Carcinogenesis Flashcards
Cancer is a ___ disease
Genetic
Cancer involves the ___ of the cell
Alteration
1/3 of cancer deaths are from modifiable factors such as…
-Tobacco
-Weight
-Alcohol
-Fruit and vegetable intake
-Physical activity
30% of cancer results from cancer-causing infections like…
-HPV
-Hepatitis
The best chance of cure is through what two things?
-Early detection
-Effective treatment
It is estimated that ___ million new cases of cancer will be diagnosed in 2022
1.9
What are the three most prevalent forms of cancer in men?
-Prostate cancer (26%)
-Lung cancer (12%)
-Colon and rectal cancers (8%)
What are the three most prevalent forms of cancer in women?
-Breast (30%)
-Lung (13%)
-Colon and rectal (8%)
What 3 types of cancer cause the most deaths in men?
-Lung (22%)
-Prostate (11%)
-Colon and rectal (9%)
What 3 types of cancer cause the most deaths in women?
-Lung (22%)
-Breast (15%)
-Colon and rectal (8%)
There have been many strides made with some cancers with immunotherapy, but ___ cancer is usually diagnosed late (new tools are being developed to help screen earlier
Lung
Carcinogenesis is also known as…
-Oncogenesis
-Tumorigenesis
Cancer occurs due to the ___ of normal cells
Transformation
The process of carcinogenesis includes changes at a ___, ___, and ___ level and abnormal cell division
Cellular, genetic, and epigenetic
Normally, there is a balance between cell ___ and cell ___ (in the form of apoptosis)
Proliferation and death
According to the prevailing accepted theory of carcinogenesis, the ___ ___ ___, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes of cell proliferation and cell death
Somatic mutation theory
The upset in the balance between cell proliferation and cell death results in ___ cell division and the evolution of those cells by natural selection in the body
Uncontrolled
Only certain ___ lead to cancer whereas the majority of them do not
Mutations
Ancient ___ thought of cancer as a curse
Egyptians
In 3000 BC, Edwin Smith Papyrus discovered ___ cancer
Breast
In 1500 BC, Ebers Papyrus discovered what types of cancer?
-Skin
-Uterus
In the 16th century, ____ discovered the 1st correlation between the environment and cancer
Paracelsus
In 1914, Theodor Boveri was the 1st to hypothesize that segregation of chromosomes to ___ cells leads to tumor development
Dgt
Ancient people used to think that ___ bile cancers were incurable and ___ bile cancers were curable
Black, yellow
___ was the first to use the word “cancer” to describe tumors
Hippocrates
Cancer is derived from the Greek word “karkinos” which means ____
Crab
It is thought that Hippocrates was referring to the appearance of ___, with the main portion of the tumor being the crab’s body and the various extensions of the tumor appearing as the legs and the claws of the crab
Tumor
Cancer is caused by ___ of DNA that lead to cellular damage
Mutations
Mutations enable cancer cells to divide continuously, without the need for normal ____
Signals
In some cancers, the unchecked growth results in a ___ called a tumor
Mass
Cancerous cells may invade other parts of the body, interfering with ___ ___ ___
Normal body function
____ tumor cells grow only locally and cannot spread by invasion or metastasis
Benign
____ tumor cells invade neighboring tissues, enter blood vessels, and metastasize to different sites
Malignant
Progression of carcinogenesis (5 steps):
-Mutation inactivates suppressor gene
-Cells proliferate
-Mutations inactivate DNA repair genes
-Proto-oncogenes mutate to oncogenes
-More mutations, more genetic instability, and metastatic disease
The microenvironment may help the cancer cells grow; ____ increases the blood supply and this feeds the cells so that they are able to continue to grow
Angiogenesis
A ____ mutation is one that exchanges one base for another which would encode a different amino acid and cause a small change in the protein produced
Substitution
___ ___ ___ is caused by a substitution in the beta-hemoglobin gene, which alters a single amino acid in the protein produced
Sickle cell anemia
If there is a change in a codon to one that encodes the same amino acid and causes no change in the protein produced, this is called a ___ ___
Silent mutation
If there is a change in a codon to one that encodes a ____ codon, this would cause an incomplete protein and can have serious effects since the incomplete protein would most likely not function
Stop
____ are mutations in which extra base pairs are inserted into a new place in the DNA
Insertion
____ are mutations in which a section of DNA is lost or deleted
Deletion
In ___ mutations, the DNA is parsed wrong which usually generated proteins that are useless and uninformative (caused by insertions or deletions)
Frameshifts
While many mutations have small effects, mutations to ___ ___ can have major (and sometimes even positive) effects
Control genes
Control genes control other genes, determining when and where other genes are turned ___
On
Mutations in parts of the gene that control other genes can substantially change the way an organism is ____
Built
Mutations to control genes can cause a cascade of effects in the ____ of genes under its control
Behavior
Most mutations have no ___ because they either do not affect the function of the cell, are repaired by DNA repair genes, or are lost as a result of the death of a cell
Consequences
Mutation of genes that control the growth or that protect the stability of the genome may result in a clone of cells with ___ ____
Growth advantage
Successive mutations of these genes result in increasingly different clones until a ___ phenotype eventually emerges
Malignant
What are the two basic kinds of genetic mutations?
