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Hemat/Onc EXAM 1
Hemat/Onc EXAM 1 - Schober Onc
33
Pharmacology
Graduate
01/11/2012

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Cards

Term
introduction to cancer biology
Definition
the process of cancer begins with mutations in genes that are involved in cell growth and differentiation

the time between initiation stage (acquisition of mutations) and final stages of tumor progression (invasion and metastasis) can take many years
Term
tumor cell
Definition
has mutations and modifications in genes that result in uncontrolled growth (clinical significance)

derived from a normal cell (epithelial, muscle, bone, blood, nerve)

cell division is normally tightly controlled so that cells produce and maintain normal tissue structure

cancer cells have mutations that cause the cells not to respond normally to extracellular and intracellular regulation resulting in abnormal tissue structure (a tumor)

tumors can exist anywhere on the spectrum from completely benign to very malignant
Term
metastasis
Definition
movement of tumor cells from primary site to distant tissue

through blood vessels or lymphatic system
Term
invasion
Definition
tumor cells enter (invade) and grow inside other tissues

normal cells cannot divide inside other tissues of a different cell type or among other tissues in which they are normally not found

cancer cells have ability to divide in other tissues

happens more locally than metastasis
Term
benign tumor
Definition
no metastasis or invasion

abnormal tissue growth, but cells still retain many properties and appearance of the normal cell counterpart

benign tumors usually do not invade other tissues and do not metastasize (remain localized and are often encapsulated)
Term
malignant tumor
Definition
metastasis and invasion

cells are very different from their normal counterpart

cells undergo de-differentiation (revert back to state resembling cell precursors or stem cells)

cells from malignant tumors metastasize and invade other healthy tissues
Term
proto-oncogene
Definition
a gene that promotes cell division and differentiation

a gene that is involved in control of cell division and tissue organization, and promotion of cell survival

these genes have potential to cause cancer when mutated

normal version of a gene who's products regulate the cell cycle division and growth
Term
oncogene
Definition
mutated version of a proto-oncogene

associated with cancer

the mutations result in higher expression or over activity of the protein
Term
tumor suppressor gene
Definition
associated with limiting cell division and promoting apoptosis

these genes restrict (limit) cell division and may promote cell apoptosis

they are called tumor suppressor genes b/c mutations that cause low protein expression or loss of function are associated with cancer
Term
differences between tumor and normal cells
Definition
CONTACT INHIBITION
division stops when cells come into physical contact with each other
cancer cells do not respond to cell-cell contact (they keep dividint)
the concept of contact inhibition comes from observation of cells in culture dishes

RESPONSE TO AND PRODUCTION OF GROWTH FACTORS
growth factors cause cells to enter cell cycle (promote division) and promote cell survival (inhibit apoptosis)
tumor cells tend to produce more growth factors and have exaggerated response to growth factors

PRESENCE OF ONCOGENES
a mutated form of a normal gene (proto-oncogene) that contributes to carcinogenesis
certain mutations cause the gene product to be expressed in a cell at higher levels or cause the gene product to have higher activity
result of oncogene expression is uncontrolled cell division and resistance to apoptosis

LOSS OF TUMOR SUPPRESSOR FUNCTION
the function of this class of genes is to keep cell division and growth in check
loss of function of these genes is associated with cancer
a good example is p53 transcription factor

IMMORTALITY
cancer cells can undergo unlimited divisions
normal cells undergo a certain amount of divisions (depending on the cell type) and then stop (cannot divide anymore, called cell senescence)
immortality is related to maintenacne of telomere length by the enzyme telomerase

