Tissue Cell and Renewal Flashcards
1
Q
What is apoptosis? How does it occur?
A
Apoptosis- programmed cell death; this process is part of controlling a cell’s growth and development.
In apoptosis, the organelles within parenchymal cells separate, condense and fragment into pieces. Then phagocytotic cells engulf fragmented cell and send to lysosomes where they are degraded.
2
Q
What is a residual body?
A
Residual body- vesicle filled with particles that cannot be digested.
3
Q
Describe the different morphological characteristics of apoptotic cell death.
A
Characteristics:
- apoptosing cells shrink, condense and round up.
- Nuclear envelope disassembles
- Chromatin condenses (pyknosis) and breaks into fragments (karyorrhexis)
- Cytoskeleton collapses
- PM blebs and bulges, but PM still remains intact
- Cell corpse may break into fragments (called apoptotic bodies)
- Surface of corpse changes to be recognized by neighboring cells for phagocytosis
- engulfed by neighboring cells before contents spill out (apoptosis vanish)
4
Q
Compare and contrast a normal WBC vs. apoptotic WBC.
A
Normal- wbc has microvilli, membrane covered microgilaments and extensions of cytoskeleton, round.
Apoptotic- wbc has blebs (regions detached from cytoskeleton that has broken down).
5
Q
Differentiate between apoptosis and necrosis functionally and physically.
A
Apoptosis- active, ATP-dependent process, mutations that can prevent apoptosis. Also cell breakdown is clean, membrane still bound.
Necrosis- passive process, no mutation can prevent necrosis from occurring. Cell break down is messy, contents LEAK out.
6
Q
Compare and contrast Apoptosis and Necrosis
A
Apoptosis- single cells or small cluster of cells, cell shrinkage and convolution, chromatin condensation (pyknosis) and fragmentation (karyorrhexis); cell membrane is intact, cytoplasm is retained in apoptotic bodies, ATP-dependent, genetically programmed, little or no inflammation.
Necrosis- contiguous cells (adjacent), cell swelling, cell separation (karyolysis, pyknosis, karyorrhexis), disrupted cell membrane, cytoplasm released, ATP INDEPENDENT, NOT genetically programmed, may cause inflammation.
7
Q
What two major pathways cause apoptosis? Differentiate between the two pathways.
A
The intrinsic and extrinsic pathway both cause apoptosis.
Intrinsic pathway- cell ITSELF will decide if it should die (something will happen to cell that will make it undergo apoptosis).
Extrinsic pathway- once cell will tell ANOTHER cell that it needs to die.
8
Q
Describe what occurs in the intrinsic pathway.
A
In intrinsic pathway you have death stimulus like radiation, hypoxia. In this pathway, the initiator caspase must be cleaved to become activated. Death receptor will initiate cascade of caspase.
Bc12 family of proteins are involved- BH3 only proteins, Bc12 protein and bak and bax.
In pathway, cytochrome c is present, with Killer T cells that damage cell and induce cell death.
9
Q
What must occur in the extrinsic pathway of apoptosis?
A
In extrinsic pathway, the death ligand must bind to death receptor to initiate the apoptosis.
10
Q
What feature of apoptosis is common to both extrinsic and intrinsic pathways? What is the amplification step in this cascade?
A
The CASPASE CASCADE is common to both pathways. A caspase must be cleaved to be activated.
The amplification step is during the executioner caspase step, leading to cleavage of nuclear components.
11
Q
Starting from procaspase, how is one caspase molecule activated?
A
initially you have two inactive procaspase molecules. These procaspase molecules will then be cleaved at their sites (cleave pro domains) and assemble together to form one active caspase molecule.
12
Q
Explain the reason behind the name CASPASES. What does this name signify?
A
Caspases- C is for cysteine and ASP is for ASPartate.
Caspases are proteinases that have a cysteine at their active site and cleave their target proteins at specific ASPARTIC Residues.
13
Q
What happens when during proteolytic cleavage of pro-caspase?
A
cleavage of pro-caspase will rearrange the protein to form active site (important to activate enzymes).
14
Q
Compare and contrast inititator caspases and executioner caspases. What do they have in common? how do they differ?
A
Initiator caspases and executioner caspases have different structures.
Both initiator and executioner caspases are activated by proteolytic cleavage.
Initiator caspases are activated when they DIMERIZE
Executioner caspases are activated when they are CLEAVED by INITITATOR caspases.
15
Q
What occurs in the amplification step of proteolytic cascade?
