Barsky 1 Flashcards
What is the progress of a normal cell to a malignant & metastatic cell?
Normal Cell Transformation Event Selection Pressure Tumorigenic Invasive Metastatic/Malignant
What are some of the genetic events that are related to tumor progression?
mutations
rearrangements
amplifications w/ proto-oncogenes
reduction to homozygosity of tumor suppressor gene deletions or mutations
What is the progression of a normal duct to an invasive ductal cancer?
Normal Duct Intraductal Hyperplasia Intraductal hyperplasia with atypic Intraductal Carcinoma in Situ Invasive Ductal Cancer
T/F Most cancers are multi hit events, which helps with early detection & screening.
True.
This also explains why cancer is a disease of aging.
Why is it difficult for the body to fight cancer, evolutionarily speaking?
b/c most cancers occur after the age of procreation
no evolutionary selection pressure that has equipped us to deal with this disease
What are 4 important properties of cancer?
- uncontrolled growth
- invasion & metastasis
- clonal dominance-meaning that they all come from one ancestral cell
- loss of differentiation
T/F All sub clones are the same.
False. There is some heterogeneity amongst the mutant sub clones.
What are the important heterogeneous factors of mutant sub clones?
heterogenous in these ways: invasiveness metastatic ability antigenicity responsiveness to chemotherapy
What are 5 types of cancer therapy?
- surgery
- radiotherapy
- chemotherapy
- immunotherapy
- gene therapy
What are 3 important limitations in treating cancer?
- lack of tumor specific antigen
- tumor cell heterogeneity
- micrometastasis
What are the causes of human cancer?
ENVIRONMENTAL CARCINOGENS UV RADIATION OTHER IONIZING RADIATION VIRUSES LIFESTYLE, DIET, IMMUNE STATUS HEREDITARY FACTORS OR GENES
Describe some of the actions of uv radiation in contributing to cancer?
ACTION IS SIMILAR TO CHEMICAL CARCINOGENS - FORMATION OF DNA ADDUCTS
ACTION IS CAN BE DIFFERENT FROM CHEMICAL CARCINOGENS: SINGLE AND DOUBLE STRAND DNA BREAKS
Give 3 examples of oncogenic viruses.
- HPV
- EBV
- Hep B virus
How many types of HPV are there? Which are responsible for papillomas or warts?
80+ types
Papillomas & Warts: 1, 2, 4, 7
Which types of HPV are responsible for invasive squamous cell carcinoma of the cervix?
Types 16 & 18
What’s the deal with HPV types 6 & 11?
low malignant potential
What are the early products of HPV (bad types) that inactivate tumor suppressor genes?
Gene products E6 & 7
What are the tumor suppressor genes that are inactivated by E6 & E7?
TP53 & RB
What are the 4 types of tumors that are associated with Epstein Barr Virus?
Burkitt’s Lymphoma
B cell lymphoma (if immunosuppressed)
Hodgkin’s Disease
Nasopharyngeal Cancer
What percentage of people have EBV in non endemic areas?
20%
What happens with Burkitt’s Lymphoma? Which gene is associated with this?
cell proliferation with decreased immunoregulation
MYC gene t(8:14)
Where is nasopharyngeal cancer endemic?
south china
What are some examples of lifestyle factors that contribute to the formation of cancers?
People who are sun worshippers, go to
tanning salons,etc have a high incidence of
skin cancer
Women who have multiple sexual partners have a higher risk of cervical cancer.
Women who are nulliparous have a high rate of breast cancer
Men who are obese have a higher rate of cancer of the esophagus
What are some diet factors that contribute to cancer?
Women who eat fatty foods have a higher rate of breast cancer
Men who drink alcohol and smoke have a higher rate of head and neck cancer
People who eat red meat may have a higher incidence of colon cancer.
