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70 Cards in this Set

  • Front
  • Back
Somatic mutation Hypothesis of Cancer:
1) What is under genetic control
2) What causes malignant transformation
3) What is the tumor mass made of
Cell growth, differentiation and survival are under genetic control

Malignant transformation is the result of mutations accumulating in a specific class of genes

The tumor mass is from clonal expansion of one progenitor cell that incurred the damage
6 Phenotypic Hallmarks of Cancer:
1) Dysregulation of cell proliferation (contitutive activation of growth stimulatory pathways/GFs) OR independence of proliferation signals
2)Insensitivity to growth inhibitory signals or loss of growth inhibition pathways
3) Evasion of apoptosis
4) Limitless potential to replicate
5) Angiogenesis
6) Invasion and metastasis
Genes in carcinogenesis:

Oncogenes and proto-oncogenes=

Tumor suppressor genes =
required for and promote cell proliferation

inhibit cell proliferation or block a step in cell cycle
Genes involved in apoptosis or cell senescence =
pro or anti apoptotic proteins and immortalization genes (telomerase)
Caretaker Genes =

Landscaper Genes =
DNA repair enzymes (looking inward to cell)

(looking outward to environment) proteins regulating angiogenesis, cell-cell and cell-matrix adhesion, proteolytic enzymes for invasion

encodes a protein that mediates or stimulates cell proliferation

inappropriately activated proto-oncogene via mutation or aberrant expression (over-expression or ectopic expression)
How many Oncogenes?

Types of proteins encoded by oncogenes?
~100 identified

growth factors, GF receptors, signal transduction molecules, steroid hormone receptors, transcription factors, cell cycle proteins
Growth Factors: example v-cis

Growth Factor Receptor: example transmembrane tyrosine kinase
oncogene v-sis is from proto-oncogene c-cis -> encodes PDGF (autocrine stimulated loop)

oncogenic versions of transmemb kinase receptors are overactive, stimulate mostly EGF-R family
(EGF-R (c-erbB1) overexpressed in 80% squamous cell carcinoma of the lung)
(HER2-neu (c-erbB2) amplified in breast, ovary, lung, stomach cancers)
Cell cycle proteins =

Signal Transduction molecules: (3)
cyclins and CDKs

1) Non-receptor protein-tyrosine kinases (src)
2) Cytoplasmic serine/threonine kinases (raf)
3) GTP-binding proteins (ras)
mutations (examples)
critical in signal transduction from RTKs

Mutations = single most common abnormality of dominant oncogenes in human tumors

Ki-ras: involved in lung, ovarian, colon and pancreatic cancers

N-ras: involved in leukemias
How are proto-oncogenes activated?
gain of function mutations
What are gain of function mutations?
2 types and example for each
Dominant mutation
1) Qualitative: Loss of regulatory elements via changes in gene structure -> abnormal gene product (oncoprotein) with uncontrolled, aberrant function (e.g. ras)

2) Quantitative:
upregulation of a structurally normal growth promoting protein (e.g. breast cancer cells often produce excess cyclin D and cyclin E)
Ras mutation that increases ras signal -
decreased GTPase activity (because ras is a g protein activated by a growth factor receptor)
2 mechanisms of oncogene activation and examples:
gene amplification e.g. MDM2 in soft tissue sarcomas

Chromosome rearrangement e.g. IgH and c-myc in Burkitt's lymphoma, or EWS gene rearrangement in some pediatric sarcomas

What is it, what does it cause?
What is the translocation?
What is the resulting protein?
An oncogene in CML

First chromosomal abnormality ever linked to a specific cancer

Translocation: t(9;22)fusion between the proto-oncogene c-abl and bcr

Overactive tyrosine kinase activity and abnormal cellular localization
What is STI157?
a pharmaceutical aka Gleevec which is the first drug to directly turn off the signal from the protein causing the cancer

It effectively lowered the white cell count during treatment
Insensitivity to growth inhibitory signals:

Tumor suppressor genes =
inhibit cell proliferation

Inactivation or loss -> tumor development by eliminating negative regulatory signals
Evidence for tumor suppressor genes

What is most frequently observed genetic abnormality in solid tumors:

Henry Harris's cell fusion experiment:
did what
suggests what

Two-hot hypothesis of Alfred Knudson:
deletion of genetic material

Fused one tumor and one normal cell -> a hybrid non-tumor cell
Suggests that cancer is recessive trait

explained that cancer is due to accumulated genetic mutations
- children with retinoblastoma were born with one mutated gene, only needed one more mutation to develop disease (earlier onset, more affected)
- adults with retinoblastoma needed two mutations to occur, more unlikely (older onset, less affected)
Loss of heterozygosity =
used to detect
DNA sequences in various regions
With one gene deletion PCR shows
Where does LOH happen?
- loss of Tumor Suppressor Genes (TSGs)
- Are usually slightly different (heterozygous)
- One band
- prevalence differs at different positions in genome, more prevalent at certain hot spots (TSG locations)
Possible ways to eliminate a normal gene:

Recessive mutations =
nondisjunction -> chromosome loss

nondisjunction -> duplication

mitotic recombination

gene conversion


point mutation

When Both copies need to be eliminated (as in tumors)
Cell cycle checkpoints

Involve what?
Ensure what?
Failure -> ?
involve tumor suppressor genes

ensure no progression until preceding phase in completed with high fidelity

apoptosis or genomic instability
RB/pRb =


Regulated by:

Mutation of Rb ->

LOH plays a role in:
primary regulatory protein of G1/S phase transition

Rb represses transcription of many genes involved in cell cycle progression and DNA synthesis

Regulated by cyclinD/CDK compelxes -> these phosphorylate and inactivate pRb -> release of critical transcription factors

inactivation, removing a key regulator of cell cycle progression -> retinoblastoma

Retinoblastomas, osteosarcomas, SCLC (small cell lung cancer), adenocarcinomas
Cyclin-dependent kinase inhibitors: (e.g.)
induce cell cycle arrest

e.g. CDKI p16INK4a induces G1 arrest by inhibiting CDK4 and CDK6

when cyclins are bound to CDKs they phosphorylate serine and threonine and drive the cell cycle forward, when cyclins decrease they are no longer bound, CDKs are no longer active and the cell cycle halts
p53 =
responsible for

"Guardian of the genome"
a transcription factor that is responsible for
- arrest of cell cycle (so DNA damage can be repaired before replication/division)
- apoptosis upon DNA damage

p53 activates transcription of CDK inhibitor p21 ->
p21 blocks cell cycle in G1 and G2 -> allows time for damaged DNA to be repaired
Loss of p53 ->

involved in how many cancers?
Most common genetic alteration for?

Li-fraumeni syndrome =
increased mutation frequencies, general genome instability

up to 50% of cancers

sporadic human malignancies

genetic mutation in p53 gene -> increase susceptibility to cancer
How does p53 trigger apoptosis?

Is p53 always recessive?
by activation of transcription of pro-apoptotic genes (e.g. Bax)

No, can be dominant unlike other TSGs via a Dominant Negative Mutation in one allele that prevents the function of the other allele (usually by physical association such as dimerization)
why are p53 levels upregulated in cancer?

because many mutations increase p53 half life on top of reducing p53 function

altered MDM2 binding, ubiquitinization?
Viral Oncogenesis:

e.g. -
some DNA viruses have transforming sequences not derived from cellular genes

code for proteins that complex with and inactivate p53

- HPV E6 binds to and promotes p53 degradation
- HPV E7 binds pRb and displaces E2F transcription factors

high risk genotypes found in 82-85% invasive squamous cell carcinomas of the cervix
Caretaker genes:
DNA repair genes - maintain genetic stability and prevention of mutation