A
In the amplification step:
one initiator caspase can activate many executioner caspases, leading to amplification of apoptotic signal.
a proteolytic cascade involving initiator and executioner caspase lead to apoptosis.
16
Q
Describe the different functions of proteins in Bc12 family of proteins? Which are the pro-apoptosis? Which are anti-apoptosis?
A
Bc12 family of proteins:
1. proteins that are pro-apoptosis- BH3 only proteins, and Bak and Bax proteins.
2. Proteins that are anti-apoptosis- Bc12- tries to keep the cell alive.
BH3 only proteins- sense difference signals and act as sensors to inhibit anti-apoptotic cells by inactivating Bc12. BH3 activates Bak and Bax proteins.
Bc12- try and keep cell alive and induce, by inhibiting Bak and Bax proteins.
The Bak and Bax proteins- pro-apoptosis; they make holes in mitochondria to release cytochrome c
Once cytochrome c is lost, cell is not functional
Cytochrome c will bind to protein Apaf1 (adaptor) and form complex apoptosome which activates initiator caspase.
17
Q
What role does BH3-only proteins play in apoptosis?
A
BH3 only proteins- acts as sensors of a variety of apoptotic signals. They inhibit anti-apoptotic Bc12 proteins, and allow pro-apoptotic effector proteins to cluster and release cytochrome C.
Some BH3 only proteins- bind effector proteins directly to stimulate aggregation.
18
Q
What is the role of anti-apoptotic Bc12 protein and BclXL? Where are they located?
A
They are located on cytosolic surface of outer mitochondrial membrane, where they bind and block activation (by preventing oligomerization) of pro-apoptotic (Bax and and Bak ) Bc12 family proteins.
19
Q
Why are Bc12 proteins important?
A
Every cell needs at least one ACTIVE anti-apoptotic Bc12 protein to SURVIVE.
20
Q
How do all proteins in Bc12 family proteins regulate apoptosis?
A
they regulate apoptosis by controlling the mitochondrial membrane permeability and release of cytochrome c and other intermembrane proteins into the cytosol.
21
Q
What is the role of Bc12 family effector proteins (Bak and Bax)?
What would happen to cell without effector Bc12 proteins?
A
The activated pro-apoptotic effector Bc12 proteins (Bak and Bax) AGGREGATE on outer mitochondrial membrane and cause intermembrane proteins to be released.
Without effector Bc12 proteins, a cell cannot respond to an intrinsic apoptotic signal.
22
Q
Describe the involvement of mitochondria in the intrinsic pathway of apoptosis.
A
The intrinsic pathway of apoptosis involves mitochondria, as the release of cytochrome c from intermembrane space of mitochondria goes into cytosol.
23
Q
Describe the steps that occur in intrinsic pathway of apoptosis.
A
Steps in intrinsic pathway:
- Diverse apoptotic stimuli (not death receptor) initiates signaling that activates Bc12 family proteins Bak and Bax.
- Bak and Bax activation changes inner mitochondrial membrane and leads to opening of a pore.
- the loss of mitochondrial transmembrane potential occurs and causes release of mitochondrial proteins into cytosol.
- Cytochrome C binds adaptor protein (Apaf1), which heptamerizes into apoptosome.
- after binding to cyto c, adaptor protein binds pro-caspase-9 (initiator caspase) and forms hexamer.
- multimerization of pro-caspase-9 leads to proteolytic cleavage and activation. It can now cleave executioner caspases.
24
Q
How can apoptotic cells with released mitochondrial cyto c be differentiated from non apoptotic cells (retain cytochrome)
A
They can be differentiated through FLOURESCENCE MICROSCOPY.
a cell that merged green fluorescence in cell indicates cell with cytochrome c in cytosol, left mitochondria.
25
What happens when cytochrome C binds to adaptor protein (Apaf1)?
The binding of cytochrome C causes the adaptor protein to unfold partly, exposing a domain that interacts with same domain in other activated adaptor protein molecules.
26
What is an apoptosome?
A protein complex made of adaptor proteins, cytochrome C and Pro-caspase-9 molecules bound together into a hexamer shape.
27
What does the adaptor protein do, after binding to cytochrome C?
After binding cytochrome C, adaptor protein binds to pro-capspase-9 (initiator caspase) molecules to form hexamer.
28
Describe the steps that occur in the extrinsic pathway, and the cellular structures involved.