Is there ever a hereditary component to cancer?
sometimes
Some cancers are inherited (germline) with gene identified
Some cancers are familial with genes not identified
Many cancer have a familial component; fewer cancers have a inherited component
In Li Frameuni Syndrome, what is the contributing inherited gene?
p53
In Breast Cancer, what are the contributing inherited genes?
BRCA1 & BRCA2
In Lynch syndrome, what are the contributing genes?
microsatellite instability genes
T/F Inherited retinoblastoma gene can play a factor in cancer.
True.
What is the cause of most cancers?
Most cancers are spontaneous, sporadic. Their cause is unknown.
What are the 2 key properties of cancers?
Uncontrolled Growth
Invasion & Metastasis
What do oncogenes code for?
oncoproteins that are associated with neoplastic transformation
not regulated by normal growth factors & signals
What are protooncogenes?
normal genes that affect growth & differentiation
retroviruses can mess with these: create v-onc
can also change in situ to c-oncs.
Cancer comes from what greek word?
karkinos
this means crab
**based on how cancers look like the crab on the sign of the zodiac, as it infiltrates neighboring tissues
What is the cancer with the highest incidence in men, as of 2012?
prostate cancer
What is the cancer with the highest incidence in females, as of 2012?
breast cancer
What are the cancers with the 2nd & 3rd highest incidences for both men & women?
2nd: lung & bronchus
3rd: colon & rectum
What is the cancer that causes the most death for both men & women?
lung cancer
99% of all cancers are sarcomas/carcinomas.
carcinomas! develop from epithelial cells
1% are sarcomas–cancers of the stroma, mesenchyme
T/F The reason that carcinomas are so common is that epithelial cells have the highest rate of turnover.
False. If this were the case, then a neonate would get a bunch of cancer. But cancer is a disease of aging.
Another theory is that epithelium is exposed to the external environment-but this is only a part of the picture.
What has happened to lung cancer incidence since the 1930s? What can this be attributed to?
it increased rapidly after 1930 & peaked around the 1990s. then it began to decline
this is explained by the rise in smoking + a period of latency. Mainly following a certain degree of smoking cessation–the incidence decreased
What has happened to the rates of gastric cancer since 1930s?
it has steadily decreased
one theory is refrigeration, no longer used a carcinogenic substance to keep food fresh
**but people don’t really know
What has happened to the incidence of colorectal cancer & prostate cancer? What could explain this?
they have both steadily decreased
prostate peaked around the 1990s and has def decreased since then.
Thought is: PSA & colonoscopies have been successful screening tools.
What has happened to the rates of pancreas cancer, liver cancer, and leukemia since 1930?
they have stayed roughly the same!
Breast cancer deaths have steadily decreased since 1930…name 2 factors that may account for this.
- mammogram screening in post-menopausal women.
2. less hormone replacement therapy
When did lung cancer deaths start to increase for men? For women?
For men, after WWI
For women, after WWII. Esp in the 1990s, b/c of latency & peak in women smoking in the 1970s.
Why have cervical cancer deaths decreased since 1930?
b/c of the increase in pap smear screenings. but also an unknown factor!
T/F There were serious epidemics of prostate cancer in men & breast cancer in women in the 1990s.
False. There was the initiation of PSA & mammogram screenings. Thus, a bunch were detected. Artificial trend.
When should women receive the HPV test?
not until their 30s. Has a different significance than for women in their 20s.
Should women who are at a child-bearing age have a mammogram done?
probably not b/c their breasts are so dense that it won’t necessarily detect things well
also–it will just expose them to radiation–could cause cancer!
A while back we talked about the possible genetic factors involved in cancer. List some of the epigenetic factors.
methylation status for promoter
histone deacetylase status for promoter
**regulate expression of certain cancer genes
Cancer is characterized by a methylation v. histone deacetylation imbalance.
A while back we talked about the stages to go from a normal duct to an invasive ductal cancer. At the stage of intraductal carcinoma in situ…what’s the deal with the positions of the cancer cells?
they are confined within the duct
**at the stage of invasive ductal cancer…they have burst thru the basement membrane & invaded.
How long could the process take to get from a normal duct to an invasive ductal cancer?
could take up to 12 years b/c it is a multi hit phenomenon.
