fabian cancer biology slide 81-120 Flashcards
What is the difference between a tumor suppressor and oncogene in terms of function?
-tumor suppressor=loss of function (cant add a drug to add function for missing/altered protein)
-oncogene is gain of function
How does synthetic lethality occur in cancer?
-if we have a gene B cancer mutation, then we are hyperdendent on gene A, but if Gene A gets inactivated then this will lead to cell death
What are the 2 benefits for using synthetic lethality based strategy?
What is it selective for, what can it be applied to?
-synthetic lethality is selective for cancer cell- specific genetic mutations.
This strategy can be applied to any type of cancer mutation, including tumor suppressors and mutations deemed ‘undruggable’
What are the DNA damage repair mechanisms for X-rays, Uv light and replication errors?
-x-rays/spontaneous rxn repair=base excision repair (BER)
-UV light =nucleotide excision repair (NER)
-X-ray/anti tumor=recombinational repair (HR homologous recomb or EJ)
-replication error=mismatch repair
What is an example of a synthetic lethal approach?
What is it an inhibitor for?
What is BRCA?
-The first synthetic lethal therapy using (poly(ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1-mutant or BRCA2-mutant ovarian and breast cancers)
-BRCA is a tumor suppressor gene
How do you screen for synthetic lethal interactions
What are you looking for?
-you use a Ras wild type and Ras mutant and a small molecule library to see what is common lethal between them and what is recessive lethal between the Ras mutant
-you want to screen for somthing that kills cancer cells but not normal cells
What are the 2 major types of cell immortilization?
What are the definitions of each?
-replicative senescene and crisis
-Replicative Senescence: an irreversible halt in cell proliferation with retention of cell viability over extended periods of time.
2. Crisis: “genetic catastrophe” that leads to death by apoptosis.
What is the difference between quiesence and senescense?
What do cells remain in senescense?
What is this often limit termed as, what does it mean?
quiesence=reversible and senescense=not reversible
-cells that remain metabolically active but have lost the ability to reenter cell cycle
-hayflick limit= the number of times a normal human cell population will divide until cell division stop
What are the various roads to senescence?
-
What does an oncogenic signal lead to?
What do Rb+p53 work to start?
-leads to downstream tumor suppressor breaks (rb+p53)
-they work to start senesence which is a cell arrest
What is sensecence triggered by?
-Senescence is triggered by telomere shortening, which can be bypassed by disruption of tumour suppressive (i.e.p53 and Rb) pathways
What happens after senecence bypasses?
What type of event is this?
after senescence bypass, cells undergo crisis, during which time chromosomes fuse leading to apoptosis (p53-independent).
Important: asynchronous event
What happens when there is unprotected chromatid ends?
-leads to end to end fusion
How do cancer cells escape crisis?
What happens to cells that have escaped crisis?
Cancer cells can escape crisis by expressing telomerase enzyme to keep long telomeres (85-90% of human tumors are telomerase positive)
-can then proliferate indefinitely and are therefore said to be immortalized
What is hypertrophy of cell?
When does this occur?
What are 2 examples?
-increase in cell size in reaction to a
physiological or pathological stimulus
-occurs in cells unable to divide.
* Ex. Skeletal muscle hypertrophy with training.
* Ex. Increase in cell size in cardiac muscle
What is hyperplasia?
When does it occur?
What are 2 examples?
-Hyperplasia: increase in cell number in response to a physiological or pathological stimuli, it is reversible
* Occurs in cells with a capacity to divide.
* Ex. Hyperplasia of epithelial cells in female breast during pregnancy.
* Ex. Liver regeneration
What is neoplasia?
How does it arise?
What can neoplasias be?
-Neoplasm: new growth. A pathological disturbance of growth characterized by excessive and unceasing proliferation of cells, independent of normal regulatory controls and therefore is irreversible.
-Arise from genetic alterations.
-Neoplasms may be benign (not cancer) or malignant
(cancer)
What is difference between hyperplasia and neoplasia?
-cells are genotypically and phenotypically normal.