Extrinsic pathway:
1. Starts with FAS ( trimeric death receptor) and Fas ligand. Trimeric Fas ligand binds trimeric Fas receptor
2. The death domains on the cytosolic tails of Fas bind intracellular death domain adaptor proteins (FADD), which then binds initiator caspases (primarily Caspase-8) forming a DEATH INDUCING SIGNALING COMPLEX (DISC).
3. DISC allows dimerization and activation of initiator caspases, which cleaved their partners, which are then released to activate executioner caspases and induce apoptosis.
29
What is the DISC? what are its components?
DISC- Death inducing signaling complex composed of initiator caspase (caspase 8), FADD and Fas death receptor. This complex helps dimerize initiator caspases, prepare for cleavage and activate executioner for apoptosis.
30
Describe the structure of death receptors. also discuss what kind of family these receptors belong to as well as their ligands.
Death receptors are transmembrane proteins that contain an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular death domain.
These death receptors belong to TUMOR NECROSIS FACTOR RECEPTOR (TNFR) family. Their ligands belong to TNF Family of signaling factors.
ligands do not float freely in cell.
31
What kind of structures are both death ligand and death receptor. What occurs when ligand binds to receptor?
Both the death ligand and death receptor are TRIMERIC structures.
Binding of ligand to receptor will alter conformation of receptor, so that it binds a DEATH DOMAIN ADAPTOR protein (FADD), which recruits and activates initiator caspase (caspase 8), triggering caspase cascade that leads to death.
32
Describe the pathology of disease ALPS (autoimmune lymphoproliferative syndrome).
ALPS- is associated with dominant mutations in death receptor FAS (include point mutation and terminal truncations).
In individuals heterozygous for mutations, lymphocytes do NOT die at their normal rate and accumulate (hence lymphocyte proliferation)
33
Describe the series of human diseases that have either too much or too little apoptosis as a major factor.
1. Heart attacks and strokes- many cells die by necrosis due to ischemia (lack of blood supply), but some also die by apoptosis (receive damage signals)
2. Autoimmune disease- caused by mutations in Fas death receptor or Fas ligand which leads to overproduction of lymphocytes and a breakdown of self-tolerance.
3. Neurodegenerative diseases- like Alzheimer's, Parkinson's, Huntington's diseases and ALS: cells die due to oxidative stress, perturbed calcium homeostasis and mitochondrial dysfunction.
4. Cancer: mutations in Bc12 lead to B-cell Lymphoma: p53 gene is mutated or inhibited in more than half of cancers, thus blocking signal from DNA damage to apoptotic pathway.
34
Which anti-cancer drugs aid in prevention of the blocking of apoptosis and where are they bound? Which protein blocks apoptosis?
Anti-cancer drugs like ABT-737 inhibit the anti-apoptotic Bc12 family proteins (they prevent apoptosis)
This ABT-737 drug binds to anti-apoptotic Bc12 family proteins like BC1XL, and prevent them from blocking apoptosis.
The drug will bind to Bc1XL within long hydrophobic pocket of Bc1XL (where pro-apoptotic BH3 only proteins bind).
35
Describe the three types of extracellular signaling molecules and their functions.
Extracellular signaling molecules:
1. Survival factors- block apoptosis
2. mitogens- promote cell entry into S phase by overcoming intrinsic inhibition of cell cycle.
3. Growth factors- stimulate growth in cell size and mass by promoting biosynthesis and inhibiting degradation.
36
Why do cells compete for survival factors? provide an example.
Cells compete for limited amounts of survival factors produced by other cells to prevent their apoptosis to control tissue development and maintenance.
Ex: normal overproduction of nerve cells in developing mammalian CNS makes nerves compete for survival factors (limited supply) that are secreted by target cells that they connect to .
Nerve cells that die must have active a default death pathway that must be inhibited by survival signal for them to survive.
37
What is the role of extracellular survival factors in apoptosis?
Extracellular survival factors may STIMULATE TRANSCRIPTION of anti-apoptotic Bc12 protein which leads to blocking of apoptosis.
38
What is the difference between growth factor and mitogen. What are their similarities?
Growth factor and mitogens DIFFER in the effect each have on CELL BEHAVIOR.
mitogen- cause the cell to replicate, and stimulate cell division
Growth factor- causes cells to grow and cell to become larger; stimulate cell proliferation
Growth factor and mitogens are both extracellular signals.
39
What are myoblasts and where are they located? What is their function.
Myoblasts (aka Satellite cells) are muscle stem cells in adult muscle.
Myoblasts- dividing cell that can produce muscle; aka satellite cells, they receive signals to inhibit over-proliferation.