ALTERED HISTONE ACETYLATION AND DNA METHYLATION
modifications of both histones and DNA is observed in tumor cells
histones are the proteins that DNA wraps around
Term
characteristics of cancer cells: loss of tumor suppressor gene function and DNA methylation
Definition
[image]

hypermethylation of CpG regions in the promoters of tumor suppressor genes (TSG) results in decreased gene transcription

hypermethylation of these promoters has been observed in many different cancers

acquired and inherited mutations may also result in loss of TSG function
Term
environmental factors that cause cancer
Definition
environmental factors may favor the growth of cancer without causing mutation or may cause mutation (acquired) in genes that control cell growth and division (proto-oncogenes and tumor suppressor genes)

environmental factors may or may not cause a gene mutation

examples of environmental factors that cause mutation:
benzene
halogenated chemicals
radon
viruses
UV radiation
chemotherapeutic agents

exposure to many different factors that may be found in our environment are associated with the production of acquired mutations and development of particular types of cancer

benzene exposure can cause certain types of leukemia

halogenated chemicals can cause bladder and liver cancer

herpes virus is associated with Kaposi's sarcoma (in AIDS patients) and HPV (human papilloma virus) is associated with cervical cancer

radon gas can cause lung cancer

UV light is strongly associated with skin cancer (melanoma)

some anti-cancer drugs can cause mutations that result in cancer

examples of other environmental factors (mutation independent):
diet
chemical exposure
physical exercise
age

there are factors in the environment that can promote development of cancer without directly causing mutation (mutation independent)

healthy diet may play a role (also calorie restriction)

some chemicals can favor the growth of dysplastic or tumor cells without causing mutation

there are studies showing a correlation between exercise and cancer development

age is also a factor which could be explained by hormonal changes, less efficient DNA repair, or immune system decline
Term
inherited factors that can cause cancer
Definition
certain variation in gene sequence may predispose us to the development of cancer at some point in our life
Term
DNA damage and repair
Definition
[image]

this table shows examples of different factors that cause damage

row 1 - factors that cause damage

row 2 - type of damage they cause

row 3 - the different repair mechanisms

one main message of this table is our body has various mechanisms to correct the damaged DNA and moreover, when the repair mechanism is overwhelmed or defective, permanent mutation can occur leading to cancer

tumor cells may acquire enhanced repair mechanisms that confer resistance to anti-cancer drugs that work through DNA damage
Term
oncogenes
Definition
proto-oncogenes are genes that control cell growth and division through various mechanisms

oncogene is the mutated form of a corresponding proto-oncogene

the types of mutations are ones that result in uncontrolled cell growth and division

the mutations result in increased gene product production or gene product activity

known oncogenes that are associated with increased probability of specific types of cancer:

mutations in growth factor receptors are associated with certain cancers

mutations in intracellular signaling molecules (RAS, a small GTPase) are associated with several cancers

BCR-ABL (strongly associated with chronic myelogenous leukemia, CML) fusion gene

molecular oncogene targets of FDA approved anti-cancer drugs:
EGFR or ERB-B1 - codes for epidermal growth factor receptor (glioblastoma, breast cancer, squamous carcinoma
HER-2 or ERB-B2 - codes for a growth factor receptor (breast, salivary gland, prostate, bladder, and ovarian cancers)
K-RAS - code for guanine nucleotide proteins with GTPase activity (lung, ovarian, colon, pancreatic cancers
BCR-ABL - codes for a nonreceptor tyrosine kinase (chronic myelogenous leukemia)
Term
tumor suppressor genes
Definition
tumor suppressor genes regulate cell growth and prevent cells from developing into cancer cells

when TSG function is lost as a result of mutation, cells are more likely to develop a malignant phenotype

2 well known TSGs are RB1 and p52

normally RB1 functions to stop division (cell cycle)

when RB1 is mutated cells undergo division unchecked

p53 normally stops cell division and can activate cell apoptosis (cell death)

certain p53 mutations cause the cell to be resistant to apoptosis (p53 mutation is associated with many different types of cancer)

other TSGs function to repair DNA damage

currently there are no FDA approved drugs that bind TSG products

RB1 and p53 are important for tumor cell immortality
Term
steps in the development of cancer (carcinogenesis, oncogenesis)
Definition
initiation -> promotion -> transformation -> progression

all of the steps involve acquisition of gene mutations

INITIATION
a single normal cell acquires mutation(s) in proto-oncogenes and/or tumor suppressor genes
these mutations cause the cell to grow or divide abnormablly
the cell is considered pre-cancerous