Does a pap smear detect dysplasia or invasion?
detects dysplasia, hopefully before invasion
allows for early detection & treatment
can surgically remove
What are some of the steps involved in an invasive carcinoma?
stromal dissolution
basement membrane dissolution
lymphatic invasion
blood vascular invasion
T/F Due to the concept of monoclonal dominance, all cancer cells are the same.
False. Like identical twins, cells that come from the same ancestral cell still develop to have different characteristics. Develops thru genetic instability
What are some of the ways that we can see that cancer cells with different characteristics all came from the same ancestral cell?
x inactivation
male repeat sequence
microsatellites
**eventually get a picture that we have clones with different features, not cancerous cells from different parents.
Why do we not have a tumor specific antigen that we can use to treat cancer?
b/c it is a cancer of our own cells! they look like self
Why does tumor cell heterogeneity make it difficult to treat cancer?
b/c the different cancer cells will respond to different treatments.
What’s the deal with micro metastasis in breast cancer?
most patients who come to the clinic with a breast mass have already experienced micro metastasis. Unfortunately, only takes a few tumor cells to cause that metastasis.
What are some environmental factors that affect cancer rates?
chemical carcinogens (direct & indirect)
electrophiles
initiator & promoter
Phase I & Phase II enzymes
What makes a chemical carcinogen direct v. indirect?
depends on whether it is activated by the body’s cyt p450 or not
What is an electrophile?
this is something that is neg. charged & binds to DNA’s pos charges.
Ex: initiators are electrophiles
What is an initiator?
an electrophile that binds DNA & forms a DNA adduct & subsequent mutation.
What is the promoter?
this is an epigenetic factor that increases cell division after the initiator creates a DNA adduct. It accelerates the response.
If it weren’t for the promoter–the mutation caused by the initiator would die with that cell.
What is a DNA adduct?
carcinogen + DNA
What happens after a DNA adduct is formed?
the body tries to remove it by repair mechanisms
if the body’s efforts are unsuccessful then you get a mutation.
if it is in a key gene like an oncogene or tumor suppressor gene–sets cancer into motion with the help of the promoter.
What are some things that ionizing & UV radiation can cause?
chromosome breakage
translocations
point mutations
What can UV radiation lead to?
skin cancer
those with xeroderma pigmentosum are at crazy high risk for basal cell carcinomas b/c of a lack of a certain enzyme
9% of children who are exposed to significant radiation develop what?
thyroid cancer
What are some examples of the cancerous & damaging effects of radiation?
Hiroshima & Nagasaki
Nevada’s above ground nuclear testing in the 1950s @ area 51
Hep B virus puts you at higher risk for which form of cancer?
hepatocellular cancer, although this is probably multifactorial
What is attributable risk?
% of people with the cancer due to a certain factor
What is an example of a cancer with a high attributable risk to one factor in the US?
smoking–lung cancer.
90% of lung cancers are due to smoking.
Which area of the world has a 99% attributable risk of hepatocellular cancer due to Hep B virus?
Asian countries
What does the Hep B virus do roughly to cause hepatocellular cancer?
it makes a protein that disrupts growth control by activating pro to-oncogenes
may also inactivate p53
What events in a liver’s life can predispose it to mutations by environmental agents?
injury & regeneration
Why might it be that men who are obese have higher rates of esophagus cancer?
perhaps b/c gastroesophageal reflux can lead to barrette’s metaplasia. Risk factor for carcinoma of the esophagus.
A relative risk factor > ___ can suggest that a factor is causative, rather than correlative
Greater than 4!
Usu need a double blind prospective randomized study to control all of the random variables & determine causality.
Does it take 1 allele mutation or 2 allele mutations to cause the activation of proto-oncogenes to oncogenes?
only 1 allele needs to be mutated
Where are 3 ways that protooncogenes can be activated into oncogenes? Give examples.