-Germline mutation
-Somatic mutation
A germline mutation is responsible for ___% of cancer cases and is heretible
15
Somatic mutations are random mutations from ____ influence
Carcinogenic
____ mutations result in most cancer cases
Random
Only ___-___% of mutations result in cancer
5-10
Since all cells in our body contain DNA, there are lots of places for mutations to occur, however, some mutations cannot be passed on to offspring and do not matter for ___
Evolution
A single germline mutation can have a range of effects, like…
-No change occurring in phenotype
-Small change in phenotype
-Big change occurs in phenotype
Some mutations don’t have any noticeable effect on the phenotype of an organism; this can happen if the mutation occurs in a stretch of DNA with no ___, or the mutation occurs in a protein-coding region but ends up not affecting the amino acid sequence of the protein
Function
Some very important phenotypic changes are caused by a single mutation, like ___ ___ in insects
DDT resistance (pesticide)
Mutations that cause the death of an organism are called ____
Lethals
__ __ ___ are single-nucleotide substitutions of one base for another; they occur in more than one percent of the general population
Single Nucleotide Polymorphisms (SNPs)
SNPs are the most ___ type of genetic variation
Common
Each SNP represents a difference in a single DNA building block, called a ____
Nucleotide
SNPs occur through a person’s DNA about once every ____ nucleotides on average, which means that there are roughly 10 million SNPs in the human genome
300
Most commonly, SNPs are found in the DNA between ____
Genes
SNPs can act as biological markers, helping scientists locate genes that are associated with ____
Disease
When SNPs occur within a gene or in a regulator region near a gene, they may play a more direct role in disease by affecting the gene’s ____
Function
Most SNPs have mo effect on health or development, but many have proven to be very important in the study of ___ ___
Human health
Researchers have found SNPs that may help predict…
-Someone’s response to certain drugs
-Susceptibility to environmental factors such as toxins
-Risk of developing particular diseases
SNPs can also be used to track ___ of disease genes within families
Inheritance
Some SNPs generate ____ variation between people (some lead to differences in health or appearance, most have no observable changes)
Biological
Not all single-nucleotide changes are SNPs, though; to be classified as a SNP, two or more versions of a sequence must each be present in at least ___% of the general population
1
SNPs can happen in the cell line responsible for…
-Genes encoding proteins involved in drug transport and metabolism
-DNA repair
-Encoding drug targets and proteins involved in oncogenesis and cell signaling
If SNP happens in a cell, it results in a code for a different protein which can lead to the evolution of a cancer’s inability to respond to a ___
Drug
In human beings, ___% of bases are the same the the remaining percentage is what makes a person unique
99.9%
The variations in humans can be…
-Harmless (change in phenotype)
-Harmful (diabetes, cancer, heart disease, Huntington’s Disease, hemophilia)
-Latent (variations found in coding and regulatory regions, are not harmful on their own, and the change in each gene only because apparent under certain conditions, like susceptibility to lung cancer)
SNPs in genes involved with DNA repair and drug-metabolizing enzymes which are responsible for metabolism and detoxification of ____ can as act cancer susceptibility genes through the activation of chemical carcinogens and decreased ability of a cell to detox and repair mutagenic damage
Carcinogens
____ mutations cause alteration of large amounts of DNA, often on the level of the chromosome by moving one part of a chromosome to a different chromosome
Translocations
What two types of cancer are caused by translocation mutations?
-Leukemia
-Lymphoma
___ ___ is when there is production of many copies of a gene or set of genes at one location on a chromosome
Gene amplification
____ are segments are DNA that are released from a chromosome that are then re-inserted in the opposite orientation
Inversions
____ is the loss of gain of an entire chromosome
Aneuploidy
____ changes are changes to the DNA and chromatin that do not change the sequence
Epigenetic
A ____ mutation is an alteration of one or a few base pairs (transition or transversion mutation)
Point
A ___ ___ mutation causes larger effects (insertion or deletion)
Frame shift
A chromosomal translocation in the bone marrow is associated with ___ ___ ___
Chronic myelogenous leukemia (CML)
The ____ chromosomes is very common in chronic myelogenous leukemia
Philadelphia
If you find a mutation, you are better able to target the ____
Treatment
____ ____ are most often hematologic malignancies and are generally caused by chromosomal translocations, but sometimes bu chromosomal inversions
Chromosomal rearrangements
Sometimes, the same ____ appears in several different locations
Proto-oncogene
Whar types of cancer are caused by chromosomal rearrangements?
-Burkitt Lymphoma (85%)
-T cell acute lymphoblastic leukemia
Point mutations occur most often in the ___ family (K-ras, H-ras, N-ras)
Ras
K-ras carcinomas are responsible for…
-30% of lung adenocarcinomas
-50% of colorectal cancer
-90% pancreas
N-ras is responsible for ____ malignancies
Hematologic
K-ras, H-ras, and N-ras can all cause ____ cancer
Thyroid
What are three important factors in genetic alteration?