* hyperplasia usually ends when the stimulus ends
(e.g. mammary epithelial hyperplasia). It’s reversible
What is a benign tumor confined to?
What has a bening tumor not penetrated?
-a growth that is confined to a specific site within a tissue and gives no evidence of invading adjacent tissue.
-has not penetrated through the basement membrane
What is the harm level of bening tumors?
What can some cause?
-Mostly are harmless; however, some can cause problems if they release high levels of hormones or are in specific locations (i.e. brain)
What is a malignant tumor?
What are most cancer related deaths the result of?
-describing an aggressive growth that shows evidence of being
locally invasive and possibly even metastatic.
-90% of cancer-related deaths are the result of metastasis
spawned from original primary tumors
What do we need in order to get a tumor that is 1cm in diamter?
-you need lots of doublinng in order to get a tumor that is 1cm diameter (1 billion cells)
-takes a while for tumor to grow
How long cancers take to develop?
What is a key factor in cancer formation?
What cancer doesnt have good early detection methods?
-Most human cancers develop over many decades of time.
* age is a surprisingly large factor in the incidence of cancer
-pancreatic cancer
Why does lung cancer related deaths have a slight delay compared to ciggarate smoking?
-there is a lag in the tumor being produced bc it takes many years
Where is the cancer growth model well documented ?
Well-documented in the epithelia of the intestine (high rate of turnover)
WHat underlies the epitelia of intestinal tract?
What is the epithelial layer the site for?
Where are cells rapidly dividing?
-Underlying these epithelia is a basement membrane (basal lamina) to which these cells are anchored.
-epithelial layer is the site of most of the pathological changes associated with the development of colon carcinomas
-in epithelial cells
What do cells accumulate as tumor progression proceed?
What regulates cell proliferation?
In what stage can polyps be seen?
What is the early adenoma
genetic and epigenetic alterations
-APC (tumor suppressor gene)
-in the intermediate adenoma stage
-bening formation
What gene inactivation leads to transition from late adenoma to carcinoma?
-inactivation of TP53 tumor suppresor gene
What is carcinoma in situ?
What does it have the characterisitcs of?
But what are the 4 things that have not occured yet?
Is not a benign neoplasm but rather a carcinoma (stage 0)
-Has the biological genotype and phenotype of a malignancy, but…
* Has not invaded through the basement membrane.
* Cannot metastasize in it’s current state.
* Considered ‘pre-malignant’ or ’pre-cancerous’.
* As long as it’s completely removed/treated the patient will be cured.
What does carcinoma in situ have the potential for?
-has potential to metastisize and become invasive because it has not yet passed the BM but can if left untreated
What is EMT?
What is an important part of?
-it is the epithelial to mesenchymal transition
-wound repair and plays a role in cancer mutation/metastisis
What occurs in the EMT process?
What do cells display
EMT is a cellular process during which epithelial cells acquire mesenchymal phenotypes and behaviour following the
downregulation of epithelial features.
* Cells display fibroblast-like morphology as well as increased migratory capacity
What are the 4 core EMT (epithelial to mesenchymal transition) changes
Core EMT changes include:
1. Cytoskeletal remodeling.
2. Cell-cell adhesion weakening.
3. Acquisition of cell motility.
4. Basement membrane invasion.
What is an intravasation?
-when mesenchymal cells enter the bloodstream
What are the first 2 steps to invasion metastasis cascade?
1.Localized invasiveness enables in situ carcinoma cells to breach the basement membrane.
2. Intravasation into lymphatic or blood vessels.
What are the last 2 steps for invasion metastasis cascade?
-3. Blood vessels can transport cancer cells to distant sites.
4. Cancer cells colonize to form metastatic tumors
What is MET?
What do they acquire, reorganzie and exhibit?
MET (mesenchymal to epithelial transition).
* mesenchymal-like cells may acquire apical–basal polarity, reorganize their cytoskeleton, and exhibit increased cell–cell adhesion, resulting in an organized epithelium
Where can cancers metastisize?
to many different locations
