20 Flashcards
What is cancer
Cancer is a distinct type of genetic disease in which not one, but several, mutations are required. Each mutation drives a wave of cellular multiplication associated with gradual increases in tumor size, disorganization and malignancy. Three to six such mutations appear to be required to complete this process.
Key properties of cancer
Uncontrolled growth and proliferation and increased survivability that defy the normal restraints that is caused by accumulation of mutations.
Invade and colonize territories normally reserved for other cells.
Increase in cell number is hyperplasia and causes an abnormal cell mass called tumor or neoplasm.
If the tumor is not yet invasive- it is benign. For benign tumors, the surgical excision, usually eliminates the tumor.
A tumor is considered a true cancer if it is malignant, that is when cells invade the surrounding tissue. Sometimes or at advanced stages, these cells break loose and enter the blood stream or lymphatic system and form secondary tumors called metastases
PET scan reveals high uptake of
(radioactive ) ___ in cells characteristic of
cancer cells- indicating…
5-fluorodeoxyglucose (fdg) metastases.
Cancer Cells Bypass Normal Proliferation Controls and Colonize Other Tissues
normal - no cancer cells
benign tumor - adenoma
malignant tumors - adenocarcinoma
Growth of a typical human tumor
10^8 cells - tumors first visible on xray
10^9 cells - tumor first palpable
10^12 cells - death of patient
Clonal origin of tumors– e.g. Philadelphia chromosome
Most cancers originate from a single aberrant cell!
The translocation between chromosomes 9 and 22 responsible for chronic myelogenous leukemia. The smaller of the two resulting abnormal chromosomes (22q–) is called the Philadelphia chromosome, after the city where the abnormality was first recorded.
Cancer cells contain somatic mutations
Development of a clone of cancer depends on genetic changes.
Inherited cancers due to mutations in germline (sperm or egg cells) constitute less than 10% of tumors and they increase the risk of developing cancer (E.g. BRCA1/2 –BReast CAancer gene)
Tumors contain somatic mutations - mutations that occur in the soma or body cells (not in germline)
Cancers are also driven by epigenetic changes – persistent –heritable changes in gene expression that result from chromatin modifications without changes in DNA sequence.
Cancer incidence as a function of age
Most cancers develop from many independent and rare genetic mutations and epigenetic changes that occur in the lineages that emanate from a single cell.
Age-dependency of cancers indicates that cancer is caused by progressive, random accumulation of a set of mutations in a single lineage of cells (monoclonal).
A malignant tumor is more dangerous than a benign tumor because __________.
its cells invade surrounding tissue.
Cancers Develop Gradually from Increasingly Aberrant Cells
For cancers caused by external factors, the disease is usually detected long after the exposure to the carcinogen ( cancer causing agent).
Tumor Progression
normal - looks normal
low-grade intraepithelial neoplasia - slowly starts building
high-grade intraepithelial neoplasia - a lot more cancerous cell seen
invasive carcinoma - starts invading other tissues
Tumor Progression Involves Successive Rounds of Random Inherited Change Followed by Natural Selection
clonal evolution
accidental production of mutant cells, cell with 2 mutations (and cells surround it with 1st mutation), cell with three mutations (cells around it growing more mutated, leading to dangerous cell proliferation as it spreads.
Cancer as a microevolutionary process-tumor progression by natural selection
One cell in a large cell population sustains an initiating mutation (red section) that helps it proliferate and survive over other cells. Eventually natural selection operating within this mass of somatic cells, causes this mutant cells to dominate and displace the cells that lack this mutation causing first clonal expansion. When this clone expands, a second mutation may occur with a frequency of ~10^6 resulting in a doubly mutated cell with greater proliferative and survival advantage. This process of expansion of mutants repeats itself with accumulating mutations. Eventually (at later stages of tumor development) the accumulation of multiple independent mutations that are advantageous for continued survival and expansion leads to multiple clonal expansions. This causes heterogeneous tumors.
Human cancer cells are genetically unstable that aids in tumor progression
Chromosomes from a breast cancer displays abnormal chromosome number- 48 instead of 46 and several chromosomal rearrangements. Arrow indicates -2 pieces of chromosome 8 (green) and a piece of chromosome 17 (purple) by translocation.
Defects in chromosome segregation can give rise to aneuploidy and/or chromothripsis
aneuploidy - one cell has n+1 and one cell has n-1
chromothripis - micronucleus formed in a cell, turning into “pulverized” chromosome
is A single mutation enough to convert a normal cell to a cancer cell.
no
The lifetime cancer risk is correlated with
the division rate of the cell of origin of the cancer
Some Cancers May Harbor Small Population of stem cells
a) transit amplifying cells and stem cells come forma. single stem cell
b) mixed cell population - stem cell propagates new tumor, and transit amplifying cells eventually die
key attributes of cancer cells
Altered homeostasis that results in cells growing and dividing at a faster rate than they die.