-Proto-oncogenes/oncogenes
-DNA repair genes
-Tumor suppressor genes
An oncogene is a _____ that has been mutated
Proto-oncogene
Proto-oncogenes stimulate the cell to ____, ___, and move through each cell cycle checkpoint to be inspected
Grow, divide
If a proto-oncogene mutates, it becomes an oncogene and no longer stops at cell ____ to ensure its normal
Checkpoints
___ ___ genes act to stop cell growth
Tumor-suppressor
DNA repair genes fix ____
Errors
Oncogenes are bad and turn ___ ___ ___ on
Abnormal cell growth
There are about ____ proto-oncogenes in our DNA
70
Oncogenes are mutated genes whose ____ can stimulate the development of cancer
Presence
Oncogenes are “___ ___ ____” genes that gain the ability to drive non-stop growth
Gain of function
A single mutated oncogene is usually not enough to cause ____ all by itself because tumor suppressor genes are acting to stop the growth from getting out of control
Cancer
Oncogenes aren’t usually involved in ____ forms of cancer because most occur as comatic mutations and can’t be passed down
Inherited
____/___ is an oncogene that encodes for a cell surface receptor that can stimulate cell division; this gene is amplified in up to 30% of human breast cancers
HER-2/neu
____ overexpression has been associated with a number of cancers including lung cancer, anal cancers, and glioblastoma multiforme; these are somatic mutations involving this gene that lead to its constant actuation, which leads to uncontrolled cell division
EGFR
The ___ oncogene products are involved in kinase signaling pathways that ultimately control transcription of genes, regulating cell growth and differentiation
Ras
The ____ oncogene is a transcription factor and controls expression of several genes
MYC
The ____ was the first oncogene discovered; the protein is a tyrosine kinase, which regulates cell activity
SRC
The ____ oncogene codes for an enzyme (telemerase) that maintains chromosome ends (telomeres)
hTERT
Tumor suppressor gene act as a braking signal during phase ___ of the cell cycle to stop or slow down the cell cycle before the S phase (if tumor suppressor genes are mutated, normal break mechanisms will be disabled, resulting in uncontrolled growth)
G1
Mutations in tumor suppressor genes cause ___-___-___ mutations
Loss of function
Loss of function mutations generally only show up when ___ copies of the gene are mutated (when there is a pair of tumor suppressor genes mutated, this might allow cancer to develop)
Both
Individuals who inherit an increased risk of cancer are often born with one ___ ___ of a tumor suppressor gene (if the second copy becomes mutated, then the person may develop cancer because there is no longer any functional copy of the gene)
Defective copy
____ is a tumor suppressor gene that regulated cell division and cell death
p53
___ is a tumor suppressor gene that alters the activity of transcription factors and therefore controls cell division
Rb
____ is a tumor suppressor gene that controls the availability of a transcription factor
APC
DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to ___ ___
Cell division
DNA repair genes are active throughout the cell cycle, particularly during ___ after DNA replication and before the chromosomes divide
G2
Certain forms of hereditary ___ cancer involve defects in DNA repair genes
Colon
Two very important DNA repair genes are ___ and ____ which are most known in relation to breast cancer
BRCA1 and BRCA2
BRCA1 and BRCA2 are also big in ___ and ___ cancer
Ovarian and pancreatic
___-___% of pancreatic cancer have a BRCA gene mutation
10-15
For decades, doctors believed that cancer was caused by irreversible damage to some critical stretch of DNA within one’s genome, but some cancers are actually caused by ___ ___ that are caused by tiny chemical tags that accumulate over time and can turn genes on or off
Epigenetic changes
Unlike genetic damage, epigenetic changes can sometimes be ____, and with treatments that are far less toxic to the patient
Reversed
After 9/11, there was an increase in ___ ___ from benzene from the jet fuel which caused a chemical tag that coils around the histone (this is an epigenetic change)
Mylodys Syndrome
Another example of an epigenetic carcinogen is ____, which is a drug that was found to be damaging to fetuses when given to pregnant women
Diethylstilbestrol (DES)
Epigenetics can also alter gene expression by changing…
-DNA methylation (abnormal methylation has been seen in cancer cells)
-Histone acetylation (when histones squeeze DNA tightly, they hide the gene which renders it un-usable)
-Altered expression non-coding RNA
Epigenetics can be ___ mutations, meaning they drive the progression of cancer
Driver
Epigenetics can also be ___ mutations, meaning they are just random events
Passenger
Methylation changes are thought to occur more ____ than mutations in the DNA, and so they may account for many of the changes during the neoplastic progression, particularly in the earlier stages
Frequently
What are two examples of demethylating agents used to treat Myelodysplastic Syndrome (MDS)?
-Azacitabine (Vidaza)-> orphan drug, meaning it has been developed specifically to treat a rare medical condition
-Decitabine (Dacogen)
What is a demethylating agent used in the treatment of cutaneous T-cell lymphoma?
Vorinostat (in clinical trial)
What are three functions of proto-oncogenes?
-Regulates cell growth and differentiation
-Signal transduction
-Execution of mitogenic signals
Steps of oncogenesis (starting from healthy cell):
-Healthy cell
-Damage
-Overgrowth
-Cell transforms to a cancer cell
-Cancer cells replicate
Hanahan and Weinberg originally described ___ principle cellular traits shared by virtually all forms of human cancers which collectively, dictate tumor development and growth
6
What are the original 6 Hallmarks of Cancer?
-Self-sufficiency in growth signals (activate H-Ras oncogene)
-Insensitivity to anti-growth signals (lose Rb suppressor)
-Evading apoptosis (produce IGF survival factors)
-Sustained angiogenesis (produce VEGF)
-Limitless replicative potential (turn on telemorase)
-Tissue invasion and metastasis (inactivate E-cadherin)
The 7th Hallmark that is soon to be added is…
Ability to invade the immune system
The current 10 hallmarks of cancer:
-Sustaining proliferative signaling
-Evading grow suppressors
-Avoiding immune destruction
-Enabling replicative immortality
-Tumor-promoting inflammation
-Activating invasion and metastasis
-Inducing or activating vasculature
-Genome instability and mutation
-Resisting cell death
-Deregulating cellular metabolism
What are 4 new emerging hallmarks/enabling characteristics?
