BIO 302 - Final Exam - Study Guide Flashcards
HELP HINT: study the “Take Home Messages” at the ends of each lecture slide set.
Study Guide - Exam 1
Cancer: The Big Picture
What is the most common class of malignant neoplasms in human beings?
Carcinomas.
Cancer: The Big Picture
What is the type of carcinoma that has the highest incidence in men? In women?
Prostate, lung, and colorectal cancer occur the most in males, while breast, lung, and colorectal cancer are predominant in females in the United States.
Cancer: The Big Picture
What are the top 3 most common cancer killers in the USA? What is the most common cancer killer in the world?
Lung (Including Bronchus)
Breast
Prostate
Colon and Rectal (Combined)
Lung (Including Bronchus)
Cancer: The Big Picture
Is the cancer death rate in the USA going up or down? Why? What about the total number of cancer deaths?
Statistics show decreases in death rates for some cancers
beginning in 1992 (lung, breast, colon, prostate).
* American Cancer Society (ACS) reports that from 1991-2018 cancer death rates fell 31% .
* But the total number of cancer deaths continues to rise!!!!!
* Nevertheless, due to death rate declines, a record 18.1 million cancer survivors in the USA in January 2022 (NCI).
Cancer: The Big Picture
What is the single most common risk factor for cancer (across all cancer types)?
Age.
Cancer as Biological Entity
What is the root cause of cancer? How does cancer begin?
Cancer evolution = mutation + selection
* Mutated cancer cells acquire ‘fitness” with respect to competition, adaptation and survival within the body’s biological environment.
Cancer as Biological Entity
What’s a mutation? Name 4 different types of mutation in DNA.
A mutation is a permanent change in the nucleotide sequence of DNA. Mutations can be of many types, such as substitution, deletion, insertion, and translocation.
Mutation may change form and/or function if it produces a mutated protein.
A mutated protein may:
* Change the functional characteristics of the protein
* Change the functioning of the cell pathway in which the protein acts
* Changes the functioning or behavior of the cell as a result
* A mutated regulatory protein (protein from a gene that controls the degree
of expression of other genes) may:
* Change the amount or function of regulatory RNA or normal protein made.
* Change the functioning or behavior of the cell as a result.
Substitution of one base for another with no change in the total number of nucleotides
The addition (insertion) of a single nucleotide
The addition of a nucleotide sequence
The deletion of a nucleotide
The deletion of nucleotide sequence
The rearrangement of entire segments of chromosomes (translocations)
Cancer as Biological Entity
What factors cause mutations inside cells? Outside cells?
Mutation-production may result from dynamics or agents that are either internal or external to the body:
Internal – intrinsic to the normal organism:
* Replication error
* Damage from inflammation
* Inherited mutations
External to the normal organism:
* Radiation
* Infectious agents
* Smoking
* Exposure to mutagens (agents capable of causing mutation)
The key to normalcy is MUTATION CONTROL: repairing mutations or preventing mutated cells from replicating.
What is a “single nucleotide polymorphism” (SNP)
A “single nucleotide polymorphism” (SNP) is a kind of mutation that is considered to be in the realm of normal human variation.
* A “SNP” (as compared to an analogous change called a “mutation”) is defined by convention according to frequency:
* SNP - found in >1% of the population
* Mutation – found in <1% of the population
Cancer as Biological Entity
Are all mutations cancer-causing? What conditions must exist for a mutation to “initiate” a cancer?
Cancer cells exhibit a loss of proliferation control
* Sustained proliferative signaling
* Evasion of growth suppression
Cancer as Biological Entity
Autocrine, Paracrine & Endcrine stimulation.
Autocrine stimulation: when the cytokine producing cell has the receptor for its own cell product on its surface.
Paracrine activation: the cytokine producing cell puts out the chemical in the environment of a nearby cell (diffusion). The other cell with a receptor will pick up the signal.
Endocrine stimulation: Thyroid creates a cytokine that stimulates a cell far away. The cytokine must get into the circulation and must be carried there to the distant cell that has the receptor.
All these processes are proto-oncogenes.
Cancer as Biological Entity
What are the 3 key characteristics/capabilities all cancers have in common and represent aberrations of normal cell capabilities that allow cancer cells to out-compete normal cells and tissues?? With which “hallmarks of cancer” do these correspond?