Bypass of normal constraints to cell proliferation (circumventing stress responses such as DNA damage response, avoiding replicative cell senescence, etc).
Evasion of cell death signals.
Altered cellular metabolism- such as glycolysis instead of oxidative phosphorylation
Manipulation of tissue microenvironment to support cell survival and to evade a deleterious immune response.
Escape of cells from tissue of origin to proliferate in new sites (metastasis)
Cancer Cells Have an Abnormal Ability to Survive Stress and DNA Damage
normal cel division and normal apoptosis - homeostasis
increased cell division and normal apoptosis - tumor
normal cell division and decreased apoptosis - tumor
Lack of contact inhibition in cancer cells as shown in cultured cells
1) contact-inhibited monolayer of normal cells in tissue-culture dish
- cell transformation
2) transformed cells lose contact inhibition
- cell division
3) foci of uninhibited transformed cells
Direction in which a cell is extruded from epithelium can lead to invasion
up-regulated survival signals; cell bypasses apoptosis and escapes
Cancer cells escape an inbuilt limit to cell proliferation- Replicative Senescence
Replicative Senescence – progressive shortening of telomeres at the ends of chromosomes that induces cell stress and leads to stopping of cell division in normal cells. The shortened telomers induce cell stress and lead to a DNA damage response that stops the cell cycle (activation of p53). Tumor cells express telomerase and use other mechanisms to prevent shortening of telomeres and to continue proliferation.
Telomerase complex has TERT and TERC.
TERT is the Telomerase Reverse Transcriptase subunit.
TERC is the Telomerase RNA Component.
Cancer Cells Have an Abnormal Ability to Survive
Stress and DNA Damage
(There is constant cell death in large tumors.. but still growing)
Cancer Cells Have an Altered Sugar Metabolism – Warburg Effect
proliferative tissue and tumor tissues and glucose undergo glycolysis. 10% of the matter is used for building blocks (which doesn’t usually happen), pyruvate is made, but then 85% goes to lactate and 5% goes to oxidative phosphorylation (usually its relatively even or more oxidative phosphorylation). Results in net product of energy, building blocs and nadph rather than energy, co2 and h2o.
does a great deal of lactate produce in tumor cells even in the presence of oxygen.
yes
tumor microenvironment
tumors evade immune response
angiogenesis - new blood vessels are formed to survive the hypoxia in large tumors
Steps in the process of metastasis.
normal
cells grow as benign tumor in epithelium
cells become invasive and enter capillary
adhere to blood vessel wall in liver
escape from blood vessel to form micrometastasis
colonize liver, forming full-blown metastasis
The surrounding network of connective tissue that supposes the tumor is called
stroma
Cancer critical genes- Gain-of-Function and Loss-of Function Cancer Mutations Oncogenes and Tumor Suppressor
gain of function - overactivity mutation - in a normal cell, a single mutation event creates oncogene. Activating mutation will enable oncogene to promote cell transformation, which then allows cells to be en route to cancer
loss of function - underactivity mutation - in a normal cell, a mutation event inactivates tumor suppressor gene. There will be no effect of mutation in one gene copy. but then a second mutation event inactivates second gene copy. these two inactivating mutations functionally eliminate the tumor suppressor gene promoting cell transformation, and the cells will be on route to cancer.
Model for how the Src-oncogene became a part of a retrovirus
alv vision will undergo infection, reverse transcription, making dsdna provirus, and this will lead to integration next to c-src (on host cell chromosomal dna), which leads to co-transcription of viral and c-src sequence, which then is packed into a capsid, making a RSV vision carrying src sequences.
Cellular Src (c-Src) - proto-oncogene (tyrosine kinase important for cell growth and division)
Viral Src (v-Src-is mutated)- oncogene
Model for how the Src-oncogene became a part of a retrovirus
alv vision will undergo infection, reverse transcription, making dsdna provirus, and this will lead to integration next to c-src (on host cell chromosomal dna), which leads to co-transcription of viral and c-src sequence, which then is packed into a capsid, making a RSV vision carrying src sequences.
Cellular Src (c-Src) - proto-oncogene (tyrosine kinase important for cell growth and division)
Viral Src (v-Src-is mutated)- oncogene
Retroviruses do play a role in most human cancers, but study of retroviruses was very important in
leading to the identification of oncogenes. Several oncogenes were then identified in the human
genome that did not
come from viruses.
Retroviruses do play a role in most human cancers, but study of retroviruses was very important in
leading to the identification of oncogenes. Several oncogenes were then identified in the human
genome that did not
come from viruses.
Ras becomes oncogenic by activating mutations
Ras activating mutations inhibit its GTPase activity keeping Ras always bound to GTP and therefore it stays always in an “ON” state.
Ras mutations are observed in more than 30% of human cancers. Most other cancers have mutations in other downstream effectors of Ras or show hyperactive Ras signaling.
The three Ras isoforms (H-Ras, K-Ras, N-Ras) are mutated in many cancers.