-Unlocking phenotypic plasticity
-Nonmutational epigenetic reprogramming
-Senescent cells
-Polymorphic microbiomes
One of the 6 original hallmarks of cancer is sustained proliferative signaling, which means that cancer cells stimulate their own ___, independent from normal signaling to achieve sustained proliferative signaling
Growth
Another one of the 6 original hallmarks is that cancer cells can evade growth suppressors, allowing them to avoid or overcome the signals that normally counteract and balance ____
Proliferation
Another of the 6 original Hallmarks is that cancer cells can resist cell ___
Death
The next of the original hallmarks of cancer is that cancer cells can induce angiogenesis to stimulate ___ ___ growth signaling
Blood vessel
Another of the 6 hallmarks of cancer is that cancer cells can activate invasion and metastasis to develop the ability to colonize ___ sites
Distant
The last of the 6 original hallmarks is that cancer cells can overcome the Hayflick limit and enable replicative immortality to achieve limitless ____ potential
Replicative
One emerging hallmark is that cancer cells can avoid ____ destriction
Immune
Another emerging hallmark is that cancer cells can de-regulate cellular ____ to support continuous cell growth and proliferation
Energetics
One enabling characteristic of cancer cells is that they have ___ instability and mutation, which causes them to generate random mutations including chromosomal rearrangements
Genome
Another enabling characteristic of cancer cells is that they benefit from the ___ ___ induced by immune cells in pre-malignant and malignant lesions, promoting tumor progression
Inflammatory state
Varmus and Bishop were the ones to find genes that allowed ____ (proto-oncogene–> oncogene)
Mutations
The purpose of cellular proliferation is growth maintenance and reproduction, but cancer cells multiply without a ___ ____
Controlled signal
Normal cells maintain homeostasis with ___ ___ ___, but cancer cells deregulate this mechanism and enable growth factors, primarily tyrosine kinase, to kind to the cell surface
Mitogenic growth signals
Cancer cells generate many of their own ___ ___, thereby reducing their dependence on stimulation from their normal tissue microenvironment
Growth factors
Cancer cells achieve autonomy in cell proliferation in what 3 ways?
-Increase in growth factors
-Increase in the number of receptors on the surface (more receptors, more growth factor is activated)
-Alteration in the structure of the receptors to promote proliferation of cancer cells
When the Ras gene is switched on by incoming signals, it subsequently switches on other proteins which then turn on other genes involved in ___ ___, differentiation, and survival (Ras mutations can lead to overactive signaling inside the cell, leading to cancer)
Cell growth
H-Ras, K-Ras, and N-Ras are found in __-__% of all human tumors
20-25
Somatic mutations in the H-Ras gene are associated with ___ cancer
Bladder
Specifically, the mutation in the H-Ras gene replaces the amino acid ___ with the amino acid ____ at position 12
Glycine-> valine
The mutation in H-Ras causes the protein to be ___ ___, leading to the uncontrolled cell division and formation of a tumor
Permenantly activated
Mutations in the H-Ras gene are also associated with progression and ____ after treatment
Recurrence
Tumor suppressor genes limit cell growth and proliferation, but when mutated, lose their function and also cause loss of ___ ___
Contact inhibition
At the molecular level, most or all anti-proliferative signals are funneled through _____-related proteins
Retinoblastoma (Rb)
When hypophosphorylated, Rb sequesters and alters the function of ___ transcription factors, which normally serve to activate a number of genes required for transition from G0 to S phase (in normal cells, it stops the cell cycle at G1 to stop proliferation, induce differentiation, or promote apoptosis)
E2F
What two types of genes, when mutated, can increase the risk that cancer will develop?
-Oncogenes
-Tumor suppressor genes
Even when a point mutation converts a proto-oncogene to an oncogene, ____ may still occur through the tumor suppressor gene (so mutations in tumor suppressor genes increase the risk of cancer)
Repair
If a person inherits only one functioning copy of the ___ from their parents, they are predisposed to cancer and usually developed several independent tumors in a variety of tissues in early adulthood (rare, known as Li-Fraumeni Syndrome)
p53
Mutant p53 can no longer bind DNA in an effective way, and as a consequence, the ___ protein is not made available to act as the “stop signal” for cell division
p21
Normal cells grow in a culture dish until they cover the surface as a monolayer (contact inhibition), but cancer cells grow in ____ ___ and they pile up one over each other
Multilayer clumps
____ individuals are at increased risk for the development of cancer (mostly virus-induced cancers)
Immunocompromised
Tumor incidence is increased with what three types of deficiencies?
-CD8 cytotoxic T lymphocytes
-CD4 helper T cells
-Natural killer cells (NK)
CD8 and CD4 cells curb cancer development by producing ___ and ____
Interferons (IFN) and cytotoxins
Chronic ____ may reduce the function of cytotoxic lymphocytes (allowing cancer cells to develop)
Inflammation
What mechanisms can cancer cells use to avoid immune destruction?
-Ability to hind from the immune system
-Resistance to immune cell attacks
-Inflammation and tumor environment may lead to immunosuppression
Tumors produce antigens, which an intact immune system would destroy, but with someone who is immunocompromised, cancer cells can escape ___ ___
Immune surveillance
One normal cells reach a certain number of divisions, they stop growing; this is known as ____
Senescence
The limit for most normal cell types is __-__ divisions, after which they enter senescence
60-70
A key rate-limiting mechanism in cell division is the length of chromosome ___, which decreases by 50 to 100 base pairs with each consecutive cell division (at some point, telomeres loss induces genetic instability and crisis ensues)
Telomeres
Many, if not all, tumor cells address this issue by up-regulating ____, the enzyme that extends telomeres; this is a key component for enabling limitless replication potential in tumor cells
Telomerase
Tumors contain ___ cells which provide growth factors, proangiogenic agents, nutrients, and survival factors
Immune
In healthy tissues, inflammation aids in repair and recovery, but in cancer cells, inflammation allows for…
-Increased proliferation
-Increased growth siganling
-Stimulation of tumor-associated cells
Chronic inflammation increases the risk of cancer and weakens the __ __
Immune system
____ accounts for 90% of cancer deaths
Metastases
Several families of proteins involved in tethering cells to their surrounding tissue are altered during metastases such as…
-Cell-cell adhesion molecules (CAMs)
-Integrins (mediate cell-matrix interactions)
One example of the communication between the cell and the environment is offered by ____, which is expressed on the surface of epithelial cells; the bridging of its receptors between adjacent cells triggers anti-growth signals within the cell via B-catenin; a number of epithelial cancers block this pathway
E-Cadherin
Integrins have many subtypes with distinct substrate preferences; successful colonization by tumor cells at a distant site requires adaptation, which is often achieved through shifts in the spectrum of ___ and ___ subunits displayed by migrating cells
Alpha and beta
The process of metastasis can be explained in what three parts?