40
What is myostatin and its function?
Myostatin- extracellular signaling molecule that does opposite of mitogen. Myostatin PREVENTS cell from dividing AND becoming MUSCLE.
Muscle fibers secrete myostatin, which is a TGF beta family member, in order to inhibit proliferation and differentiation of myoblasts.
41
What cellular structure secretes myostatin, and for what use? What kind of molecule is myostatin? What happens to mice who lack myostatin? As well as cattle with mutation in myostatin gene?
Muscle fibers secrete myostatin, which is a TGF beta (transforming growth factor) family member, in order to inhibit proliferation and differentiation of myoblasts.
mice that LACK myostatin have muscles 2-3x than normal.
Cattle with mutations in myostatin gene are double-muscled.
42
Describe the evolution of multicellularity. How do cells specialize in their functions?
Cells in the human body have lost capacity for independent survival. instead, cells are members of cohesive and integrated organism.
Each cell type is highly specialized, each having particular biochemistry, behaviors, shape, and arrangement that serve the needs of the body as whole.
43
How many cells are in the human body? how many distinct cells in adult human body? What do they all have in common?
There are more than 10^14 cells in human body (10^11 in milky way)
There are 210 distinct varieties of cells in the adult human body.
They all have the SAME GENOME.
44
What happens to undifferentiated cells during development?
Similar-looking undifferentiated cells give rise to very different adult organisms through process of DEVELOPMENT.
45
What type of epithelium is skin?
Skin is stratified squamous epithelium.
46
What happens to our cells throughout our lives?
Throughout our lives, a fraction of our cells are stem cells and progenitor cells that divide and divide into mature cells of our tissues and organs.
a bulk of our cells are not dividing or differentiating.
47
What makes development an ongoing process?
Development does not stop with birth, puberty, adulthood or age.
(cells keep shedding dead cells and replacing all the time, ex: CNS,, lens cells and oocytes (cell turnover for life).
48
What are the three main factors that contribute to the stability tissue organization?
1. cell to cell communication: direct contact and diffusible signals will influence the survival, proliferation and behavior of cells. Ex: tissue growth can induce formation of blood vessels; nerves die if they do not find cell to innervate.
2. Selective Cell adhesion- Cadherins and other cell adhesion molecules follow certain molecular rules such as homophilic binding. Cells form selective attachment to other cells or to basement membrane or ECM. Loss of attachments can change cell behavior.
3. Molecular cell memory- gene expression patterns established during development are stabilized, thus maintaining cell identity throughout life.
Even as cells proliferate and generate new cells, they pass on this inherited to their cellular progeny.
49
What is the role of basement membrane or basal lamina?
Basement membrane or basal lamina DIVIDES epidermis and dermis. it surround surface of epithelial and endothelial cells.
50
What are three layers of skin and their components?
The three layers of skin:
1. Epidermis- contains keratinocytes (protection against foreign invaders ), melanocytes (pigment, provide skin color), and Langerhans cells (immune response)
2. Dermis: loose connective tissue- fibroblasts, lymphocytes, collagen fibers, and and endothelia cell
Dense connective tissue- fibroblasts, elastic fiber and collagen fiber
3. Hypodermis- made of fatty connective tissue.
51
Compare what happens to skin cells at the basal membrane and as they move to the top of layer.
in basal membrane layer- there are signals that mean cells are allowed to divide.
As cells like Keratinocytes, move upwards towards the surface of skin (top layer), the cells enlarge, flatten and DIE.
52
What type of epithelium is intestine? Distinguish where the dividing and nondividing cells are in the crypt of intestine. Which cells divide slowly vs rapidly?
Intestine has simple columnar epithelium, also has microvilli.
In the crypt, the dividing cells are at the bottom, with stem cells at bottom, and precursor cells at middle of crypt that also divide. The nondividing cells are at the top (they are terminally differentiated) and include absorptive and secretory cells.
Stem cells- divide slowly
Precursor cells- divide rapidly.
53
What are paneth cells and their functions?
Paneth cells are non-dividing, terminally differentiated cells that are at bottom of crypt in intestine (next to stem cells)
Paneth cells are secretory epithelial cells that produce antimicrobial proteins.
54
What kind of cells do self-renewing tissues have? What are features of stem cells?
Self-renewing cells have STEM cells.
The features of stem cells:
1) multipotent (many cell types) or pluripotent (all cell types of body); even totipotent (all cell types AND extraembryonic tissues)
2) unlimited division potential
3) daughters either remain stem cells or become committed to differentiation.
