Cancer Biology Part 1

What are the six properties that usually contribute to cancerous growth?

1. Cancer cells go through the cell cycle when they shouldn’t

2. Cancer cells utilize metabolism in a diff. way then most normal cells

3. Cancer cells evade cell senescence through production of telomerase or by an alternative mechanism (gives cell unlimited lifespan)

4. Cancer cells become invasive and are capable of metastasizing

5. Cancer cells have abnormal stress responses

6. Cancer cells are genetically unstable

When do cells usually stop dividing? How do cancer cells differ?

cells stop dividing when nutrients are scarce. Cancer cells divide in very harsh environments where nutrients are scarce. They found a way to circumvent checkpoints.

What does it mean for cancer cells to metastasize?

they leave their home organ or tissue and go somewhere else. Spread to other sites in the body

How do normal and cancer cells differ under stress?

normal cells are lethargic and don’t function well. Cancer cells can circumvent this.

What does it mean for cancer cells to be genetically unstable?

they continue to make mutations

What does the cell cycle monitor?

ensures that a cell is in a proper state and is able to divide through checkpoints

What are the cell cycle checkpoints?

G1, S , G2 , M

G1

checking on cell size, cell environment, nutrients that are available to cell. Making sure cell is growing sufficient enough

S

synthesis: DNA is getting replicated, organs replicated (sometimes in G1 and G2). checkpoint is making sure replication happened correctly and there are no mutations within DNA.

G2

makes sure DNA is replicated correctly. Similar to G1: checking environment, checking cell size, checking organelles

M

Metaphase: chromosomes lined up in the middle. Spindle fibers at each pole that will come and attach to each chromosome. As they attach, you want to make sure they are attaching to the opposite ends at the chromosomes (one fiber attaches to one chromatid while the other fiber attaches to the other chromatis). if not, the chromosomes are not split evenly and the cells have an uneven amount of chromosomes.

What happens if a cell has issues during the cell cycle, such as DNA damage?

cell either kills itself (apoptosis) or tries to repair itself

What proteins do cells have which help to determine is a cell passes a checkpoint or not?

cyclin and cyclin dependant kinase (CDK)

how present is CDK and how does it function (briefly)?

Always present within the cell, but doesn’t function without cyclin.

when is cyclin present?

only if a cell is able to pass the checkpoint, causing cyclin levels to go up

MPF

(maturation promoting factor): complex that is formed when CDK binds to cyclin

What does MPF allow for?

for a cell to get past a checkpoint

what is cyclin like throughout checkpoints?

cyclin is different depending on the checkpoint

What happens when a cancer cell tends to avoid apoptosis?

cell death often happens on a mass scale due to difficult living conditions and competition amongst cancer cells for oxygen and nutrients

What type of cell death do cancer cells/tumors have rather than apoptosis?

necrosis

homeostasis

normal cell division and normal apoptosis
(start and end with same number of cells)

tumor

increased cell division and normal apoptosis
OR
normal cell division, decreased apoptosis

what does the “hallmarks of cancer cells” mean?

properties of cancer cells

How do normal cells behave in regards to anchoring and cell density?

normal cells anchor themselves to the extracellular matrix through cell surface proteins. if something prevents that from happening (such as too many cells), the cells initiate an apoptotic pathway.
Normal cells stop dividing when a monolayer is formed. Cells die off if you get multiple layers → apoptosis until monolayer

How do cancer cells behave in regards to anchoring and cell density?

there is reduced sensitivity to density dependent inhibition of growth and they will continue to go through rounds of cell division, resulting in cells piling up on one another

Cancer cells transformation

new type of property or new phenotype → abnormal motility
deviate from contact inhibition, change in morphology

what are anaerobic conditions?

low oxygen (also called hypoxic conditions)

what do normal cells do under anaerobic conditions?

generate pyruvate, which is reduced to lactate

What does lactate do?

inhibit cell growth as much

what do normal cells do under sufficient oxygen conditions?

oxidize to carbon and glucose and generate CO2 as a byproduct

what do tumors do under oxygen sufficient conditions?

A growing tumor needs nutrients in order to make new macromolecules. This makes tumor cells behave similar to that of a growing embryo. They will use glucose at a significantly higher rate. The amount of oxidative phosphorylation used by tumor cells is lower, with priority placed on the production of lactate — a byproduct of fermentation.

warburg effect

a metabolic phenomenon in cancer cells where they use glycolysis for energy production instead of oxidative phosphorylation even in the presence of oxygen

How are both strands of DNA replicated?

leading strand is always going to have a primer and DNA is replicated straight through
lagging strand is replicated through okazaki fragments. each fragment i going to have a primer at the beginning

What happens when the primer is removed?

replace with DNA by DNA polymerase (begin 5’ and add to 3’ end)

What is the end replication problem?

when primer is removed at the end of a chromosome, there is no base for DNA polymerase to come in to replace the primer w/ DNA. There is going to be a gap, which is not safe. So, it is eventually cut off within cells (that are not stem cells) and the telomeres get shorter in normal cells (which is good as it allows cells to die off)

Which strand has the end replication problem?