-Invasion
-Intravasation
-Extravasation
During the process of ___, cells are able to detach from the original tumor and overtake surrounding tissues
Invasion
During the process of ____, the cancer cells travel through the blood vessels and metastasize at the new destination
Intravasation
During the process of ____, the cancer cells integrate themselves in the layers of the new tissues through different biochemical interactions
Extravasation
Once the cancer cells are integrated in new tissues, they can divide and proliferate to create a new ____
Tumor
The most common sites for metastasis of lung cancer are…
-Adrenal glands
-Bones
-Brain
-Liver
-Other lung
The purpose of vasculature is to…
-Supply oxygen and nutrients
-Remove waste
Angiogenesis is regulated in healthy tissues, but cancer cells develop ____ ability so the switch is always on
Angiogenic
____ and ___ induce angiogenesis, while ____ suppressed angiogenesis
VEGF-A and FGF1/FGF2; TSP-1
Tumor cells encourage blood vessel invasion/growth by ____ inducers and ____ inhibitors
Upregulating; suppressing
Once cancer cells have acquired the ability to disrupt and migrate into neighboring tissues, ____ requires for them to reach blood or lymphatic vessels
Metastasis
Once the cancer cells have invaded the surrounding tissue and reached the blood or lymphatic vessels, they need to disrupt ___ cells to gain access to the vessel (intravasation) to be washed away to other body sites where extravasation takes place
Endothelial
Mutations in the cell genome results in ___ and -___
Growth and dominance
What are three examples of DNA maintenance mechanisms?
-Detecting DNA damage and activating repair mechanisms
-Direct DNA repair
-Inactivate mutogenic molecules before they have damaged DNA
Developing resistance towards apoptosis contributes to the survival of ____ cells
Malignant
Apoptosis involves ___, which guard the cell, and ___, which break the cell apart
Regulator and effectors
Important players of cell division:
-Protein-retinoblastoma (blocks cell division)
-P53 (guardian of the genome, can detect damage in DNA)
If there is damage to the gene that codes for the creation of ___-___, the protein cannot be created and the block on cell division is lifted (leads to uncontrolled proliferation of the cell)
Protein-retinoblastoma
It is common for cancer cells to be missing the ___ protein, which would remove the cell’s ability to perform apoptosis and therefore have uncontrolled proliferation
P53
___ is a self-degradative process that balances energy sources necessary to respond to nutrient stress; this is a barrier to tumorigenesis
Autophagy
Damaged cells may avoid autophagy, which allows cells to be ___-___
Self-sustaining
____ cells release proinflammatory substances
Necrotic
Chronic inflammation potentiates genetic ____ in cells
Instability
Metabolism of cancer cells focuses on ____ production and proliferation (metabolic resources are finite)
Biomass
Cancer cells produce energy through ____
Glycolysis
Byproducts of glycolysis support cell ___
Proliferation
Cancer cells require ___ times more glucose than normal cells to produce energy
20
There is increased glycolysis that results from ____, mutant tumor suppressor genes, and hypoxia
Oncogenes
Tumor cells meet glucose demands by…
-Upregulating glucose transporters
-Upregulating enzymes used during glycolysis
The tumor microenvironment, or the environment around a tumor, includes…
-Blood vessels
-Immune cells
-Fibroblasts
-Signaling molecules
-Extracellular matrix
Cytotoxic T cells (CD8+) detect ___ ___ ___ expressed on cancer cells and target them for destruction; the presence of cytotoxic T cells is often associated with a positive prognosis in cancer patients
Abnormal tumor antigens
Aside from killing tumor cells, cytotoxic T cells also suppress ____ through the secretion of IFN-y
Angiogenesis
What are the three stages of carcinogenesis?
-Initiation
-Promotion
-Progression
During ____, a carcinogen interacts with and damages the DNA (repair can happen after this point and the process can be reversed)
Initiation
____ causes reproduction or proliferation of these damaged cells, forming a mass of cells or a benign tumor (at the beginning of this stage, removal of the promoting agent can stop the expansion of the tumor)
Promotion
____ is irreversible and involves a number of sequential mutations in genes including oncogenes and tumor suppressor genes; the end result of progression is a tumor that eventually converts to a malignancy
Progression
The entire process of initiation, promotion, and progression can take ___ years or more
20
You need the ____ AND the ____ to move on to progression
Initiator, promoter
The ____ period of cancer formation can last 20 years or more
Latency
Promotion required ____ exposure to the promoter and is reversible in early stages
Prolonged
What are some examples of promoters?
-Hormones
-Drugs
-Chemicals
A promoting event may be inactivation of a ___ ___ ___ which has previously kept an oncogene from activating
Tumor suppressor gene
___-___ factors may also play a role in promotion like smoking, infection, nutritional factors, and immune system function
Non-mutational
The ____ (supportive tissue of an epithelial organ) is a critical regulator of metastasis
Stroma
The ____ system is responsible for the colon cancer “seed” in the liver via the portal vein
Ciculatory
Lymph nodes draining tissue of cancer origin are colonized first (seen in ___ disease)
Hodgkins
____ nodes are seen in breast and colon cancer
Sentinal
Sentinal nodes eliminate the need to do a total ____
Lymphadenectomy
Blue dye can be injected into the area where the tumor was removed; the blue dye will color the sentinel node and then the node can be removed and ____
Biopsied
Tumors can not grow beyond around __-__mm3 due to lack of oxygen and other essential nutrients
1-2
To maintain their oxygen supply, tumors induce angiogenesis by secreting ___ ___ like VEGF
Growth factors
A tumor that can be clinically identified must be ___ gram in size and have gone through 30 population doublings
1
Before the point when a tumor has been clinically identified, the growth of the tumor has been the ____ and no growth has drastically slowed down
Fastest
The growth curve of cancer is expressed by the ____ equation
Gompertzian
According to the growth curve, most tumors originate ___ ___ before detection
2 years
The rate of tumor growth is reflective of what three things?