- Point mutations
Ex: RAS is an oncogene that is formed this way - chromosomal translocation
**something moved near the promoter or something gives a chimeric gene product - Gene amplification
Ex: N-MYC in neuroblastoma
Her-2-neu in breast carcinoma
What are the 5 basic categories of oncogenes? What do they all have in common?
- *all are related to growth
1. Growth factors
2. Growth Factor Receptors
3. Signal Transducing Proteins
4. Nuclear Transcription Factors
5. Cyclins & cyclin dependent kinases
What is the different b/w oncogenes & antioncogenes? How many mutant alleles are required to form cancer w/ antioncogenes?
**need 2 antioncogene mutations to cause cancer
antioncogenes are inactivated cancer suppressor genes
Which is an example of gain of fcn & which is an example of loss of fcn?
Oncogenes
Antioncogenes
oncogenes: gain of fcn
antioncogenes: loss of fcn
What are 4 categories of awesome cancer suppressor genes that can be inactivated forming antioncogenes?
- Growth inhibitory factors
- molecules that regulate cell adhesion
- molecules that regulate signal transduction
- molecules that regulate nuclear transcription & cell cycle
TP53 is called what? What is it?
Called the guardian of the genome
**commonly mutated gene in almost all cancers
it has fcns of anti proliferation & apoptosis
In more detail, describe what p53 does.
p53 senses DNA damage & arrests the cell in G1. It induces DNA repair
- *increases CDK1 p21 (preventing phosphorylation of RB)
- *induces GADD45 (to aid DNA repair)
What does p53 do if DNA can’t be repaired?
apoptosis is induced! Via genes like BAX that are induced
WHat’s the deal with Li Fraumeni syndrome?
inherit one mutant p43 or RB
you have increased risk of multiple types of cancers
but you need the second hit to get that cancer!
**oddly can be inactivated by certain DNA viruses (oncogenic HPV, HBV, EBV)
What is the retinoblastoma gene? WHat is it associated with? What percentage of the people with the RB gene inherit it v. get it sporadically?
tumor suppressor gene
associated with childhood tumor retinoblastoma & other types of cancer, like osteosarcoma
40% familial
60% sporadic
Is the RB gene (inherited form) aut rec or aut dom?
autosomal dominant!
So…you have the RB gene–do you automatically have cancer?
NO!! 2 hit hypothesis
if you inherit it or get it sporadically to 1 allele–that is 1 hit.
Still need environmental second hit.
Why is her-2-neu called that?
neu-for neuroblastoma, found in rats
her-family of receptors
What is the definition of cancer invasion?
active migration of neoplastic cells out of their tissue of origin & across host tissue boundaries
Ex: carcinoma cells thru the basement membrane & into adjacent CT
What is the definition of metastasis?
a secondary tumor colony discontinuous from the primary tumor
arising from a tumor cell translocated from the primary tumor
T/F Invasion is synonymous with metastasis.
False. You need invasion to get metastasis. But you just b/c you have invasion doesn’t necessarily mean that you have metastasis.
Why is it difficult to differentiate b/w a malignant & a benign sarcoma?
sarcomas are tumors of the mesenchyme. Difficult to tell if it has invaded & is malignant b/c there is no basement membrane.
Sarcomas tend to invade blood vessels/lymphatics.
Carcinomas tend to invade blood vessels/lymphatics, but can invade either.
Sarcomas tend to invade blood vessels.
Carcinomas tend to invade lymphatics.
What are the 3 routes that malignant neoplasms tend to spread thru?
- lymphatics
- blood vessels–usu affect lung, liver, brain, bone marrow, adrenals
- transcoelomic spread-seeding of body cavities–peritoneal, pleural, pericardial & subarachnoid space
Why is it important to grade & stage a cancer?
it is vital in estimating aggressiveness & planning therapy
What is grading? What are the different grades?
this is done thru microscopy I--IV I is good--well differentiated. II--moderately differentiated III--poorly differentiated IV is bad--undifferentiated. cancer that is highly proliferative
Describe the staging of a tumor.
anatomic extent of the tumor.
