Cancer Biology Part 1 Flashcards
Hyperplasia
deregulated proliferation of cells, but when they assemble onto tissue, it looks pretty normal when you look at it under a microscope
Tumors
Get separated into two broad categories; benign and malignant
Benign Tumor
local growth that does not invade adjacent tissues; non invasive
also has a regular nuclear shape, and a well defined tumor boundary (still the same shape as normal cells, slightly diff color)
Benign Tumor Impact
Can have thyroid adenomas, can cause excess amount of thyroid production and pituitary adenomas, that release growth hormones, but still not a death sentence so benign tumors, even if they provide pressure for certain regions, aren’t life threatening themselves
Malignant Tumors
growth of cells that has escaped the home tissue by breaking away from the basal lamina, this comes with the possibility of it migrating elsewhere
looks like a deep red, and shifted in terms of boundaries (irregular shape of both nuclei (the dot) and the cell shape- looks jagged)
metastases
spreading of a tumor
difference btwn benign and malignant tumor
both benign and malignant tumors have deregulated proliferation, but the benign tumors stays in one place and malignant breaks the basal lamina and travels via blood stream or lymphatic vessels
primary tumor
Initial site where cancer cells start off; not responsible for death associated with cancer
How do cancer cells move once they break through basal lamina and become malignant?
Through circulatory system or lymphatic vessels; very few cells survive (1 in 1000), but since there are so many cells, number of cells surviving are increased
Extravasation
Cancer cell in circulatory system attach to blood vessel/micro vessel in another organ, which causes a pause in it’s traveling
the cancer cells enter the organ and form a micrometastasis
micrometastasis
small area of cancer cells within the organ- this is a new site as cancer cells moved from primary tumor
colonization
the spread of cancer cells; proliferation
macrometastases
full blown metastasis in new organ
metastasis are responsible for death, not primary tumor
breast cancer
primary tumor in mammory gland, can have removed if benign and no problem, but if it becomes metastatic breast cancer and moves = no good
why is metastatic cancer, like breast cancer so dangerous/lethal?
if it is not metastatic, the mammory gland can be removed as it is not essential and that is where the primary tumor is. If it is metastatic and go to places such as the lungs, brain, kidney, bones, etc, these are essential organs that cannot be digged up or removed in the same way as mammory gland without chances of impacting quality of life as those organs are essential. Also the cancer itself impacting those essential organs is bad. ex: cancer in bone = to bone erosion
angiogenesis
creating blood vessels
hypoxic
lack of oxygen; cancer cells go through aerobic respiration as they proliferate (to have energy), so their environment becomes hypoxic
how do blood vessels help cancer cells with their lack of oxygen
blood vessels have erythrocytes, and erythrocytes are responsible for gas exchange; meaning the correlation btwn access oxygen and access to blood (through blood get the O2 they need for aerobic respiration)
how angiogenesis occurs (the growth of blood vessels for cancer cells)
two factors that promote growth of blood vessels; only gonna talk about one; VEGF
What is VEGF
growth factor; protein that when secreted can act on nearby endothelial cells (blood vessels), and stimulate digestion of their basal lamina
this results in little sprouts/extensions to start to work their way through the cancer cells
Characteristics of new blood vessels
the sprouts formed are fragile and permeable; but this is beneficial to tumor cells bc it makes it more effective to go through circulation
Is angiogenesis required for a cancer cell to be invasive?
NO! Angiogenesis only happens based on the need of the cancer cell; proliferating to much, need more oxygen; if the tumors are already proximal to blood vessels, they don’t depend on production of additional spouting to achieve additional movement through a vessel
importance of blood vessels
although angiogensis isn’t required for invasion, having blood vessels in general, whether through angiogeneis or priximity is essential to tumor growth
why are blood vessels important for cancer cells?
