Oncology Lecture w/ Dr.

Wilkinson 17 January 2012

The Topic of This Lecture Is: Epidemiology of Cancer

A quarter of the deaths in the U.S. are from cancer. Both incidence and mortality increase
with age.
o Men are slightly more likely to get cancer, but substantially more likely to die than
women.
o Theres excess mortality in minority groups: blacks, Alaskan natives, Native
Americans, & Hawaiians.
Among men, risk is highest in blacks and lowest in Hispanics. This disparity is
less in women.
In men, the big 5 cancers are prostate, lung, colorectal, bladder, and melanoma (in that
order).
o The biggest killers are lung, prostate, colorectal, pancreas, and leukemia.
o In women, lung cancer has almost caught up to breast. Then, its uterus, lymphoma,
and melanoma.
Mortality is highest in lung, breast, colorectal, pancreas, and ovary.
o The worst cancers are those that are hard to test for and are asymptomatic until
very extensive.
In pediatrics, cancer is the leading cause of disease-related death up to 14. (Accidents are
the #1 cause).
o Theres an ongoing discussion on how to monitor the cardiovascular systems of
cancer patients.
o Kids get leukemia (esp. ALL), lymphoma, CNS tumors, neuroblastomas, and Wilms
tumors.
The two greatest causes of cancer are tobacco and diet. Infections and exposures are
well below those.
o Primary prevention: promoting a healthy lifestyle, decreasing exposures,
identifying genetic risk
o Secondary prevention: Screening, public health interventions (literacy), tobacco
cessation programs
o Tertiary prevention: Targeted therapy (hopefully few side effects), futile
alternative therapies
Like 20% of the U.S. smokes. Most people that smoke regularly as adolescents smoke into
adulthood.
o Theres a major skew of smokers toward being impoverished and of low education.
o A quarter of cancer deaths are from tobacco use: lungs, oral, esophageal, laryngeal,
bladder, etc.
The goals for the future are to increase cancer registries, increase quality of life, and
increase 5-year survival.
This picture pertains to the next lecture.

Cell Biology Lecture w/ Dr. Warren 17 January 2012

The Topic of This Lecture Is: Not Oncology, Just Horrifically Basic Stuff about Signal Transduction

Growth is mediated at every step of a signal transduction pathway, including the signal
and its receptor.
o Intracellular transducers and receptors (Ras) are important too, as are transcription
factors (myc), DNA repair proteins (BRCA1), cell-cycle control proteins (Rb; p53),
and apoptotic proteins (Bcl-2).
As absolutely disgusting as it is, we have to know all of the molecules for GPCRs and RTKs.
Suck it up.
Trimeric G proteins have a GDP-bound -subunit and a -complex. When activated, subunits bind GTP.
o Ligand-bound receptors act as a scaffold, binding the entire trimer. activates, and
dissociates.
o An activated GTP--subunit may bind an effector protein, resulting in hydrolysis of
GTP to GDP.
The first receptor is a GEF (guanine-nucleotide exchange factor); the effector
is a GAP.
o -adrenergic receptors use this method, using adenylyl cyclase as an effector
protein.
Binding of an -subunit yields cAMP, which is able to activate PKA as a
growth stimulator.
Activated PKA passes through nuclear pores to activate genes, affecting cell
cycle control.
o Obviously, not all GPCRs are stimulatory. The effect on the cell is a summation of
receptor activity.
For RTKs, a signal molecule induces dimerization and activation via auto-phosphorylation.
o They are then able to use a GEF to activate an effector (like Ras) by exchanging
GDP for GTP.
o Activated Ras starts the activated kinase cascade of RAF MEK ERK, affecting
gene expression.
Another pathway involves activating phospholipase-C (PLC), which cleaves phosphatidyl
phosphate (PIP2).
o IP3 acts as a ligand for a Ca2+ channel, while diacylglycerol (DAG) can bind to
protein kinase C (PKC).
Both DAG and Ca2+ are required to activate PKC, which enters the nucleus.
Many cancer cells subvert the previous pathway by phosphorylating PIP2 to PIP3, rather
than cleaving it.
o The enzyme responsible for creating PIP3 (which actually has 4 Pi) is PI3-kinase.
Theres an important tumor suppressor that opposes PI 3-kinase. It is PTEN
phosphatase.
o PIP3 is able to activate PKB (a.k.a. AKT), which activates an inhibitor of apoptosis
Bcl-2.
Again, this only occurs if the cancer cell is able to inactivate PTEN
phosphatase.
AKT activates mTOR via many intermediates. This maintains protein synthesis and
promotes cell growth.
o The anti-tumor drug rapamycin works by inhibiting mTOR and downregulating
those signals.
Epithelial cells are stabilized by adherens junctions, which also regulate the growth of the
cells.
o -catenin is found in these. Free-floating -catenin can go to the nucleus as a
growth promoter.
Still, it also has to bypass an APC that leads to ubiquination and destruction
of -catenin.