Don't directly promote tumorigenesis

Inactivation -> increased gene mutation rate (all genes!) -> accelerated tumorigenesis
Caretaker genes examples:
XP - nucleotide excision repair for UV light damage
BRCA1 and BRCA2 - recombinational repair for xray damage
HNPCC - mismatch repair for replication errors
Evasion of Apoptosis

Apoptosis/stress pathway:
steps and players in each step
Triggers = chemo, XRT (radiation), hypoxia, genetic damage, GF or cytokine withdrawal, loss of cohesion/adhesion

Modulators = many factors/pathways including Bcl2/Bax family (Bax is part of the Bcl2 family, promotes apoptosis by competing with bcl2 proper

Effectors: caspase cascade (essential for apoptosis, acts as a protease)

Substrates: DNA, cytoskeleton (are destroyed by caspases)
Dysregulation of anti-apoptotic signals vs loss of proapoptotic signals: (examples)
dysgreg of anti:
in 80% follicular lymphomas, there is a t(14;18) -> overexpression of Bcl2 (antiapoptotic) -> lymphocytes fail to undergo normal apoptotic death in lymphoid follicles

Loss of pro-apoptotic:
inactivated proteins can include PTEN, p53, Bas -> independence from survival factors
What are implications for therapy based on the lack of pro or increase of anti-apoptotic signals?

What are the most curable cancers?
these mutations in the apoptotic pathway -> chemotherapy and radiotherapy resistance

cancers in which p53 is not mutated = hematopoietic and germ cell tumors
Limitless replicative potential

Senescence =

How can the cell circumvent senescence?

Crisis =

Immortalization =
cells have a finite replicative potential, and stop dividing after a certain number of divisions -> senescence

by disabling pRb (retinoblastoma tumor suppressor protein) and p53

cells that have circumvented senescence continue dividing until they enter crisis = massive cell death, karyotopic disarray, end to end fusion of chromosomes

1 in 10^7 cells will become an immortal variant that can multiple without limit
The role of telomeres in crisis:
telomeres are a counting device, with each cell division they shorten by 50-100 BPs

This is because DNA polymerases can't completely replicate the 3' end during S phase

Telomere erosion -> lose the ability to protect ends of chromosomal DNA

End to end chromosomal fusions occur -> karyotopic disarray associated with crisis and death

* therefore, normally cell death will occur after too many divisions due to loss of telomeres and crisis
Telomerase =

in connection with neoplasia -
an enzyme that elongates telomeres, usually only present in germ cells and stem cells

telomerase levels generally higher in malignant than benign neoplasms
Some malignant neoplasms don't have detectable telomerase -> suggests an alternate mechanism of telomere stabilization or lengthening


depends on:
tumors MUST have blood supply to grow

local ratio of angiogenic inducers to anti-angiogenic agents
angiogenic inducer e.g.

normal rate of angiogenesis =

"Angiogenic switch"
a) in normal physiologic conditions caused by
b)in pathologic conditions caused by

low to no vascular prolif

Normal physiologic:
Wound healing
Normal development
Physiologic hyperplasia

subclone develops ability to stimulate angiogenesis due to clonal progression
Tumors as angiogenesis inhibitors

what has been found to happen?
why does this happen?
the removal of certain tumors (breast, colon, and osteogenic sarcomas) has been shown to result in increased/rapid growth of distant metastases from different types of tumors

This suggests that e.g. a breast cancer can inhibit melanoma metastases

proposed mechanism is that the primary tumor secretes factors which directly inhibit vessel proliferation at secondary tumor sites called micrometastases via endocrine effects
Specific angiogenesis inhibitors:
Angiostatin - from lewis lung carcinoma, 38kD internal fragment of plasminogen

(plasminogen is precursor of plasmin which is an enzyme that degrades fibrin clots)