-Proportion of actively dividing cells (growth fraction)
-Length of the cell cycle (doubling time)
-The rate of cell loss
Variations in these three factors are responsible for…
Variable rates of tumor growth observed among tumors of differing histologies as well as among metastatic tumors of the same histology
Some cells, like ___ cells, are radioresistance and don’t divide rapidly
Radioresistant
___ cancer cells can live a long time before they spread
Liver
Three determinants for cancer development:
-Nature
-Nurture
-Luck
The Knudson 2 hit theory proposed that carcinogenesis requires what 2 hits?
1st hit: initiation (carcinogen)
2nd hit: promotion (promoter)
The ___ ___ is the time between the exposure (first hit) and development of clinically apparent cancer
Lag period
People with a hereditary susceptibility to cancer inherit a damaged gene on one chromosome, so their first “hit” occurs at ____
Conception
Is alcohol an initiator or promoter?
Initiator
The ____ experiments showed that a high-dose exposure causes malignancy, or a low-dose exposure plus a promoting agent causes non-reversible malignancy
Berenblum
Carcinogenesis induced by chemicals involves what three separate and independent processes?
-Initiation
-Promotion
-Latency
Benzypyrene (the initiator) caused a mutation in stem cells that became apparent only when the ___ ___ (the promoter) was applied
Croton resin
A mutation caused by the initiation process can remain ____ forever (latency)
Dormant
There is an ___-___% risk for smokers for lung cancer
11-22
___ cancer is the 2nd most deadly cancer
Pancreatic
___ and ____ cancer is very difficult to treat
Head and neck
Most cancer, including breast cancer, is ____ and not hereditary
Somatic
Infectious agents cause about __/__ of all human cancers worldwide
1/5
____% of cancers are caused by viruses that are linked to human oncogenesis
12
What 7 viruses are linked to oncogenesis?
-Epstein-Barr Virus
-Hepatitis B
-HPV
-Human T-cell lymphotropic virus
-Hepatitis C virus
-Kaposi’s sarcoma Herpesvirus
-Merkel cell polyomarvirus
Mechanisms for cancer formation from viral infection:
-Chronic inflammation
-Interaction with cellular DNA
-Immunosuppression
HPV can cause cancer of the ____
Cervix
Hepatitis B can lead to ____ cancer
Liver
Epstein-Barr Virus can lead to what two types of cancer?
-B cell Lymphoma
-Nasopharyngeal cancer
RNA retrovirus produced ___ ____
DNA provirus
DNA viruses act by blocking ___ ___ products (ex. of DNA viruses: HPV, EBV, Hep B)
Suppressor gene
____ are a small group of genes composed of DNA or RNA surrounded by a protein coat; they cannot reproduce by themselves
Viruses
Viruses use the cell’s machinery to enter a ___ ___ to make copies of themselves
Living cell
Mechanism of HPV infection:
-Infects epithelial cells
-Makes proteins that interfere with cell function
-Promotes excessive growth
___ and ___ cancer are both caused 90% of the time from HPV infection
Cervical and Anal
____ cancer is caused 60-70% of the time by HPV virus
Oropharyngeal
An HPV vaccine called ___ has been developed for the use against the most prevalent types of HPV linked to cervical cancer
Gardasil
The Epstein-Barr Virus affects ____% of the population worldwide (primarily asymptomatic, occurs within the first three years of life)
95%
EBV-infected cells resist ___ by the induction of anti-apoptotic proteins
Apoptosis
EPV is responsible for about ___% of stomach cancers and most nasopharyngeal cancers
15%
Epstein Barr Virus is associated with ___ and/or ___ ___
Burkitt and Hodgkin Lymphomas
Hep B and Hep C viral can cause ___ infection and can increase a person’s chance of liver cancer
Chronic
Long-term Hep C virus infection might be linked with other cancers, such as ___ ____
Non-Hodgkin Lymphoma
If someone has HIV, they are at a higher risk of developing…
-Kaposi sarcoma
-Cervical cancer
-Non-Hodgkin lymphoma (especially central nervous system lymphoma)
-Other types of cancer that may be more likely to develop: Anal cancer, Hodgkin’s disease, Lung cancer, Cancers of the mouth and throat, some types of skin cancer, and Liver cancer)
HTLV-1 belongs to a class of viruses called _____
Retroviruses
Retroviruses use ____ for their genetic code
RNA
To reproduce, retroviruses much go through an extra step to change their RNA to ____
DNA
New DNA genes can then become part of the ____ of the human cell infected by the virus (this is how the cell grows and divides, which can sometimes lead to cancer)
Chromosome
Discovered in 2008, __ __ __ is a rare and aggressive type of skin cancer
Merkel cell carcinoma (MVC)
Most people are infected with ___ ___ ___ at some point (often in childhood) and it usually causes no symptoms
Merkel Cell Polyomavirus (MCV)
In a few people with MCV, the virus can affect the ___ inside of cells, leading to Merkel cell cancer (nearly all Merkel cell cancers are now thought to be linked to this infection)
DNA
A bacteria known as ___ ___ is known to cause (factors why are unclear)
H. Pylori
Data show that more than ___ of all cases of stomach cancer may be linked to H. pylori infection (but most people who have these bacteria in their stomachs never develop cancer)
Half
Cancer cells also must evade the ___ ___; if normal cells mutate enough and escape surveillance, they become cancerous
Immune system
Antigens expressed by tumors have several sources like:
-Oncogenic viruses
-Organism’s own proteins that occur at low levels in normal cells, but reach high levels in tumor cells
-Proteins normally important for regulating cell growth and survival that commonly mutate into cancer, inducing molecules called oncogenes
An enzyme called ___, that when expressed at high levels, transforms certain skin cells into tumors called melanomas
Tyrokinase
The main response of the immune system to tumors is to destroy the abnormal cells using ___ ___ ___, sometimes with the assistance of helper T cells
Killer T cells
Tumor cells often have a reduced number of ____ molecules on their surface, thus avoiding detection by killer T cells
Specialized
___ ____ causes DNA damage and genetic mutations
Ultraviolet radiation
Ultraviolet releases ___ ___ ___, which reduces immune responses
Tumor necrosis factor
UV sunlight causes ___ and __ ___ cancers
Squamous and Basal cell
___ forms with increased growth factor and activation of protein kinase pathway
Melanoma
UVA Rays are the ____ rays and they deeply penetrate skin layers, damaging collagen and DNA, cause wrinkling and loss of elasticity and pigmentation; they are up to 50 times more prevalent that UVB rays
Aging
UVB rays are the ____ rays which mostly affect the outer layers of the skin, cause sunburns, and increase the risk of skin cancer
Burning
Alcohol is a ___ carcinogen, not a direct carcinogen (once in the body, it is converted to acetaldehyde which can damage DNA)
Promoting
Drinking alcohol can lead to ___ ___ in cells, damaging the inside of cells (this may be increased with nutritional deficiencies)
Oxidative stress
Occupational hazards have a complicated involvement with what types of factors?