PROMOTION
more mutations occur and other factors (for example, diet and gene polymorphisms) favor division of a single cell into many daughter cells (clonal selection and expansion)

TRANSFORMATION
pre-cancerous cells continue to acquire mutations and divide to a mass (large cell number) that is clinically detected and recognized as a tumor

PROGRESSION
the tumor cells invade other tissues and/or metastasize
tumor angiogenesis occurs

[image]

initiation: a cell is exposed to radiation or carcinogens which cause genetic change producing an initiated cell or cells

promotion: the initiated cells have defective growth control and dedifferentiate (change into cells resembling precursor cells); the initiated cells divide and form a pre-cancerous (preneoplastic lesion)

transformation: further genetic change and growth leads to formation of clinical cancer

progression: tumor invasion and metastasis occurs (to brain and liver as shown above)

the bottom box with arrows describes continued genetic changes during the whole process of cancer development:
activation of proto-oncogenes
inactivation of tumor suppressor genes
inactivation of antimetastasis genes

[image]

chemicals, viruses, and radiation cause acquired mutations

the mutations, acquired or inherited, in proto-oncogenes or tumor suppressor genes increase probability of cancer

other factors (diet, age, hormone, and immune system changes) promote or permit growth of the mutated cells

the cells proliferate, dedifferentiate, and are more resistant to apoptosis

cells maintain telomere length

the cells grow and develop into a clinically detectable tumor mass and spread to other parts of the body

metastasis involves production of preteases that breakdown extracellular matrix protein (matrix metalloproteinases) and angiogenesis
Term
characteristics of cancer development and progression
Definition
MULTIPLE MUTATIONS
it was once thought that cancer resulted from a single mutation
now we know this is not correct
the whole process of cancer development (initiation through tumor progression) requires accumulation of multiple mutations
some of the mutations arise early in cancer development and others arise late in cancer development

IMMORTALIZATION
a characteristic of cancer cells, but not normal cells
cancer cells acquire certain mutations that confer ability to divide continuously

TUMOR GROWTH KINETICS
follow a predictable curve, the most rapid cell division (% change in tumor mass) usually occurs before the tumor is detected clinically

ANGIOGENESIS
the growth of new blood vessels from pre-existing blood vessels (blood vessel sprouting) and is required for tumor growth larger than 1-2 mm diameter
angiogenesis strongly favors cancer cell metastasis

METASTASIS AND INVASION
often the most clinically damaging part of cancer progression
Term
development of cancer requires ACCUMULATION OF MUTATIONS
Definition
[image]

a normal cells acquires a first mutation and divides

the first mutation causes a minor change in proliferation rate

one of the daughter cells with the first mutation acquires a second mutation

the second mutation causes faster division, but the cell still resembles a normal cell

one of the cells with the first and second mutation acquires a third mutation which causes the cell to divide more rapidly and appear morphologically abnormal

one of the cells with 3 mutations acquires a fourth mutation

the cell with 4 mutations may dedifferentiate, divide very rapidly and appear very different from the normal cell

some of the other cells on the left side of the figure may acquire other different mutations

occurrence of multiple mutations in different cells results in a genetically heterogeneous tumor
Term
development of cancer cell IMMORTALIZATION
Definition
[image]

a hallmark of cancer is development of cell immortalization

this figure shows the relationship between telomere length, cell proliferation, and cell death (apoptosis)

2 main factors determine if a cell lineage becomes immortalized: inactivation of tumor suppressor genes (commonly p53 and pRB) and expression of the enzyme telomerase

1. in the beginning the cancer cells can rapidly divide and none of the cells die; telomere length is long
2. after the cancer cells continue to divide at a rapid rate the telomeres shorten (medium length); no cell death occurs
3. after more division telomers are short and if p53 and pRB remain active (non-mutated) the cells enter senescence (a state in which the cells can no longer divide, we hope this occurs); if p53 and pRB function is lost b/c of mutation, the cell retains ability to divide
4-5. and if the cells satrts producing telomerase the telomere length is restored and the cells can continue to divide (the cells are immortalized)
Term
tumor growth kinetics
Definition
[image]

cell cycle: preparing for or undergoing cell division (G1, S, G2, M)