Cancer cells:
* Utilize normal biological mechanisms in abnormal ways
* Flip biological switches inappropriately
* Activate or de-activate normal cell behaviors in inappropriate ways
* Ignore or bypass normal control mechanisms
* Cancers do not invent NEW biology, they draw on and distort normal
biological capabilities.
Cancer as Biological Entity
What is the characteristic of cancer that causes most cancer death (i.e., what cancer characteristic is most lethal for cancer patients?)
Only malignant tumors are properly referred to as cancers, and it is their ability to invade and metastasize that makes cancer so dangerous.
Cancer as Biological Entity
What is the feature of cancer that poses the biggest challenge to effective treatment and is the underlying reason for most of our treatment failures in cancer? (Hint: it is a consequence of tumor progression and repeated sub clone formation.)
Tumor Heterogeneity and acquired chemo-resistance.
Cancer as Biological Entity
What is meant by “differentiation”? Why is differentiation or that lack of differentiation important in cancer biology, having implications for the cancer patient?
In cancer, this describes how much or how little tumor tissue looks like the normal tissue it came from. Well-differentiated cancer cells look more like normal cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells.
Cancer as Biological Entity
What’s a “driver gene”?
Mutations in genes that contribute to the phenotype (observable behavioral characteristics) of cancer are called driver genes.
Mutations that do not contribute to the cancer cell behavioral characteristics (biologically neutral) are called passenger mutations.
Cancer as Biological Entity
What class of driver genes is the cause of all inherited cancer syndromes (like the one Angelina Jolie has)?
Nuclear tumor suppressor genes: BRCA1 and BRCA-2 DNA repair genes
Cancer as Biological Entity
What are oncogenes and tumor suppressor genes?
○ What do they do?
What happens when they are mutated? What are the consequences?
○ What steps are required to cause a functional change (gain of function) in an oncogene?
○ What steps are required to cause a functional change (loss of function) in a suppressor gene?
○ Can driver genes be “drugged” (treated by targeted therapy?) How?
The two classes have opposing function in normal cells. When they lose their control of function, it leads to havoc: Oncogenes and Tumor Suppressor Genes. These are mutations of your own genome that control cell division.
Oncogenes are mutated versions of genes in your stem cells called protooncogenes that control cell division. When an oncogene is mutated, it is a dominant mutation. A mutation in one allele (of 2), it becomes dominant, and that gene is off to the races. It will always be one.
Tumor suppressor genes control mutations, find and fix mutations. If they cannot fix them, its repair or die. Tumor suppressor genes, when mutated, if you mutate one (of 2) nothing happens. Its recessive. For a tumor suppressor gene to lose its function, something must happen to the opposite allele (another mutation or loss of DNA (deletion)). You allow that mutated allele to be expressed, and when it is, the gene loses its function. It can no longer control repair and die.
Oncogenes are a gain of mutation and tumor suppressor genes are a loss of contra mutation. You end up with genetic instability and different variants. All have different genomes that have been unrepaired.
Cancer as Biological Entity
What is the cell cycle? What are cell cycle checkpoints? Why are they important? What happens at checkpoints in cancer cells?
Cancer cells lose cell cycle checkpoint control
* Checkpoint control proteins prevent the cell cycle
from preceding when one of the following problems
is present:
DNA has been damaged and needs repair
or
Spindle assembly is incorrect and cannot support
normal chromosome attachment and segregation
* Checkpoint control Involves tumor suppressor
genes, including p53
* Cancer cells continually and inappropriately
enter and proceed through the cell cycle, by-
passing normal checkpoint controls.
Cancer as Biological Entity
What happens during cancer initiation, promotion, and progression?
○ Which of these steps involve mutation?
○ Which of these can be prevented?
“Initiators” (mutation-causing factors) cause mutation in a stem cell.
“Promoters” cause clonal expansion (proliferation) of initiated (mutated) cells.
“Progressors” cause additional mutations that confer additional growth-aggression advantages on expanding clones.
Cancer as Biological Entity
Describe the changes in form and function that occur during tumor progression that allow neoplastic cells to be identified under the microscope?
○ What is dysplasia?
○ What is carcinoma in situ?
○ What is invasive carcinoma?
○ What is metastatic carcinoma?
What is dysplasia? As genetic alterations accumulate, cells begin to look different from their normal counterparts
What is carcinoma in situ? Carcinoma in situ: cancer that has not gone through the basement membrane.
What is invasive carcinoma? Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer.
What is metastatic carcinoma? cancer that has spread (metastasized) from the original site to another part of the body.