blood vessels help serve two roles:
1. help provide the nutrients necessary, oxygen, to go through anaerobic respiration and grow
2. cancer cells go through circulation to metastases in other parts of the body
so the tumor at the localized section of body grows as well as allows it to go through circulation to grow in other parts of body
Angiogenic Protein- VEGF
VEGF is secreted by cancer cells to bind to extracellular receptors that are found on surface of endothelial cells; this leads to signal transduction pathway which impacts genes in cell; downstream effect= secretion of MMPS; MMPs are protease’s that degrade basal lamina of parent capillary, and produce sprouts; those sprouts are able to reach cancer cells and help nutrient them to help them grow (provide oxygen) and travel to diff parts of the body via circulation
what triggers VEGF to be secreted by cancer cells
when there is a low concentration of oxygen, hypoxic conditions, this will lead to low concentration of HIF1α; HIF1α gene influences production of VEGF protein by stimulating VEGF gene to make VEGF protein
Cancer cells changing balance
cancer cells increasing pro angiogenic factors (growth of blood vessels), like VEGF AND ALSO decreasing angiogenesis inhibitors; example of how cancer cells manipulate signal transduction pathway to their benefit
Metaphase Plate
Shows an image of all the chromosomes; a tumor cell’s imaging looks diff from a normal cell
how do cancer cells and normal cells look diff on the metaphase plate in terms of their chromosomes
cancer cells are aneuploidy (irregular amount of chromosomes), could be in the presence of additional chromosomes or the loss of chromosomes; can also be translocation, where a segment breaking off of one chromosomal arm and fusing to another chromosome
these all result in instability
How else can you see that cancer cells are unstable
it is shown through the origin of the same cancer in diff patients; patients will have the same cancer and yet display diff symptoms and have diff journey’s
Cancer is a multistep process consisting of three steps…
- initiation
- promotion
- tumor progression
Initiation
conversion to a precancerous state bc of a mutation; makes the cell more sensitized to other mutations
Promotion
already sensitized cell has another mutation; goes to cell proliferation
Tumor progression
tumor grows and differentiations; continued changes (mutations), where we reach a point of the purple cells seen in the image
Thinking of a cell as a microevolutionary process
thinking of selection and amplification, and also natural selection
Getting cancer isn’t easy to get
needs round of mutations, proliferation, to progress to tumor progression; also depends on what type of mutations and on what genes, and what those genes do; not just any gene that has mutations turn into cancer; very complex process
Cancer Critical Genes
Two cancer critical genes:
- oncogenes
- abnormal tumor suppressor genes
Oncogenes
Proto-oncogenes; that are responsible for normal cell division, differentiation, and cell growth, when there are mutations turn into oncogenes that lead to cancerous cells
Abnormal Tumor suppressor gene (talked about again in slide 48; 40-47 is about different ways for proto-oncogene to be overactive- turn into oncogene)
tumor suppressor genes, normally found in cell, go through mutations and lead to cancerous cells
Cancer critical gene: proto-oncogene zoom in
there is a gain of function mutation, known as overactivity, that turns proto-oncogene into oncogene
A mutation of one of the copies in a diploid cell (as it has two) is enough to cause the change from proto-oncogene to oncogene, meaning it has a dominant effect
How do we get an overactive gene? (other than with gain of function mutation)
we get an overactive gene through a point mutation
what are the two diff point mutations that can happen?
point mutation within coding sequence and point mutation within regulatory region
point mutation in coding sequence
have a hyperactive protein, which means we have a protein that is made in normal amounts, but that protein itself has active behavior
An example of this is Ras as when there’s a point mutation in the coding sequence of the amino acid- so from gylosine to valosine, this results in the protein Ras to be overactive. This turns the proto-oncogene Ras into oncogene. It never shuts off which means there is overproduction of Cyclin and CDK, leading to MPF activity always being on, which allows cells to bypass checkpoints and continue to proliferate, which is how the oncogene aras leads to cancer because of the point mutation that turned it into an oncogene.
point mutation in regulatory region
regulatory region, upstream of where you are trying to transcribe and translate, a point mutation there will lead to overproduced amount of normal protein; excess genes results in all of those genes being transcribed and then translated; as a result we have normal proteins but excess amount of it
How do we get an overactive protein- with chromosomal translocation
with chromosomal translocation, this is chromosome rearrangement
two options:
1) abnormal hyperactive protein; DNA breaks off and rejoins; forms a fusion protein, and may fuse in such a way that it creates an abnormal hyperactive protein
2. normal in abundance; could change certain regulatory regions and in doing so lead to normal proteins being overproduced
either of these can happen with chromosomal translocation
How do we get an overactive gene: local DNA rearrangements
local DNA rearrangements would be changes within the base sequences of the proto-oncogenes
these changes could be:
- insertions
- deletions
- inversion (removal of sequence followed by reinsertion in the opposite direction)
- transposition
How do we get an overactive gene- insertional mutagenesis
Insertional mutagenesis is when retroviruses incorporate their viral DNA into host DNA; insert it close to the proto-oncogene in order to integrate their viral DNA and as a result convert the host cell from a proto-oncogene to an oncogene; a chance mutation; can lead to excess normal protein
Another cancer critical gene: tumor suppressor gene
this is a loss of function gene (as apposed to a gain of function gene like oncogene), and is recessive, meaning both gene copies in diploid cell have to have been inactivated via mutation, so two mutations for tumor suppressor gene to be inactivated. if only one mutation occurs and one gene copy is inactivated, don’t see negative impact as the other copy compensates; only when another mutation occurs and both copies are inactivated that it cannot do it’s role
what do tumor suppressor genes do
trying to inhibit any inappropriate response and provides some level of regulation that prevents the idea of cell transformation (cancer cells to occur)
gain of function versus loss of function
proto-oncogene has overactivity when it turns into oncogene, and is gain of function as it is doing something more advanced than normal cell is doing. tumor suppressor genes are loss of function genes as they lose their function, but are recessive and need both copies to be inactivated to see an impact of not having tumor suppressor gene.
How to lose a copy of tumor suppressor
nondisjunction events; inappropriate segregation of chromosomes can lead to aneuploidy; lost out of normal copy so all we have is one mutated one out of the two
chromosome loss followed by chromosome duplication: maintained our ploidy, but both copes harboring the mutation of Rb gene
mitotic recombination event/ gene conversation during mitotic recombination: during mitosis, recombination and exchange of info that led us to gain mutated Rb
deletion: removal portion of normal copy in normal chromosome
point mutation:
inactivation of that particular gene in normal copy