TNM (tumor, lymph node, metastases)
AJC
What’s the deal with staging the T in TNM?
this is size of the tumor For breast cancer (different for every cancer): T1: less than 2 cm T2: 2-5 cm T3: greater than 5 cm
What’s the deal with staging the N in TNM?
Are there lymph nodes involved?
N0: zero nodes
N1: 1-3 lymph nodes involved
N2: more than 3 lymph nodes involved
What’s the deal with staging the M in TNM?
metastases
if they aren’t overt–M0
Can you get a carcinoma that is N0 but M3?
Yes, if it chooses to spread via the blood vessels
Describe some of the things that must happen in order to get tumor cell dissemination.
- cells must become less cohesive.
- attachment to matrix components must be lessened (like less laminin & fibronectin attachment)
- degradation of ECM via metalloproteinases, collagenases, plasmin
- migration–done via cytokines & cleavage products of ECM
What happens when you get vascular dissemination of tumor cells?
they can form emboli with leukocytes & platelets or circulate as single cells
**their end home depends on vascular & lymphatic drainage, tumor adhesion molecules, microenvironment with proteases etc.
What is the soil seed hypothesis of Paget?
certain cancers like to go to certain parts of the body
Breast cancer–lung
Colon cancer–liver
Lung cancer–brain
**kidney & spleen resistant to metastasis
Is systemic metastasis an early event? What is the role of CTCs & DTCs in metastasis?
Yes, it is an early event.
CTCs: circulating tumor cells…these are found in the blood & carry the metastatic cells.
DTCs: disseminated tumor cells…these are about to end in an organ (were at one point CTCs).
However, DTC is not synonymous with metastasis.
When is DTC indicative of an impending full blown metastasis?
it is indicative when there are stem cells present that will cause proliferation after dormancy.
When is DTC not indicative of an impending metastasis?
when there aren’t stem cells in the DTCs.
At an early stage of breast cancer, T1…what is the percentage of women that have CTC or DTC? how can you test for each?
33%!
Test for CTC w/ a blood sample.
Test for DTC w/ a bone marrow biopsy.
Give an example when doctors are really thankful for CTCs.
There has been metastasis, but the metastatic site is difficult to access.
Just draw some blood & test it for chemosensitivity.
What are cancer stem cells?
a small fraction of cancer cells 1/10 of 1% that are dormant & resistant to cancer treatments. these are the cells that are responsible for growing a tumor back after a period of remission.
T/F Every cancer cell is capable of repopulating a tumor.
False. Only the stem cells.
What are the different types of stem cells?
Embryonic Stem Cells
Induced Pluripotent Stem cells (adult ones that are transacted)
Adult Somatic Stem cells (liver)
Stem cells involved in tissue homeostasis
Cancer stem cells
What are the common characteristics of all stem cells?
self renewal–make a new one of yourself, symmetrical division
asymmetrical division–making a new proliferating terminally differentiated cell
pluripotency–can be a part of all 3 germ line cell types–ectoderm, mesoderm, endoderm.
What are 4 important properties of cancer stem cells?
exist in a dormant state
resist chemotherapy & radiotherapy
express embryonic stem cell pathways
replenish the dividing cell pop. of a tumor
Hedgehog Notch Bmi-1 Wnt Pten What are these?
these are all embryological stem cell pathways that are activated in cancer
they are activated in cancer stem cells
What are some cell markers that indicate–I’m a stem cell who will regrow a breast cancer tumor!
CD44+, CD24-
What happens if a patient takes a drug that kills cancer cells, but not cancer stem cells?
the tumor regresses
the stem cells regenerate the tumor cells again, in time!
What happens if a patient is given a drug that kills the cancer stem cells?
even if the other cancer cells weren’t killed–>the tumor loses its ability to regenerate & it will eventually degenerate.