Cancer as Biological Entity
What are the multiple capabilities that cancer cells acquire (or rather, selectively reactivate from the repertoire of abilities of normal cells) to metastasize successfully – the capabilities of the decathlon phenotype?
ability to locally invade cells,
ability for intravasation into blood vessels,
ability to survive in circulation under different blood pressures,
ability to exit from blood vessels,
ability to be mobile,
ability to break basement membranes using proteases/enzymes
loss of organization of epithelial cell layers
altered cell-cell adhesion
loss of basal membrane attachment
Cancer as Biological Entity
What are the two major phenotypic changes that they undergo in the process of metastasizing? (Hint: these are the premier examples of cancer cell plasticity.)
Metastatic tumors (metastases) can occur in three ways: They can grow directly into the tissue surrounding the tumor. Cancer cells can travel through your bloodstream to distant locations in your body. Cancer cells can travel through your lymph system to nearby or distant lymph nodes
Hallmarks of Cancer
What are the “hallmarks” of cancer exactly?? How do they provide cancer cells competitive advantages over normal cells? Does every cell in a cancer exhibit all of the hallmarks?
Hallmarks of Cancer
Describe the key basic mechanisms that contribute to each of these hallmarks:
○ Sustaining proliferative signaling
○ Evading growth suppression*
○ Genomic instability and mutation*
■ These two are both related to tumor suppressor gene loss
of function – how are they related?
○ Resistance to cell death
○ Limitless replicative potential
○ Induction of new blood supply (angiogenesis)
○ Deregulation of cellular energetics (metabolism)
○ Ability to invade and metastasize
○ Ability to evade immune system
■ Describe 5 ways that cancer cells avoid immune attack.
■ Can any of these be reversed or “drugged”?
■ What are the consequences of therapeutically
manipulating the interactions between cancer cells and
immune cells to increase the probability of effective
immune attack?
Hallmarks of Cancer
Why are these hallmarks advantageous to the cancer? How do they help cancer cells out-compete normal cells?
BOTTOM LINE: Can you explain the step-wise process of cancer formation from the point of view of:
o Molecular changes?
o Changes in cell appearance and tissue architecture?
o Changes in cell behavior?
Study Guide - Exam 2
Cancer as an Evolutionary System
Describe cancer as an evolutionary system and the necessary and sufficient requirements for evolution that cancers possess: i.e., variation in the population; variation is heritable; variation affects reproduction and survival!
-Mutated cancer cells acquire ‘fitness” with respect to competition, adaptation and survival within the body’s biological environment.
-Mutation-production may result from dynamics or agents that are either internal or external to the body
-Internal - intrinsic to the normal organism:
*Replication error
*Damage from inflammation
*Inherited mutations
-External to the normal organism:
*Radiation
*Infectious agents
*Smoking
*Exposure to mutagens (agents capable of causing mutation)
Variation in the population Variation is heritable
Variation affects reproduction and survival
Cancer as an Evolutionary System
What is meant by “cheating” on multicellular cooperation?
Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system.
Cancer as an Evolutionary System
What is Peto’s Paradox?
Peto’s paradox is the observation that, at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism.[1] For example, the incidence of cancer in humans is much higher than the incidence of cancer in whales,[2] despite whales having more cells than humans. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans.
Cancer as an Evolutionary System
What approaches to therapy can take advantage of evolutionary principles?
Treat cancer by predicting where it’s going to evolve, or use therapy in a way that it doesn’t kill all the sensitive cells, but controls the growth of the cancer (adaptive therapy).
Cancer as an Evolutionary System
What are the essential features of Darwinian evolution and how do they apply to cancer? How does this explain why cancers, as they develop, acquire greater and greater survival advantages over normal cells?
- Variation (lots of different clones with different sets of mutations -some unique to each individual clone).
- “Fitness” for survival in particular conditions or environments (like in the presence of a given therapeutic drug) conferred by different genetic traits of different clones.
- Selection of the fittest clones as conditions change.
- Adaptation to a new set of environmental conditions given the wide variety of capabilities in different clones to draw on and the survival of fit clones in the presence of selection pressures/
- Evolvability meaning that the genomic features that confer “fitness” are heritable and passed down to daughter clones allowing the entire population of cells (that is, cancer are an “organism”; cancer as “the beast”) to evolve and change over time and with shifting environmental challenges.
Who Gets Cancer and Why
What kinds of factors alter the incidence rates of cancer?