Go - not part of the cell cycle, cell not preparing for or undergoing cell division

normal tissue: few or many cells in cycle

tumor: many in cycle (SMALL tumor); fewer in cycle (LARGE tumor)

the cell cycle is made of 4 different phases (G1, S, G2, M)

in G1 the cell is preparing (producing proteins and enzymes) for DNA synthesis

S (synthesis) phase is when the cell replicates DNA

after S phase the cell enters G2 phase (in G2 phase the cell is preparing for mitosis)

M phase = mitosis

% of cells in some part of the cycle depends on tissue type

small tumors (rapid growth) have greater % of the cells in the cycle compared to large tumor (slower growth)

[image]

this is a plot of cell number over time (tumor growth curve)

before the tumor is clinically detected the cell number increases very rapidly (this is a time when the tumor is most sensitive to drugs that cause DNA damage)

in the rapid growth phase most of the cells in the tumor are in part of the cell cycle (S, M, G1, or G2) and very few are in Go (not part of the cell cycle)

near the time the tumor is detected clinically, the growth rate begins to slow significantly

larger tumors form different compartments

the inner core of the tumor contains cells that are in Go or may have reached cell senescence (the cells lack telomerase)

the outer layers of the tumor mass usually contain cells that are in active process of division (in some phase of the cycle)

[image]

angiogenesis occurs as the tumor gets bigger; once the tumor reaches a certain size (1-2 mm in diameter) it becomes dependent on angiogenesis for growth
Term
progression of tumors require ANGIOGENESIS
Definition
[image]

< 1 mm (diffusion)

> 1-2 mm tumor (angiogenesis)

VEGF production

sprouting new vessels

tumor cells enter circulation

also, required for normal processes

angiogenesis is formation of new blood vessels from pre-existing blood vessels (sprouting)

growth of a small tumor can be supported by diffusion of nutrients

angiogenesis must occur for a tumor to grow beyond 1-2 mm in diameter

the tumor cells produce vascular endothelial cell growth factor (VEGF) which causes endothelial cells to divide and organize into small blood vessel precursors

angiogenesis not only facilitates tumor growth, but also promotes metastasis

angiogenesis occurs during wound healing, fetal development, during menstrual cycle and other normal processes
Term
modes of tumor progression: metastasis
Definition
[image]

1. INITIATION, PROMOTION, TRANSFORMATION
after the process of transformation, cancer progression may involve metastasis

2. MORE MUTATIONS THEN PROCESS OF TUMOR METASTASIS
a subpopulation of tumor cells may acquire mutations that confer the ability to metastasize

3. INTRAVASATION
the metastasis-enabled cells attach to the basement membrane and produce metalloproteinases
the metalloproeinases degrade basement membrane and extracellular matrix protein to allow the tumor cells to gain access into the blood vessel (intravasation)

4. TUMOR EMBOLUS
in the vessel lumen, the tumor cells may attach to host lymphoid cells and platelets to form a cellular embolus

5. EXTRAVASATION
cells from the embolus attach to adhesion receptors expressed on endothelial cells located in a distant tissue (brain, bone, lung)
cells undergo extravasation and form a secondary (metastatic) tumor
Term
principle of tissue INVASION
Definition
normal cells cannot grow when taken out of their usual tissue environment

cancer cells can divide among other cells in different tissues and cause tissue damage

another characteristic of malignant cells is tissue invasiveness

normal cells grow best when among cells of the same type or cells they normally encounter in their native tissue environment

malignant cells acquire the ability to invade and divide in other tissues

[image]

colon cancer invading the smooth muscle layer that lies beneath the colon epithelium
in this tissue slice, colorectal cancer cells can be seen growing between the muscle fibers (right image)

an example of tissue invasiveness is growth of tumor cells in colorectal cancer (a cancer of epithelial origin, carcinoma) in nearby smooth muscle layer in the intestinal wal

in general, aggressive tissue invasiveness is associated with more malignant cancer types and poorer prognosis
Term
anti-cancer drugs act at some point in this pathway
Definition
[image]

all anti-cancer drugs act at some point in this figure

the bases, purines (adenine and guanine) and pyrimidines (cytosine, thymine) are required for production of ribonucleotides

inosine monophosphate (IMP) is a precursor for both adenosine monophosphate (AMP) and guanosine monophosphate (GMP)

the ribonucleotides are used for RNA synthesis or converted to deoxyribonucleotides (by action of nucleotide reductase enzyme) for DNA synthesis