Endostatin - from a murine vascular tumor, a 20kD internal fragment of collagen XVIII
Antiangiongenic therapy:
treat cancers with antiangiogenesis drugs, e.g. endostatin

this doesn't induce acquired drug resistance - where resistant cells will not die with treatment and create a new, resistant tumor

Instead, all tumor cells are in need of nutrients from the blood in order to grow, and all could potentially be killed by this method
Invasion and Metastasis

How many tumor cells are in circulation and how often do they metastasize?
millions are shed daily into circulation, these can even be detected in patients who don't develop overt metastases

Less than 1 in 10,000 circulating tumor cells survive to initiate a metastasis
Steps to metastasis (6):
Dyscohesion: loss of cell-cell adhesion in tumor
Matrix Degradation: destruction of BM and ECM by tumor cells
Cell motility: into capillaries
Survival and adherence: to vascular wall
Extravasation: out of capillaries
Angiogenesis and Proliferation: forming metastasis
What causes loss of cell-cell dyscohesion in tumor?
Loss of cadherins
What do cadherins mediate/regulate?

What do they complex with and how?

What results from a loss of cadherins?
mediate homo-typic cell-cell interactions at adherence junctions, regulate cell proliferation, apoptosis, differntiation and cell motility via signaling pathways

Complex with cytoskeletons via alpha, beta, and gamma catenin (family of cytoplasmic proteins)

cadherin loss is correlated with increased invasiveness and metastatic potential
What regulates cell-ECM attachments?
Integrins =

Focal adhesion kinase pathways =

Integrin switching =
transmembrane receptors for BM components and ECM molecules

intracellular pathways that regulate apoptosis, proliferation and cell motility

altered integrin expression patterns by tumor cells which decreases adhesion to BM and increases adhesion to ECM -> increased migration over ECM
Matrix Degradation =

secrete what?
downregulate what?
destruction of local BM abd ECM to invade underlying stroma

tumor cells secrete proteolytic enzymes (matrix metalloproteinases/MMPs and collagenases)
Also, downregulate expression of tissue inhibitors of metalloproteinases (TIMPs) - natural inhibitors that control the activity of matrix metalloproteinases (MMPs)
Cell motility

Migration directed by:
factors that regulate tumor cell adhesion and cytoskeleton activity

Autocrine and paracrine factors and Extracellular matrix factors
Autocrine and Paracrine regulators of Migration:
Growth Factors (IGFs, FGFs, TGF-B): Stimulate tumor cell motility

Hepatocyte growth factor/scatter factor: ligand for c-met proto-oncogene receptor

Cytokines: IL-8, Histamine
Extracellular Matrix factors regulating migration:
Intact extracell molecules: vitronectin, fibronectin, laminin, type I collagen

Fragments of ECM molecules: released from matrix by MMPs
Adherence and vascular extravasation

Tumor cells interact with:
What do these do for the tumor cell?

What is responsible for adhesion to vascular membrane?
fibrin, platelets and clotting factors

these protect tumor cells in circulation from immune and non-immune destruction (monocytes/macrophages, NK cells, activated T cells)

They also facilitate attachment to endothelial cells

probably integrins
Why is metastasis angiogenesis dependent?

Experimental model of this:
immature and developing neovasculature in leaky and discontinuous allowing tumor cells to enter microcirculation

grow malignant human keratinocytes in immune deficient mice -> when VEGF-R is inactivated via blocking antibodies, angiogenesis is disrupted and invasion of malignant cells is prevented without decreasing cell proliferation -> functional reversion from malignant to benign phenotype
What determines distribution of metastases?

Most frequent location of metastases?