If Wnt binds to its receptor, the enzymes of the APC are inactivated, leading to free
-catenin.
Moreover, Wnt activates SNAI1-2 transcription factors, promoting epithelialmesenchymal transition (EMT).
o Those factors prevent epithelial cell-cell binding and allow for invasion of the
stroma.
TGF- activates something similar to an RTK. Its a tumor suppressor for normal cells,
working by Smad2-3.
o Once epithelial cells begin to metastasize, TGF- then promotes EMT and further
metastasis.
o

Cell Biology Lecture w/ Dr. Warren 17 January 2012

The Topic of This Lecture Is: Not Oncology, Just Horrifically Basic Stuff about Cell Cycle Checkpoints

The most important phase in the regulation of mitosis is G1, which includes the major
checkpoint R.
o Everything after R, including DNA synthesis, G2, and mitosis, is relatively
unregulated.
There is sequential activation of cyclin-dependent kinases and their appropriate cyclins.
o In late G1, Cyclin D activates Cdk4/6. The cell is pushed past R with the help of
Cdk2-Cyclin E.
Cyclin D is only made if there are growth factors and transcription factors like
myc.
o S phase is controlled by Cdk2-Cyclin A, and G2 and the entry to mitosis are driven
by Cdk1-Cyclin B.
Cdk4/6-Cyclin D hyper-phosphorylates Rb, which is normally bound to E2F in its
inactivated form.
o As E2F is released, it initiates positive feedback by upregulating Cd2k-Cyclin E,
which also acts on Rb.
If something goes wrong, inhibitors will act on Cdk2-Cyclin E, breaking the
cycle.
o If all is well, E2F promotes DNA replication factors, as does the formation of Cdk2Cyclin A.
The DNA damage pathway mainly focuses on p53. Double strand breaks activate ATM to
phosphorylate p53.
o MDM2 then cannot inhibit p53, which first tries for DNA repair. If it fails, it leads to
apoptosis.
p53 turns on p21, which inhibits Cdk2-cyclin E. Normal cells break down p53
if its not needed.
ATM also activates Chk1-2 and BRCA1-2, which both initiate repair of DNA
damage.
Its a global checkpoint mechanism that actually acts throughout the
cell cycle.
o

p53 uses the intrinsic pathway of apoptosis. It still activates procaspase-9 and the
caspase cascade.
The process starts with Bax triggering release of cyt-c from mitochondrial
membrane.
Bax can be antagonized by Bcl-2, which is created by AKT/PKB via PIP3
or IGF.
o Again, the generation of Bcl-2 is normally opposed by PTEN
phosphatase.
Remember that p53 is a transcription factor that uses other effectors to do its
work.

