated oncogenes
- dysfunction of CC inhibitors like p21/p27
Describe some cancer cell properties.
- replicates despite negative growth control signals (defective CC brakes)
- often leaves site of orgin and invades other tissues
- heritable properties via mutated genome
Explain the three typical cancer types.
carcinoma - epithelial cells
* possible reasons: UV and chemical mutagens
* epithelium is highly proliferative - high chance for DNA replication error (mutation)
sarcoma - connective tissue or muscle cells
leukemia/lymphoma - hematopoietic (blood) cells
Explain proto-oncogenes.
Normal gene sequence that encodes protein with low level, growth promoting ability
* mutant gene has excessive growth promotion
Explain tumor suppressors.
Loss of normal gene leads to excessive replication
.
Initial and subsequent mutations: what are possible causes of progressive mutations?
- chemical carcinogens (cause nucleotide changes)
- ionizing radiation (x-rays cause c’some breaks)
- viruses (DNA integration disrupts cell’s genes; p53 degradation)
- genetic plasticity - gene changes due to acquired mutations
Describe malignant cell properties on the chromosomal level.
- generalizations from blood cancer studies
- evidence for clonal expansion of cancer stem cells
- analysis of chromosomes and DNA sequence in tumor cells will allow identification of clonal marker and metagenic event that occured
Describe malignant cell properties on the chromosomal level.
Generalizations from blood cancer studies:
* evidence for clonal expansion of cancer stem cells
* analysis of chromosomes and DNA sequence in tumor cells will allow identification of clonal marker and metagenic event that occured
Describe malignant tumor properties on the tumor level.
Generalizations from colon cancer studies:
* progressive accumulation of mutations that confer additional growth advantage
Explain the association between HPV and cervical carcinoma.
Non-mutational loss of tumor suppressor protein function
* HPV gets replicated alongside the basal epithelial cells (mitotically active)
* HPV progeny cells are released –> shed
* HPV genome gets transcribed and tranlated –> inactivate p53 proteins and Rb proteins –> more CC –> increase gene mutations –> cancer/tumor formation
* genetic plasticity - accumulation of more mutations
What is the effect of the Gardasil-type vaccine on HPV and cervical carcinoma?
The vaccine neutralizes the HPV progeny virus and it can no longer integrate into the cervical epithelial cells
Explain the result of cancer mutation progression on the patient level. (example in class of 26-yo male w/ brain cancer)
Progressive mutations –> genetic plasticity –> cancer reoccurance
* tumors had taken over the entire body
* initial response to new drug: decresed tumors, regained weight, less pain
* after time, cancer began to grow within the entire body again - from mutations that allowed drug resistance