What are exceptions to location?
histologic type, anatomic location of primary tumor

first capillary bed encountered by the tumor cells (usually lung and liver - extensive vascular beds and slow flow)

Some primary tumors preferentially metastasize to specific sites (e.g breast and prostate cancers to bone)
Soil and seed hypothesis:
A receptor or binding site for a protein on the surface of the tumor cell may be present at a distant location -> acts as a homing mechanism

Then chemokines activate cell signaling pathways that support the metastatic focus
Therapies targeting metastasis:
Anti-adhesive agents
Matrix metalloproteinase inhibitors
Anti-motility agents
Anti-adhesive Agents:
what are they, what do they target?
peptidomimetics and monoclonal Abs targeted at integrins

Vitaxin (antagonist of avB3) induces vascular cell apoptosis and inhbits angiogenesis by blocking endothelial cell-matrix interactions
Matrix metalloproteinase Inhibitors:
Blocks what?
What are its properties in vitro and in vivo?
blocks degradation of matrix and activation of proteases and growth factors

in vitro - anti-invasive
in vivo - anti-angiogenic
Anti-motility agents:
examples and what do they block
Taxanes block microtubule cycling
Carboxyamido-triazole inhibits calcium influx
what mutations are required for the development of cancer?

How do you map mutations in each morphological stage?
mutations arising early are also expected to be present later with each successive stage marked by additional mutations

by isolating precursor lesions - Adenoma-carcinoma sequence
What mutations are present in benign tissue surrounding malignant?

List certain mutations occurring with high probabiliy at specific definable stages of colon cancer progression:
many of the same mutations as malignant but lacks at least 1

Early in the Process of transformation - converting colonic epithelial cells to hyperproliferative state: loss of tumor suppressor gene APC

Early ademona stage: hypomethylation of DNA

Carcinoma in situ: activation of oncogene Ki-ras

Later in disease with eventual development of metastastic colon cancer: Lose tumor suppressor gene DCC on chromosome 18q and Lose p53 as well
Epigenetics of cancer

genetic change =

Epigenetic change =
characteristics of epigenetic changes
alteration in DNA sequence

heritable modification of the genome, doesn't involve change in DNA sequence
-unlike classical genetics, these are reversible, act over large distances, usually result in gene silencing
epigenetics =
the study of all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA[1]. When a cell undergoes an epigenetic change, it is the phenotype of the cell that is affected. Epigenetic events during embryo development lead to the differentiation of fetal cells. The combined processes of fetal development and cell differentiation are called epigenesis. The term is also sometimes used as a synonym for the closely related topic of chromatin remodeling.
DNA Methylation:
what is hyper and what is hypomethylated?
Tumor suppressor genes are hypermethylated (gene expression is shut down)

vast areas including proto-oncogenes are hypermethylated (expression is activated)
Reversal of epigenetic changes

how can you revert malignant to non malignant phenotype without correcting genetic abnormality?
animal models have achieved this by reprogramming the epigenetic changes associated with differentiation (differentiation therapy)
Differentiation Therapy:

What is it?
Many tumor cells are arrested at a premature development stage, therefore unable to control their own growth

Differentiation therapy is an attempt to enhance cell differentiation to mature cells via cytokines (e.g with myeloid leukemia cells)

Could be target cell specific and less toxic than chemo

*the development of differentiation inducing agents to treat cancer has been limited to this date
Acute Promyelocytic Leukemia (APML) and All-Transretinoic Acid (ATRA)

What is the translocation that causes APML?
What do these genes normally do?
-PML gene (15q22): involved in protein-protein interactions
-RAR-a gene (17q21): transcription factor, mediates differentiation and growth-suppression effects in response to retinoic acid
What occurs as a result of the fusion?

What is the treatment?
PML-RAR-a fusion may inactivate RAR-a-ligand complexes (dominant negative interaction)

ATRA is treatment, restores some RAR-a-mediated transactivation, induces DIFFERENTIATION!
Example of treatment for liposarcomas:
agonist ligand for the nuclear receptor (ligand activated transcription factor) "peroxisome proliferator-activated receptor-gamma" induces terminal differentiation
Why is it important to study the molecular aspects of cancer?
to develop therapies that target deranged molecular pathways and signals, instead of relying on traditional chemotherapy and/or radiation therapy