 Also, p16-INK4/p14-ARF is a tumor suppressor that prevents Cdk4/6-Cyclin D from

phosphorylating Rb.
o It induces cellular senescence or apoptosis. Its inactivated by myc and activated by
TGF-.
o Both p16 and p14 are produced from the same gene; they just use different reading
frames.
p16 prefers senescence, while p14 will activate p53, tending toward
apoptosis.
Cell-cell junctions provide contact inhibition by acting at p27, which inhibits Cdk2-Cyclin E
as well.
A very powerful transcription factor is myc, which is upregulated by ERK (last part of the
kinase cascade).
o It increases synthesis of E2F and cyclin D while promoting the degradation of p27.
o Cells can tell if myc is being overproduced. They respond by upregulating p14-ARF.
In this way, myc is its own tumor suppressor, as it leads to stabilization of
p53.
AKT/PKB doesnt just block apoptosis. It promotes cell division by blocking p21 and p27.
What a dick.
Telomerase is an RNA-dependent DNA polymerase required to extend a cap on
chromosomes.
o Without the cap provided by telomeres, chromosomes have sticky ends that can
yield aneuploidy.
Normally, depletion of telomerase leads to senescence, mediated by p16INK4.
o A loss of p53 will lead to massive end-to-end fusion that can potentially reactivate
telomerase.
At the metaphase checkpoint, chromosomes are supposed to line up perfectly on the
metaphase plate.
o APC/Cyclosome ensures that anaphase does not begin unless the kinetochores are
aligned.
But, as weve seen, a mutated APC causes issues. Here, it destroys the
anaphase inhibitor.
o If APC/C is mutated in some way, it wont link to microtubules to kinetochores
aneuploidy!

Cell Biology Lecture w/ Dr. Warren 18 January 2012

The Topic of This Lecture Is: Cell Biology of Cancer, Which Is Less Horrifically Basic

Two-hit hypothesis: Multiple oncogenic genes (like myc and Ras) will lead to more
aggressive tumors.
o Tumor suppressors are particularly affected by a loss of heterozygosity (LoH)
(ex: Stk11).
o While tumors can have hundreds of mutations, its suspected that only 5-20 driver
genes are key.
Epithelial tumors evolve as mutant cells acquire more and more mutations
and proliferate.
EMT leads cells to push through the basement membrane and communicate
with the stroma.
o At every oncogenic alteration, theres a chance for apoptosis, senescence, hypoxia,
etc.
In order to survive, there must be continued proliferation, anigogenesis, and
invasion (EMT).
Oncogenes are essentially dominant. A single mutation event on one allele yields an
oncogene.
o Example: A deletion or point mutation prevents the inactivation of GTP on Ras.
o Gene amplification by whatever method leads to overproduction of a protein, as
in myc and PDGF.
o Chromosomal rearrangement, as in the Philadelphia chromosome, can produce
cancer (CML).
Chronic myelogenous leukemia is via fusion of the bcr and abl genes,
activating abl kinase.
Gleevec binds selectively to the active site of bcr-abl, disabling the abl kinase
gene.
Tumor suppressors are recessive; both alleles must be inactivated. A single mutation is
insufficient.
o A mutated allele can be inherited. Chromosomal rearrangement (LoH) has the same
effect.
Again, a mutation or two can lead to hyperplasia, which increases the likelihood of more
mutations.
o These cells can still survive, as they no longer need to communicate with the
basement membrane.
o A further mutation will push a cell into dysplasia. It then under goes EMT as an in
situ carcinoma.
EMT is the key to metastatic potential. Cells invade the stroma and get into
blood vessels.
The tumor and stroma exchange signals, such as VEGF, PDGF, cytokines, and
chemokines.
o EMT can be seen in epithelial cells that stop making cytokeratin and produce
vimentin (IMF) instead.
Mesenchymal cells have no cell-cell attachments, so they migrate (Wnt
SNAI1-2).
Tumor cells stimulate stem cells to make chemokines (ex. CCL5), which act on
the tumor.
o Tumor cells with stem cell properties are long-lived and dont divide as rapidly as
other tumors.
They are thus resistant to chemo, and they can reseed new tumors after
ablation.
Malignant colon cancers are more difficult to identify, as carcinomas invade muscle and
dont form polyps.