-Smokers/effect of smokers
-Environment
-Hereditary factors
___ is a chemical that may lead to Mesothelioma
Asbestos
Dyes, rubbers, and paints may lead to increased risk of ____ cancer
Bladder
Benzene exposure may lead to ___ and ___
Leukemia and Lymphomas
Chimney sweeps have a high risk of ____ cancer
Scrotal
___ is a naturally radioactive gas that may lead to increased risk of lung cancer
Radon
___ ___ decreases cancer incidence
Physical activity
How does physical activity decrease cancer incidence?
-Decrease exposure time to carcinogens (colon and estrogen)
-Decreasing insulin growth factors
-Increase free radical scavenger system
____ is linked with 14% of cancer deaths in men and 20% in women because adipose tissue is metabolically active and releases peptide hormones
Obesity
____ may induce the synthesis of peptide hormones like Insulin-Like Growth Factors that stimulate cell growth and reduce apoptosis
Hyperinsulinemia
Fat tissue produces excess amounts of ___, high levels of which have been associated with the risk of breast, endometrial and some other cancers
Estrogen
Carcinogens are present in food as ___, or created during the preparation process
Additives
____ in food might be protective of carcinogens
Micronutrients
With chronic inflammation, there is cytokine release that does not shut off, and promotes ___ in things like COX-2 which generated prostaglandins and increases colon cancer development
Mutations
____ helps to reduce the production of prostaglandins
Celebrex
Clinical signs of tumor:
-Change in bowel or bladder habits
-A sore that does not heal
-Unusual bleeding or discharge
-Thickening or lump in the breast, testicles, or any part of the body
-Indigestion or difficulty swallowing
-Obvious change in wart, mole, or skin condition
-Nagging cough or hoarseness
(CAUTION, plus maybe weight loss)
To diagnose cancer, you ideal want to obtain a ___ sample, but if you can’t, like with a lung mass, you would base treatment on CT scan
Tissue
___ is the microscopic examination of cells or groups of cells (not in the context of a tissue or organ)
Cytopathology
Cytopathology evaluates ___, and examples include pap testing and fine needle aspiration
Morphology
What are the three classifications of malignant tumors?
-Carcinoma: epithelial in origin (90%)
-Hematologic: Lymph and blood systems
-Sarcoma: bone, muscle, neuro; mesenchymal in origin
Naming of tumors is preceded by ___ ___ ___ (adeno, squamous) and followed by tissue or origin
Histological Type A
Stage 0 or TIS tumor ___ ___ found early means that the tumor hasn’t broken out of the capsule
In situ
A stage 0 tumor is not ____ and has the ability to metastasize
Benign
____ is a basic dye which will stain cell nuceli which contain DNA and RNA
Hematoxylin
___ is an acidic dye that binds with basic tissue components including the cell membranes and organelles
Eosin
Conventional hematoxylin and eosin staining, which has been used by pathologists for more than 100 years, is the ___ ____ of tumor diagnosis (grades I-IV)
Gold standard
The tumor grade represents the degree of ____ and is an estimate of the growth rate by mitotic index
Differentiation
The more progressed a tumor is, the ___ differentiated it will be and the worse it will respond to treatment
Less
Degrees of differentiation:
G1: well-differentiated
G2: moderately differentiated
G3: poorly differentiated
G4: undifferentiated
The future of treating cancer is ___ ___ ___
Individualized molecular medicine
Individualized molecular medicine is targeted therapy that aims to…
-Reduce treatment-related toxicity
-Improve outcomes in a number of cancers
A benefit of individualized molecular medicine is that it is limited to a subset of patients with particular molecular ____
Lesions
____ is the study of proteins which is important for cancer because of the changing levels of active proteins inside tumor cells; this could help determine diagnosis and treatment effectiveness
Proteomics
___ ___ technology is rapid and relatively inexpensive DNA sequencing that identified targetable mutations
Ion Torrent
___ ___ uses gene expression patterns to better choose treatment (same diagnoses, different treatment)
Drug profiling
___ ___ is used to measure the DNA content of abnormal cellular populations and to determine percentages of cells in various phases of the cell cycle
Flow cytometry
Assessment of ____-___ using flow cytometry is one of the most extensively investigated prognostic parameters in cancer biology
DNA/S-Phase
A ___ S-Phase in breast cancer is associated with an unfavorable prognosis
High
___ ___ analyzed a panel of 21 genes within a tumor to determine a Recurrence Score; this is a number 0-100 that corresponds to a specific likelihood that breast cancer recurrence within 10 years of the initial diagnosis (this may help determine who gets chemo)
Onco-DX
A high onco score means a ____ recurrence rate
High
___ ___ ___ are substances produced by cancers and include hormones, enzymes, antigens, antibodies, PSA, CEA, HCG, etc. (not 100% predictive)
Tumor cell markers
Tumor cell markers can be used for…
-Diagnostic
-Tracking
-Screening
___ ___ are a predictor of metastasis and will dictate need for adjuvant therapy
Lymph nodes
When using a ___ ___, you need to know the most likely sites for that malignancy
Metastatic workup
____ determines the size of the tumor and if it has spread
TNM
Indicators of TNM stage 1-4:
Stage 1: early disease- tumor confined to the breast (node-negative)
Stage 2: early disease- tumor spread to moveable ipsilateral axillary node (node-positive)
Stage 3: locally advanced disease- tumor spread to the superficial structures of the chest wall, involvement of nodes
Stage 4: advanced/metastatic disease- metastases present at distant sites including lymph nodes
What are two examples of local cancer treatment?