Proto-oncogene to oncogene activation
1) deletion or point mutation in coding sequence
2) regulatory mutation
3) gene amplification
4) chromosome rearrangement or
5) chromosome rearrangement
1) hyperactive protein made in normal amount
2) normal protein greatly overproduced
3) normal protein greatly overproduced
4) nearby regulatory DNA sequence causes normal protein to be over produced
5) Fusion to actively transcribed gene produces hyper active fusion, protein
Genes Mutated in Cancer Can Be Made Overactive in Many Ways
binding of growth factor triggers intracellular signaling. truncated receptor triggers intracellular signaling in absence of growth factor
Myc overproduction caused by chromosomal translocation in Burkett’s Lymphoma
located on 14q+
Mitogens stimulate Cell Proliferation by
Inhibiting the Rb Protein
Genetic Mechanisms that Inactivate Tumor Suppressor Genes (eliminating Rb)
1) nondisjunction causes chromosome loss
2) chromosome loss then chromosome duplication
3) mitotic recombination event
4) gene conversion during mitotic recombination
5) deletion
6) Point mutation
can Inhibition of Rb activity by mutation in just one allele be sufficient to cause retinoblastoma.
no
Sequencing of cancer genomes identifies distinct types of sequence changes in oncogenes compared to tumor suppressors
a lot more truncating mutations on tumor suppressor genes
more missense genes on oncogene
Many mutations in tumor cells are merely
passengers as opposed to drivers
prevalence of aneuploidy among different tumor types
For each tumor type, the total number of chromosome arms detected is plotted on the X axis. The number of chromosome arms in a normal karyotype is indicated.
Genome doubling status is also shown (black, not double; blue, one genome doubling; red, two or more genome doublings). Genome doubling is where entire sets of chromosomes are doubled or quadrupled.
Note that samples from some tumor types predominantly possess a normal karyotype, while samples from other tumor types display extreme heterogeneity with a dramatic increase in chromosome arm numbers because of extensive aneuploidy.
Both epigenetic and genetic mechanisms can contribute to
cancer evolution
Epigenetic Mechanisms Can Inactivate Tumor Suppressor Genes
DNA methylation can tag dna and activate or repress genes
Some genes are important for normal growth but they can have gain-of- function mutations that make them cancer drivers. These genes before they gain such mutations are called………….
proto-oncogene
Three major cellular pathways that contribute to tumorigenesis
1) cell cycle - rb cell cycle entry
2) cell survival - p53 tolerance to stress and dna damage
3) cell proliferation - ras signaling cascade that drives cell growth
Mutations Drive Cancer Cells to Grow
mitogen goes into receptor, causing the activation needed to drive to cell cycle, then the growth factor goes into its receptor and causes the activation needed for nutrient uptake and utilization, and both of these causes cell growth and proliferation
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells to Grow
growth factor required for nutrient uptake and utilization goes into its receptor and causes the activated receptor tyrosine kinase to signal, and then activation of P1-3 kinase, which leads to activated AKT which leads to active Mtor which binds with glucose transporter and causes increased glucose transport. Glucose then continues to be affected by mTOR, causing increase glycolysis, causing increased pyruvate which goes into the TCA cycle, causing excess citrate exported to cytosol. This is then activated by active ATP citrate lyase, which is activated by AKT, then leads to acetyl COA, causing lipid synthesis and membrane biosynthesis required for cell growth
PI3K/Akt/mTOR Pathway - PTEN tumor suppressor
PTEN (phosphatase) dephosphorylates PI(3,4,5)P3 –phosphatidylinositol 3,4,5- triphosphate and turns it off. PTEN is lost in many cancers.
Mutations in the p53 Pathway Enable Cancer Cells to
Survive and Proliferate Despite Stress and DNA Damage
Which if the following leads to hyperactivation of PI3K signaling?
Loss of expression of PTEN.
Cancers Become More and More ___ as They Progress
Heterogeneous
Colon of Familial Adenomatous Polyposis Coli (FAP) patient
Caused by inactivation of Adenomatous Polyposis Coli (APC gene). It inhibits a pathway called Wnt signaling by degrading a transcription regulator called beta-Catenin. And absence of APC leads to excessive beta-catenin and uncontrolled proliferation.
(Hereditary and non-hereditary)
apc mutations can lead to
intestinal polyps
The Steps of Tumor Progression Can Often Be Correlated with Specific Mutations
Hereditary NonPolyposis Colorectal Cancer- HNPCC – some caused by mutations in DNA-mismatch repair system
Epidemiology Reveals That Many Cases of Cancer Are Preventable
Cancer incidence is related to environmental
influences
Random DNA Copying ‘Mistakes’ aka Bad Luck are another factor contributing to cancer
When it comes to cancer-causing mutations, a new paper argues that most arise from random cell
divisions, with the environment second and inherited mutations a distant third, according to this chart
based on cancers in British women.
Fifty Percent of Cancers Could Be Prevented by
Changes in Lifestyle