However, an inherited mutation of APC leads to familial polyposis, with thousands of

polyps.
Other mutations can be in Ras, -catenin (via Wnt), p53, Smad4, and TGF-
receptor II.
Mutated APC leads to chromosomal instability, and eventual loss of p53,
Smad4, etc.
With a loss of BRCA1-2, there is insufficient DNA repair. Often, PTEN is disabled and PI3kinase is overactive.
o Again, these enzymes work while ATM activates p53 p21 blocks Cdk2-Cyclin E
less Rb activity.
o Other breast tumors have over-expressed Her2 receptors, chronically activating
Ras and the kinases.
A new therapy involves intentionally preventing DNA repair by a PARP1 inhibitor,
inducing cell death.
o Tumor cells will have two defective DNA repair enzymes; normal cells just have one
and are okay.
o

Pathology Lecture w/ Dr. Gomez 18 January 2012

The Topic of This Lecture Is: Pathology Review of Cancer

Given that she includes a 14-page summary of her lecture to go along with pretty pictures,
I have no notes.
Pathology Lecture w/ Dr. Milkowski 19 January 2012
The Topic of This Lecture Is: Pathology of GI Cancer

This is just a lecture of pretty pictures, so I dont have notes for this either. Deal with it.

Oncology Lecture w/ Dr. Lampidis 19 January 2012

The Topic of This Lecture Is: Chemotherapy

Epithelial tissue is avascular, so removing a tumor before it invades the basement

membrane is curative.
Review: chemotherapy affects rapidly-dividing cells, like gonads, hair, bone marrow,
and intestinal mucosa.
o Theres a small range of selectivity, since cancer cells are still eukaryotic, like
healthy cells.
o The log-kill hypothesis is that only a percentage of cancer cells are killed with
each dose of chemo.
Its best to start a chemo regimen at the lowest number of cells possible to
avoid resistance.
o The heterogeneity of cancer can lead to resistance. Some cells impair the
transport of drugs.
Others impair polyglutamate formation. Others increase or alter their
enzymatic activity.
Some chemotherapy drugs are antimetabolites, which work best during DNA replication
(S phase-specific).
o The growth fraction is all replicating cells over all of the replicating cells, PLUS
those in G0.

 Quiescent cells (those in G0) are immune to the toxic effects of chemotherapy.
Methotrexate (MTX) and 5-fluorouracil (5-FU) prevent the formation of nucleic
acids.
MTX is an analog of folic acid that inhibits DHFR, such that NADPH cant go to
NADP+.
5-FU goes to fluorodeoxyuridylate, which inhibits thymidylate synthase (no
dUMP dTMP).
o Analogs must be given as nucleosides, as if they are charged, they cant cross
membranes.
Either the sugar or the base can be altered to function as a chemotherapeutic
agent.
Ara-C is an analog of cytosine; azathioprine & 6-thioguanine are of
hypoxanthine & guanine.
o 6-mercaptopurine is converted to its active form by 6-thioinosinic acid, leading to
cell death.
6-MP is degraded by xanthine oxidase, which is blocked by allopurinol.
As such, a patient on allopurinol who takes 6-MP can get toxic levels of
the drug.
Tubulin-binders prevent formation of the mitotic spindle, thus preventing the separation
of chromosomes.
o These drugs are also phase-specific, as theyre only effective during the M phase
(which is short).
o Docetaxel and paclitaxel stabilize microtubules, preventing the negative end from
shrinking.
o Vinblastine (+ other Vinca alkaloids) depolymerizes microtubules by stopping
positive end growth.
Alkylating agents are those that induce depurination and cross-stranded connections,
triggering apoptosis.
o These are non-phase specific. Examples are cyclophosphamide and nitrosureas
(BCNU & CCNU).
Nitrosureas are lipophilic, so they can pass the blood-brain barrier. Other
drugs cant.
o The example given in class was alkylation of two guanine strands at N7, yielding
cross-linking.
o Cyclophosphamide is activated by P450 in the liver in the form of
aldophosphamide.
Normal cells deactivate it (aldehyde dehydrogenase). Cancers get
phosphoramide & acrolein.
Topoisomerase inhibitors (adriamycin = doxorubicin) prevent the opening of DNA for
replication.
o These are essentially eukaryotic anthracyclines. Like alkylating agents, they are
non-phase specific.
o They have cumulative dose toxicity on the heart. They preferentially accumulate in
cardiac cells.
Other toxicities we have to know are cis-platinum = nephrotoxicity; Vinca alkaloids =
neurotoxicity.
o Bleomycin & busulfan = pulmonary fibrosis; cyclophosphamide = cystitis (bladder).
Memorize this!
o