Who Gets Cancer and Why
What proportion of cancer is preventable?
Cancer is preventable 50-90% of the time.
Who Gets Cancer and Why
What is a cancer risk factor?
Who Gets Cancer and Why
Do all cancer risk factors cause mutations?
No.
Who Gets Cancer and Why
What is relative risk?
A measure of the risk of a certain event happening in one group compared to the risk of the same event happening in another group.
0.5 - risk 50% lower than average
1.0 - average
1.5 - risk 50% higher than average
10 - 10 times higher than average relative risk
Who Gets Cancer and Why
Name 3 risk factors for cancer that cannot be altered.
Age
Genetics
Gender
Ethnicity
Inherited mutations
Inherited immunodeficiency
Defect in detecting/destroying abnormal, mutated cells
Defect in destroying cancer-causing infectious agents
Family history
Personal history
World region
Who Gets Cancer and Why
Name 3 risk factors for cancer that can be altered.
Chronic inflammation
Viral infections
Bacterial infection
Dietary deficiencies
Diabetes
Hormonal status
Who Gets Cancer and Why
What is the single most common cause of cancer in the USA??
90–95% - environmental factors
5–10% - genetics
Tobacco as a single cause (25–30%)
Diet andobesity as a category (30–35%)
Infections (15–20%)
Radiation (both ionizing and non-ionizing, up to 10%)
Environmental pollutants
Who Gets Cancer and Why
Do we know the cause of all major cancers at this point?
Cancer is caused by a permanent alteration (mutation) of normal nucleotide sequences in the genes of normal cells. A cancer-initiating mutation occurs in a driver gene in an adult stem cell, a cell capable of undergoing mitosis and expanding the number of cells carrying that mutation.
All mutagens are carcinogens, but not all carcinogens are mutagens. Some carcinogens lack a direct effect on DNA but create or promote conditions under which DNA mutation may occur or be propagated.
Hormones are non-mutagenic carcinogens. They act a promoters that increase cell division.
Who Gets Cancer and Why
Which factors increase risk for more than one cancer?
Who Gets Cancer and Why
What are the most important behaviors that affect cancer risk??
(1) the susceptibility of the individual (e.g., genetic background that might increase the risk of acquiring mutations).
(2) the mode of exposure
(3) the duration and/or degree of exposure
Who Gets Cancer and Why
Why is smoking a risk factor for multiple cancers?
Poisons in tobacco smoke can damage or change a cell’s DNA. DNA is the cell’s “instruction manual” that controls a cell’s normal growth and function. When DNA is damaged, a cell can begin growing out of control and create a cancer tumor.
Who Gets Cancer and Why
Why is obesity a risk factor for multiple cancers?
Obesity is associated with substantial metabolic and endocrine abnormalities:
(1) Excess production of estrogen by fat cells
(2) Increased levels of insulin and insulin-like growth factor
(3) Fat cell production of adipokines (cytokines) that stimulate cell growth, decrease apoptosis and increase inflammation (Inflammation increases production of mutation-inducing ROS).
(4) Oxidative stress (an imbalance between reactive oxygen species [free radicals] and anti-oxidants) tilts into reactive oxygen species dominating and inability to suppress them is oxidative stress.
(5) Chronic inflammation
Who Gets Cancer and Why
Why is alcohol a risk factor for multiple cancers?
Alcohol causes different types of cancers:
Mouth & upper throat
Esophagus
Larynx
Breast
Colon
Rectum
Liver
(1) EtOH is converted to acetaldehyde in the body (mainly by the liver).
- Acetaldehyde (which also causes hangovers) causes DNA damage and blocks normal DNA repair.
- Acetaldehyde stimulates liver cell division (mitosis & ability to acquire mutations.
(2) EtOH increases estrogen production and estrogen stimulates cell division in susceptible cells (those with estrogen receptors).
(3) EtOH causes cirrhosis (via chronic inflammation); cirrhosis is a risk factor for hepatocellular carcinoma
Cirrhosis is a type of liver damage where healthy cells are replaced by scar tissue. Common causes include excessive drinking of alcohol, hepatitis B and C virus infections, and fatty liver that’s caused by obesity and diabetes.
(4) EtOH increases absorption of carcinogenic chemicals from tobacco.
(5) EtOH depletes folate (needed for normal production of DNA and RNA).
(6) EtOH increases production of Reactive Oxygen Species (ROS) that directly cause DNA damage.