lagging

How do cancer cells avoid the end replication problem?

they have the enzyme telomerase, which fills the gap and the telomeres wont get shorter with each replication

what causes a cell to become senescence?

as a cell telomere gets shorter, at some point, you cut off a significant gene

relationship of hayflick limit

number of cell divisions is directly related to telomere length

hayflick limit

number of times cell can divide before entering state of senescence

hayflick limit in cancer cells

crisis → genomic instability → telomerase lengthens telomeres and cell never reaches hayflick limit

when is telomerase activated?

during crisis

telomerase

specialized form of reverse transcriptase that carries its own internal RNA template to direct DNA synthesis

what do telomerase do?

fills in overhang with complementary bases to telomeres

where are telomeres seen besides cancer cells?

stem and germ cells. however, not our normal cells

premalignant cells

precancerous cells

two types of tumors

malignant and benign

malignant

tumor can invade nearby tissues(metastasize); look morphologically different from normal cells

benign

tumor is confined to its area; can have regular nuclear shapes and look like normal cells

how to tumor cells enter the bloodstream?

either directly thru blood vessels or by lymphatic vessels

what is metastases correlated with?

increased death rates

initial site

primary tumor, which is responsible for the tumor growth

what happens when normal cells escape into the bloodstream?

they usually die off because they don’t receive signals that they need to survive

angiogenesis

form new blood vessels

cancer cells complex process of metastasizing

HAVE to be able to escape its tissue and HAVE to be able to form blood vessels

what are tumors capable of generating?

new colonies

metastatic tumor

a tumor that has spread from its original site (primary tumor) to other parts of the body

metastatic breast cancer

tumor grows from a single cancer cell

cancer cells invade neighboring tissue

cancer cells spread through lymph and blood vessels to other parts of the body

a small percentage of cancer cells may metastasize to another part of the body

what is one of the greatest hallmarks of cancer?

angiogenesis

why do cancer cells induce angiogenesis?

as cells grow more,they need more nutrients. So,cancer cells need to be able to provide nutrients for itself.

compared to the number of cells, there isn’t enough blood vessels within that area to provide nutrients.

why is the supply of blood vessels important to cancer cells?

as tumor cells proliferate and go through anaerobic respiration, the environment becomes hypoxic (inadequate oxygen supply)

what does angiogenesis secrete?

growth factors, such as VEGF

VEGF

(vascular endothelial growth factor) once secreted, they can act on endothelial cells and stimulate the digestion of the basal lamina so that new extensions can sprout from the vessel

how do the new extensions in blood vessels help the cancer cells?

the new vessels are fragile and have high permeability to allow the cells to become invasive

VEGF in normal cells compared to cancer cells

normal cells don’t have this activated. Blood vessels do. But, cancer cells have figured out a way to activate it within the cell to induce angiogenesis

blood vessels and cells in necrosis

you can see the blood vessels form and the cells in bad shape

how can cancer cells be grown in a lab?

provide nutrients

how is lab cancer different from cancer in the body?

don’t grow as much as they don’t have the ability to generate as many blood vessels as they would in the body

what is the main function of VEGF?

cause increased blood flow

what causes cells to secrete VEGF?

functioning normally and suddenly have low oxygen levels, there is going to be an induction of 1-alpha proteins, which induces the cells within that area to secrete VEGF

What does VEGF activate?

MMP, which will go and break down the extracellular matrix, causing endothelial cells to grow in that direction and start to sprout off and form new blood vessels

tumor instability

huge abnormality of chromosomes

translocation

one chromosome goes and attaches to another

regarding chromosomes, what do cancer cells have a large amount of?

heterochromatin

what does a large amount of heterochromatin effect?

DNA repair pathway

cancer multistep process

initiation → promotion → tumor progression

initiation

conversion to pre-cancer strain, which make cell more sensitive to anything that could cause promotion

promotion

repeated exposure of those sensitized cells to cancer promoting agents

tumor progression

tumor forms and it goes and differentiates

how is cancer evolutionary?

have to have continuous mutations in order for it have all of its capabilities

what are the cancer critical genes?

proto-oncogenes and tumor suppressor genes

what does mutation in proto-oncogenes cause?

oncogenes

what does mutation in tumor suppressor genes cause?

abnormal tumor suppressor genes

what type of mutation does a proto-oncogene need to become oncogene?

overactivity mutation

overactivity mutation

(gain of function) need a mutation in one of the duplicated chromosomes at a specific location for the gene to be activated, causing cell to be overly proliferated

how do you get an overactive gene?

1. point mutation of deletion: if happens at regulatory region

2. gene amplification: mistake in DNA replication, leading to extra gene copies

3. chromosomal translocation: duplex would break and rejoin, changing protein coding region

4. local DNA rearrangements: insertion or deletion or inversion or transposition

5. insertional mutagenesis: new DNA sequences (such as from a virus) integrate into an ogranism’s genome

underactivity mutation

(loss of function) if you have one mutation in the tumor suppressor gene, the other duplicated chromosome can rescue it. So, to eliminate the tumor suppressor gene, both chromosomes need to be mutated

how to lose a copy of a tumor suppressor

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