Because mutations in cancer cells are relatively frequent (1:10 6), combination therapy is
needed.
o The likelihood of a drug being resistant to two agents is thus 1:1012, so it should
work (visible at 109).

Multidrug resistance is seen in cells that block apoptosis, or those that can grow
very slowly.
The most prominent suppressor of apoptosis is Bcl-2, which inhibits the
actions of Bax.
Slow-growing anaerobic cells are more prominent in the center of solid
tumors.
These hypoxic cells can potentially be killed by inhibiting glycolysis
via 2-DG.
o Other cells have passive barriers or active pumps that work against multiple agents.
Were not really sure how the pumps work, but its an ATP-driven Pglycoprotein pump.
Target drugs can act anywhere in the signal transduction pathway (look at the diagram on
page 1).
o Monoclonal antibodies (Avastin = bevacizumab) bind directly to ligands (VEGF)
and inactivate them.
o Other antibodies (cetuximab) bind to the receptor (EGFR) and prevent ligandbinding.
o Tyrosine kinase inhibitors (erloitinib) pass through the cell membrane,
preventing phosphorylation.
Others block cell signaling, like Gleevec (imatinib), which blocks the bcr-abl
kinase.
o Bortezomib (Velcade) blocks proteasomes, triggering apoptosis of the cell (used in
MM).
The family of RTKs for EGFR is HER. Notably, overexpression of HER2 is a known factor in
many cancers.
o HER2 has to dimerize with itself or another HER receptor. That process can be
blocked by
Dimerization inhibitors, anti-HER2 antibodies, or tyrosine kinase inhibitors.
The Ames test is used to determine how relatively carcinogenic a given drug is.
o It measures the mutagenicity of a substance based on how many Salmonella can
begin producing His.
Angiogenesis is an important process for yielding large tumors with more metastatic
potential.
o HIF- degraded in the presence of O2, as the PHD enzyme is oxygen-dependent.
Without O2, HIF- isnt ubiquinated. It can bind to HIF- and promote
generation of VEGF.
o Less resistance develops in endothelial cells, as they dont mutate as readily as
epithelial cells.
Each endothelial cell can support ~100 tumor cells, so killing them amplifies
drug effects.
o VEGF receptors can be blocked, VEGF can be inactivated (Avastin), or receptors can
be solubilized.
The last mechanism works because the receptor is only effective if its on the
membrane.
Every oncogene drives glucose metabolism to the pentose-phosphate shunt, which
generates nucleotides.
o Cells cannot divide without glucose, so 2-deoxyglucose (2-DG) is an effective
chemotherapy agent.
2-DG blocks the conversions of glucose to G6P and G6P to F6P.
o

Oncology Lecture w/ Dr. Lopez 20 January 2012

The Topic of This Lecture Is: Immunology of Cancer

When a neoplastic transformation occurs, the immune response to new antigens is not
always effective.