Note: this is the goal!
If you have a tumor that is only cancer cells, no stem cells…what is the result?
No metastasis.
If you have a tumor that has cancer stem cells with only partial malignant potential…what is the result?
Dormancy followed by metastasis after many years & exposure to multiple oncogenic hits.
If you have a tumor that has cancer stem cells with full malignant potential…what is the result?
metastasis in months to a couple of years.
& metastases to other sites too!
T/F Tumor remission & response rates have little correlation with overall survival.
True. B/c of those awful cancer stem cells.
What are tumor markers?
any gene or gene product that is altered in tumor progression
- *tumors shed or secrete gene products
- *source can be tissue, cytology, fluid, or serum
What are the 4 categories of biomarkers?
Tumor Markers
Prognostic Markers
Surrogate End Point Markers
Predictive Markers
What is a paraneoplastic syndrome?
these are symptoms experienced by cancer patients that are due to humoral factors secreted by cancer cells, rather than by the presence of the tumor in its surrounding tissue.
What % of cancer patients experience paraneoplastic syndrome?
10-15%
sometimes the first sign of malignancy
What are some initial examples of cancers that produce paraneoplastic syndromes?
small cell lung cancer
SIADH
Eaton-Lambert Syndrome
Cerebellar Ataxia
Pancreatic, Lung, and other cancers…what end result do these cancers achieve terms of symptoms of paraneoplastic syndrome?
venous thrombosis–trousseu’s phenomenon
small cell cancer of the lung, pancreatic cancer, neural tumors…what do these cancers release? What is the end result in terms of symptoms of paraneoplastic syndrome?
Symptoms: Cushing’s syndrome
Mediator: ACTH or ACTHish thing
Breast, renal, and squamous cell cancers cause the release of what? What paraneoplastic syndrome does this create?
cause the release of PTHrP & TGFalpha
Get hypercalcemia
Cancer of the lung can cause what paraneoplastic syndrome?
hypertrophic osteoarthropathy
clubbing of fingers
What is cachexia?
weight loss etc in a person who is not trying to lose weight!!
includes: weight loss, weakness, anorexia, anemia
What causes cachexia?
many factors
increased metabolic rate despite reduced caloric intake
may be due to TNF alpha & other cytokines
Certain cancers can be detected by certain tumor markers. Give some examples.
PSA-prostate cancer
CEA–lung cancer & colon cancer
alpha fetoprotein
**can be used for staging & for therapy
What are prognostic markers?
these give us info about prognosis, such as disease-free survival, overall survival, length of latency
Give some examples of prognostic markers in breast cancer.
ER (estrogen receptor): ER+ do better than ER-
Ki-67
Give some examples of prognostic markers in colon cancer & prostate cancer.
Colon cancer: microsatellite instability gene products
Prostate Cancer: p21 & p27
Give a prognostic marker for bladder cancer.
Bladder Cancer: p53
What are surrogate end point markers?
aka intermediate markers
give info about effectiveness & chemopreventive or therapeutic strategy before direct tumoral measurements.
Give 2 examples of surrogate end point markers.
Minimal residual diseases of the head & neck: mTOR pathway
Bladder Cancer: FvG-actin
How could SEMs help drug development?
So…have to wait like 15 years to see if a drug helps with a certain type of cancer. These trials are crazy expensive. Sometimes effective therapies on a certain type of person look ineffective in general pop. SEMs will help with immediate feedback for trials.
What will predictive markers help with?
personalized medicine
match treatment with patients biomarkers.
What is an example of a successful predictive marker test for cancer treatments?
Hercep Test for her2 screening.
figure out who will respond to herceptin.
**important to have predictive markers b/c it can look like a drug is ineffective, but really it is only effective on certain types of patients.
What are some high throughput approaches that could help in the discovery of more biomarkers?
cDNA microarrays proteomics array CGH sequencing tissue microarrays