DNA can be replicated into more DNA or transcribed to RNA

RNA is translated to protein
Term
major classes of anti-tumor drugs
Definition
[image]

3 major classes of drugs shown above are most effective against rapidly dividing cells

1. INHIBITORS OF DNA SYNTHESIS AND INTEGRITY
antimetabolites and folate pathway inhibitors interfere with DNA synthesis and topoisomerase inhibitors interfere with DNA integrity

2. DNA DAMAGING AGENTS
some drugs result in direct damage to DNA such as alkylating agents (add alkyl group to DNA), antibiotics (cause free radical damage) and drugs that form platinum complexes (cross link DNA)

3. INHIBITORS OF MICROTUBULE FUNCTION
some drugs bind microtubules and interfere with spindle formation during mitosis (vinca alkaloids and taxanes)

4. HORMONES AND HORMONE RECEPTOR ANTAGONISTS
some types of cancer (breast and prostate) can be dependent on hormones (estrogen and testosterone)

5. GROWTH FACTOR RECEPTOR ANTAGONISTS
other drugs act through blocking the growth factor receptors (example, epidermal growth factor antagonists)

6. INTRACELLULAR KINASE INHIBITORS (BLOCK SIGNALING)
certain drugs block intracellular signaling (kinase inhibitors) of growth factor receptors)

7. ANGIOGENESIS INHIBITORS
angiogenesis inhibitors block tumor growth and metastasis (VEGF antagonist)

[image]

A - inhibit purine ring biosynthesis; inhibit nucleotide interconversions
B - inhibits pyrimidine biosynthesis
C - inhibits ribonucleotide reductase
D - inhibits dihydrofolate reduction; blocks TMP and purine synthesis
E - inhibits TMP synthesis
F - inhibit DNA synthesis
G - block topoisomerase function
H - form adducts with DNA
I - block activity
J - deaminates asparagine; inhibits protein synthesis
K - inhibit function of microtubules

A-F are drugs classified as antimetabolites (except hydroxyurea); they interfere with production of deoxyribonucleotides or incorporation of deoxyribonucleotides into DNA

G and H are drugs that damage DNA or interfere with DNA integrity; the damaged DNA induces apoptosis; DNA damaging drugs can cross link DNA strands (alkylating agents), cause free radical damage, or intercalate between DNA bases (anti-tumor antibiotics), or inhibit topoisomerase enzymes

I are various drugs that inhibit growth fac tor signaling and bind other targets that have some degree of specificity for tumor cells (enzyme inhibitors and monoclonal antibodies)

J is an enzyme that interferes with protein synthesis

K are drugs that bind microtubules and interfere with M phase (mitosis) of the cell cycle
Term
drugs may act on a specific phase of cell cycle
Definition
[image]

Go - not in cell cycle
G1 - preparation for S
S - synthesis of DNA (replication)
G2 - preparation for M
M - mitosis (division, production of daughter cell); after M cell may enter Go or may continue into G1

inhibitors of microtubules - either stabilize or depolymerize microtubules and interfere specifically with M phase

glucocorticoids - act on G1 and alter gene transcription particularly in lymphocytes

antimetabolites and folate antagonists - specifically inhibit S phase by interfering with nucleotide production or nucleotide incorporation

topoisomerase inhibitors - topoisomerases are enzymes that control winding and linking of DNA; these enzymes are needed during the transition between S and G2 phases; inhibitors act on this part of the cycle

alkylating agents and platinum complexes - although these drugs are cell cycle nonspecific (can bind DNA in any part of the cycle), they have a tendency to react with DNA in S phase; alkylating agents can also kill cells in Go, but with less potency
Term
4 different patient outcomes
Definition
[image]

the plot shows number of cells in a tumor over time

short downward pointing arrows indicate time of treatment dose

A - is growth rate of a tumor in a non-treated patient; rate of increase is fastest early in time and then slows