The response may be present, but ineffective, or it can simply be absent (lack of
recognition).
Antigens can be MHC-HLAs, tissue specific, retrogenetic (like CEA), blood
group, etc.
o There may be a mutation in self-proteins or overexpression of a protein (T-cell
recognition).
Stem cells that remain in bone marrow become B-cells. Those that migrate to the thymus
are T-cells.
o B-cells become plasma cells when induced by macrophages, dendritic cells, or
CD4+ T-cells.
o T-cells can become CD8+ (cytotoxic), CD4+ (helper), or CD25+ T reg (suppressor).
T-cells must recognize tumor cells at TCRs and then become activated by
CD28:B7.
Inflammation around tumor cells leads to lysis and tumor antigen release. APCs take up
the antigens.
o T-cells are primed in lymph nodes after APCs process the antigen and produce
cytokines.
Lastly, activated CD8+ T-cells use cytotoxic mechanisms to eradicate tumor
cells.
Innate immunity is conferred by NK cells, PMNs, and macrophages, which are activated by
T-cells.
o NK cells use IFN-, while other cytokines work on macrophages, which are
cytostatic (not toxic).
The immuno-surveillance hypothesis cant explain why cancer rates arent higher in
mice that lack a thymus.
o But, there are different tumors associated with particular immunodeficiencies.
o Immune surveillance does not completely eliminate cancer cells due to antigenic
heterogeneity.
Those that are not recognized by T-cells arent in equilibrium; they are able to
escape.
Tumors have many mechanisms of escape. Some just have low immunogenicity. Others
are able to endocytose and degrade antigens. Others secrete factors like TGF-, which
suppress T-cells.
o Some tumor antigens lead to anergy of specific T-cells by tolerizing APCs (thats not
a real word).
This allows for metastasis of tumors to lymph nodes thanks to a lack of
immune response.
In enzyme-coupled monoclonal antibodies, the Ab binds first. Then, the enzyme
activates a prodrug.
o A new therapy involves culturing WBCs with IL-2 for 3-4 days, generating killer cells
(LAKs).
o Some cancers can be treated by incubating lymphocytes with tumor cells and IL-2.
Vaccines involve getting specific IgGs into dendritic cells, which mature and migrate to
lymph nodes.
o

Oncology Lecture w/ Dr. Rodgers 20 January 2012

The Topic of This Lecture Is: Introduction to Surgical Oncology

Amusingly, Dr. Rodgers has an exact transcript of his lecture in the notes of the PowerPoint
(CLICK).
Surgery can prevent cancer, such as a total colectomy for FAP or UC or mastectomy in
familial breast cancer.
Fine needle aspiration provides a small group of cells, permitting a tentative diagnosis.
Its just cytology.
o A guided core needle biopsy (14 gauge) allows for histology, as tissue
architecture is preserved.
o For diagnosing skin lesions or assessing for invasion, a skin punch biopsy takes a
2-6 mm section out.
An incisional biopsy is done while in the OR if a core biopsy cant be done. This gets a
wedge of tissue.
o An excisional biopsy is removal of the entire mass, including a small margin of
normal tissue.
o The orientation of the incision is important. All extremity biopsies should be done
longitudinally.
The biopsy scar must also be removed at the time of surgery to prevent
seeding.
o Contamination is an important concern, so fresh gloves and instruments are needed
at each site.
Use the least invasive technique that allows for immunohistochemistry (no FNA for breast
cancer).
o Handling of tissue involves proper orientation for margins and proper fixatives (ex.
lymphoma).
Sentinel lymph node biopsy is mainly for breast cancer and melanoma. It assesses the
extent of invasion.
o The process involves injecting Tc-99 as a radioactive tracer, followed by
lymphoscintigraphy.
Blue dye can be used instead if the surgeon is inexperienced. It actually
stains the node blue.
o If a sentinel lymph node is negative, theres like a 95% chance that theres no other
lymph spread.
Surgery also permits staging of tumors, such as a laparotomy for gastric cancer. It can
look for metastasis.
Surgery can be a definitive treatment of cancer, or it can be used for resections or
debulking of a tumor.
o Quality of life is weighed against adequate treatment. The best example is a radical
mastectomy.
o Cytoreduction is done on the log-kill principle. Make the tumor as small as
possible, then add chemo.
This can be as drastic as taking half of a liver and dealing with the few
remaining metastases.
Oncological emergencies include hemorrhage, obstruction, perforation, sepsis, or CNS
compression.
In the face of distant metastases, tumors can be removed simply to alleviated symptoms
(palliative).
Plastic surgery can follow, as in a TRAM flap that combines a tummy tuck with breast
reconstruction.