-Surgery (have to know what is there)
-Radiation therapy (target what is seen mostly)
What are three examples of systemic cancer treatment?
-Chemotherapy (blunt weapon, many side effects)
-Targeted Therapies
-Immunotherapy (do not need a target, can result in GI distress, rashes, etc)
___% of all cancer patients will have some surgery
90
___% of surgeries are presumed to be curative
75
Radiation emits ____ charge and is unstable, so it damages tissue (loses charge when deeper)
Radiation
____ cells those cells that are rapidly dividing
Radiosensitive
Tissue ___ depends on different delivery systems
Tolerance
Side effects of radiation depend on __ ___
Target site
Most chemotherapy agents treat both ___ cells and ___ cells
Cancer; normal
Side effects of chemotherapy include…
-Bone marrow suppression
-Nausea
-Vomiting
-Nerve damage
In the 1980s and 1990s, new drugs were developed to control ___ ___ of chemotherapy
Side effects
What drugs reduce suppressive effects on the bone marrow?
-Filgrastim
-Sargrastim
-Erythropoietin
Nausea can be treated with…
Serotonin receptor antagonists
Finding effective treatment is complicated since it is usually ___ redundant pathways that lead to cancer (knocking out just one may not solve the problem)
Multiple
Tumor cells are ____, so cells can evolve to resist treatments that may, temporarily, seem to be working
Unstable
Cancer cells get very smart and can become ____ to chemotherapy
Resistant
___-___ ___ occurs due to a decreased uptake and increased elimination of the drugs from the tumor cells
Multi-drug resistance
A specific pump has been identified in cancer cells that is responsible for multi-drug resistance called the ____ ___, ____
ABCB1 gene, P-glycoprotein
___ expression is heterogeneous among tumor cells; cells that express this gene are resistant to chemotherapy and survive the treatment
P-gp
By triggering the immune system, therapeutic ____ can initiate a durable anti-tumor response that can attack tumor cells and lead to improved survival (the goal is to generate an active immune response against existing cancer)
Vaccines
Tumor-specific ___ ___ can elicit a direct or indirect immune response that leads to cell death
Monoclonal antibodies
There are a variety of monoclonal antibodies and these work via different mechanisms of action to cause ___ ___
Cell death
____ is a monoclonal antibody that specifically recognizes and binds to VEGF (this causes anti-angiogenesis)
Bevacizumab (Avastin)
When VEGF is attached to bevacizumab, it is unable to activate the ____ ____
VEGF receptor
Other angiogenesis inhibitors, including ____ and ____ bind to receptors on the surface of endothelial cells or to other proteins in the downstream signaling pathways, blocking their activities
Sorafenib, Sunitinib
The immune system depends on multiple checkpoints or “____ ___” to avoid overactivation of the immune system on healthy cells
Immunological brakes
Tumor cells often take advantage of these checkpoints to escape ___ by the immune system
Detection
___ and ___ are checkpoints that have been studied as targets for cancer therapy
CTLA-4, PD-1
____ such as interleukin-2 and interferon-a stimulate a broad-based immune response as opposed to generating a targeted response to a specific antigen
Cytokines
Interleukin-2 has numerous effects on the immune system and acts as a general ___ ___ ___ by binding to the surface of T cells
T-cell growth factor
____ is a drug that works by interfering with one of the ways in which breast cancer cells divide and grow
Trastuzumab
Trastuzumab blocks human epidermal growth factor by attaching itself to the ___ protein so that the epidermal growth factor cannot reach the breast cancer cells
HER2
Trastuzumab also works though ____
Cytotoxicity
____ is a chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes
Rituxan (Rituximab)
___ ___ is a class of enzymes that, when mutated, initiate abnormal cellular activity (they are EGFR receptors)
Tyrosine kinase
EGFR is also over-expressed in the cells of other solid tumors such as lung and breast cancers; this leads to inappropriate activation of the apoptotic ___ signal transduction cascade, eventually leading to uncontrolled cell proliferation
Ras
The tyrosine kinase inhibitors inhibit ___ from binding, which limits cell division
ATP
____ ___ is one of the first successful small-molecule inhibitors, and it inactivates the kinase activity from the BCR-ABL fusion protein in CML
Imatinib mesylate (Gleevec)
Imatinib mesylate has shown remarkable efficacy for the treatment of patients with ____ chromosome-positive chronic myelocytic leukemia
Philadelphia