B - the tumor is detected (10^10 cells) and then removed by surgery or destroyed by irradiation; no cancer cells remain

C - surgery or local radiation reduce the number of cells to only 10^6 b/c of metastasis and/or invasion of surrounding tissues; the patient is then treated with systemic chemotherapy; the downward pointed arrows indicate a given dose; after each given dose a constant fraction (99%) of the cells are killed; after each dose the patient is given a time period for recovery from side effects and the tumor grows back; after 5 doses the patient is free of cancer cells

D - after local treatment chemotherapy is initiated, but eventually cell number increases again due to resistance or development of dose-limiting side effects
Term
principles of cancer cell resistance
Definition
tumors are genetically heterogeneous
number of cells
duration of treatment

cancer cells are genetically unstable (mutations arise at a faster rate compared to normal cells) and mutations occur continuously so that the cells that make up the tumor are genetically heterogeneous

larger tumor size (cell number) and longer duration of treatment increases probability of resistance

in principle, just on resistant cell is required for tumor re-growth
Term
mechanisms and examples of tumor cell resistnace
Definition
1. REDUCED INTRACELLULAR CONCENTRATION OF DRUG
deaminase produced by tumor cells can INACTIVATE purine and pyrimidine analogs
methotrexate uses the folate transporter for tumor cell entry, thus, the cancer cell may produce less folate transporter resulting in PREVENTION OF DRUG UPTAKE
the p-glycoprotein can actively pump many different types of drugs (broad substrate specificity) out of the tumor cell (PROMOTES EFFLUX OF DRUG)

2. ALTERED DRUG TARGET
some of the cells of the tumor may express a mutated form (altered drug target) of dihydrofolate reductase or topoisomerase resulting in lower drug binding affinity

3. INSENSITIVITY TO APOPTOSIS
DNA damaging drugs cause tumor cells to enter the apoptotic pathway
mutations in p53 can cause insensitivity to apoptosis

4. BYPASS METABOLIC REQUIREMENT FOR TARGET
in breast cancer, tumor may switch from estrogen dependent to estrogen independent growth, or bypass some other metabolic requirement so a drug is no longer effective
Term
drug efflux medicated by p-glycoprotein
Definition
[image]

p-glycoprotein is present in many different cell types and has broad substrate specificity

p-glycoprotein (utilizes ATP) probably is an evolutionary conserved mechanism to remove toxins or unwanted molecules from the cell

a tumor is comprised of a genetically heterogeneous population of cells

most of the cells have lower amount of p-glycoprotein (more drug sensitive), but some of the cells may express high amounts of p-glycoprotein (drug resistant)

after chemotherapy all or most of the sensitive cells are killed

after stopping chemotherapy the resistant cells may rapidly re-grow to form a drug resistant tumor

next chemotherapy round will require a higher dose to kill the tumor cells
Term
p53 causes cell cycle arrest and apoptosis
Definition
[image]

1. drug causes DNA damage
2. p53 levels increase
3. cell cycle arrest in G1
4. cell death (apoptosis)

loss of p53 function causes apoptosis resistance

the product of the p53 gene has tumor suppression activity

one function of p53 is to initiate cell cycle arrest and induce apoptosis in response to DNA or other cellular damage

mutations in p53 gene are common in many cancer types especially during later stages (progression)

acquired mutation of p53 is one of the events involved in cell immortalization and is a mechanism of tumor cell resistance to drugs
Term
supplemental material
Definition
millions of tumor cells are shed daily into the circulation

very few of the circulating tumor cells successfully initiate a metastatic focus

angiogenesis is a ubiquitous event that is necessary for and promotes metastatic dissemination

circulating tumor cells can be detected in patients who do not develop overt metastatic disease

metastases may be as susceptible to anticancer therapy as their primary tumors
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