Lecture 7: Neoplasia I Flashcards
The Cancer problem
Primary tumours may be treatable by surgery, radiation and/or chemotherapy
BUT systemic disease is the cause of death
Who gets cancer?
Primarily a disease of ageing
Many solid tumours develop over years (many genetic events accumulate over time)
50% of the population will receive a cancer diagnosis at some point in their life
See figure
Points for cancer control
Prevention
Early diagnosis (research focus)
Therapies for primary tumor
Therapies for systemic disease (metastases)
Palliative care
Diameter of tumour vs tumour cell population doublings
See figure
Where does cancer arise
See figure
How can we determine the success of cancer therapies?
Compare new cases to deaths per year
Nomenclature of cancers
Epithelium - carcinoma (90% of human cancers)
Connective tissue - sarcoma
Hemopoietic - leukemia, lymphoma
Nervous system - glioma, neuroblastoma
Cancer ethology: the role of genes
Cancer predispositions
Radiation/chemical damage of DNA
Tumours show genomic abnormalities
Cell culture and animal models of cancer
Example of cancer predisposition
Association of BRCA1 and BRCA2 mutations and breast cancer in Ashkenazi Jewish women
Prostate cancer in men of african descent
Can help decide which populations should be screened for which cancers
How does radiation and chemical damage of DNA lead to cancer?
Failure to repair DNA damage can lead to cancer
What are some examples of genomic abnormalities that tumours can have?
Aneuploidy
Chromosomal rearrangement or loss
How are cell culture and animal models of cancer created?
By altering genes that control cell cycle, cell survival and cell differentiation
What occurs in a philadelphia chromosome?
DNA is damaged
Part of chromosome 22 is transferred to chromosome 9 = short 22, long 9
Evolution and selection in cancer
If cell proliferation and cell death are balanced, tissue remains stable
Abnormal cells may undergo multiple rounds of replication, lose control of proliferation, create tumour
See figure
Social control of normal cell vs cancer
Normal tissue: cells listen to neighbours, get info from circulating cytokines and growth factors, work to maintain consistent tissue structure.
When two normal cells touch each other, they stop proliferating
If this is not maintained (mutation) - over time this may cause multiple rounds of cell proliferation
Genes critical for cancer
Normal cell cycle factors: cyclins, CDKs, retinoblastoma, MIC
Other factors (cell response to signals): Ras, APC
Molecules involved in cell death: BCL2
Oncogenes
Gene that gets turned on (overactivity mutation/gain of function) to stimulate cell proliferation
Requires only single mutation event
See figure
Tumour suppressor genes (TSG)
Require loss of function (under activity mutation) to cause tumour
Both copies of gene need to be wiped out to loose function completely
See figure
How proto-oncogenes can lead to cancer:
- deletion or point mutation
- regulatory mutation
- gene amplification
- Chromosome rearrangement
See figure
Examples of oncogenes
HER1 (EGFR) - mutated or amplified in half of gliobastomas
HER2 - mutated in 20% of breast cancers (poor prognosis)
Ras - mutated in 1/3 of human tumours
Retinoblastoma (Rb1)
Tumour suppressor gene
Important in regulating cell cycle. Rb mutations cause proliferation to be out of control
See figure
Examples of TSG
P53 - most common defect in human tumours (integrity of DNA)
Rb1 - lost in both sporadic and hereditary forms
PTEN - phosphatase that regulates intracellular singling (PI3K and Akt), lost in prostate cancer
What are stability genes? Examples?
Involved in maintaining genome stability
DNA repair enzymes
Recognizing errors, UV damage
ex: BRCA1, BRCA2
Model of colon carcinogenesis
Apc - associated with polyps on colon
Environmental influences on cancer etiology
Rates of cancer around the world are different (due to environment, diet, genetics, exposures)
Cancer rates change in a population when they migrate, so it is more than genetics
Known associations - exposures and cancers
Tobacco smoke - lung + others
Formaldehyde - nasopharyngeal, leukemia
Radon gas - lung
UV radiation - skin cancer (melanoma)
Asbestos - mesothelioma
Radioactive fallout - bone marrow, thyroid
Suspected associations with cancer
Diet
Alcohol consumption
Viruses and human cancer
see fig
How do DNA viruses cause cancer?
Capture cell cycle control. Instead of switching on replication of their own genome, they cause consistent proliferation of the host genome
In HPV, viral proteins bind to RB, causing uncontrolled cell proliferation -> hyperplasia
Viral proteins bind fo p53 causing failure to repair DNA damage -> genomic instability
Characteristics of cancer cells
Disregard the external and internal signals that regulate cell proliferation.
Avoid suicide by apoptosis (enhanced survival).
Circumvent programmed limitations to proliferation, escaping senescence and avoiding terminal differentiation.
Genetically unstable (amplification each cycle)
Disregard signals for tissue homeostasis and become locally invasive
(proteolysis).
Survive and proliferate in foreign sites (metastasis - requires expression of different genes in order to get out of original tissue)
May develop capacity to pump out drugs (MDR1).
Altered metabolism in response to hypoxia (continue to metabolize and proliferate)
Tumor angiogenesis
Tumors more tha na few mm in size require blood supply
Tumors release factors that direct new blood vessel formation toward tumor (VEGF)
what it Metastasis
Tumor cells shed from primary tumor may‘seed’ other regional tissues
[eg. Ovarian cancer in abdominal cavity]
Tumor cells may enter lymphatic system and populate regional lymph nodes
[eg. prostate cancer metastases in pelvic lymph nodes]
Tumor cells may enter blood vessels and exit at
another organ to re-establish tumor [eg. colorectal cancer metastatic to liver]
see figure
What are examples of cancer critical pathways
cell-cell communication
regulated cell proliferation
cell differentiation
cell death
cell movement
and cell adhesion
p53 role
Under normal circumstances, p53 is at low levels in the body
When there Is damage to DNA, the rate of degradation of p53 slows down, and p53 accumulates.
This drives the cell to either commit suicide (apoptosis) or bar the cell from dividing until it is repaired.
So, p53 plays a protective role.