55
What are two ways cells stem cells can divide? what contributes to stem cell symmetry? Which type of stem cell division occurs rapidly vs slowly?
Stem cells can divide symmetrically or asymmetrically.
Signaling between stem cells and their daughter cells or other cells in the niche, may determine the symmetry, asymmetry or commitment.
The FAST divisions occur with stem cell ASYMMETRY.
the SLOW divisions- occur with stem cell dividing SYMMETRICALLY
56
How many liters of blood do people usually have?
People usually have 5 L of blood.
57
What are the two types of non-dividing, differentiated intestinal cells?
Absorptive cell (absorb nutrients) and secretory cell (ex: goblet cell secretes mucus)
58
What common stem cells are blood cells generated from? list the components of all blood cells derived from this stem cell.
```
All blood cells are produced throughout life, have limited life spans and are generated from common stem cell; the HEMATOPOIETIC stem cell.
blood cells derived from hematopoietic stem cell;
-Erythrocytes (RBCs)
-Leukocytes or WBCs;
-have granulocytes
-neutrophils, eosinophils, basophils
Lymphocytes: b and t cells
-monocytes
Platelets (fragments of megakaryocytes)
Osteoclasts
```
59
What are the the three main granulocytes and their functions?
What structure does a monocyte eventually become?
Three main granulocytes of WBC (contain many lysosomes and secretory vesicles)
1. Neutrophils- phagocytose bacteria (fight infection)
2. Basophils- secret histamine
3. eosinophils- attack parasites.
monocytes eventually become MACROPHAGES (engulf bacteria)
60
Describe where specialized cells are derived from and compare and contrast stem cells and differentiated cells; end result of these cells.
What happens to differentiated cells?
Specialized cell types are derived from MULTIPOTENT STEM cells (different number of each specialized cell type are produced).
-Stem cells divide slowly and give rise to rapidly-dividing cells (COMMITTED PRECURSOR cells or TRANSIT-AMPLIFYING cells). These precursor cells are fated to differentiate.
The differentiated cells DO NOT divide. They move away from stem cells.
In the intestine, the cells of villus move up and differentiated cells of crypt, paneth move DOWN).
ALL differentiated cells eventually die via APOPTOSIS and are phagocytosed.
61
What role do Paneth cells play in crypt of small intestine? what helps maintain stem cell identity?
What is the cycle time for dividing between stem cells and rapidly dividing precursor cells?
Paneth cells in crypt create stem cell NICHE.
Paneth cells do Wnt signaling, and other signals from nearby cells contribute to maintaining stem cell identity
Stem cell cycle time: 24 hours.
Rapid dividing cells (precursor)- 12 hours.
62
Describe what Wnt signaling is and how it helps define stem cells. Where in the wnt pathway activated vs inactivated?
Wnt signaling maintains proliferation zone in the crypt and helps define stem cells of intestinal crypt.
Wnt pathway active at bottom of crypt, leading to cell proliferation.
Wnt pathway inactive from top and middle of crypt where there is no cell proliferation
63
What occurs with Wnt signal vs without Wnt signal?
Without Wnt signal: the Wnt receptor will be inactive, which will cause signaling protein to be inactive and activation of APC complex that causes degradation of Beta catenin (effector) and inactive TCF complex- Wnt responsive genes OFF.
With Wnt signal: binding of Wnt signal (ligand) to Wnt receptor, will activate receptor, activate signaling protein and entire signaling cascade (active signal protein to inactivate APC complex and release Beta-omega catenin and active TCF complex) causing TRANSCRIPTION of Wnt-Responsive and PROLIFERATION of Gut stem cells.
64
Describe the typical relationships in in hematopoietic system.
lineage commitment occurs in STEPS.
precursors continue to divide and are essentially transit amplifying cells.
Ex: stem cell- hematopoietic
Precursor- lymphoid, NK/T, granulocyte/macrophage, myeloid, megakaryocyte/erythroid
Differentiated cells- NK cell, T and B cells, neutrophil/basophil/eosinophil, macrophage, mast cell, platelets, erythroblast/erythrocyte.
65
What are organoids and how do they form?
Organoids are formed from aggregates of pluripotent cells.
Organoids are small organ-like structures (group of cells grown in lab that mimic cell arrangement of fully grown organ), like eye-like structures.
66
What are IPS cells, and where can they be derived from? What solution do IPS cells provide?
IPS- induced pluripotent Stem cell can be derived from an individual's own fibroblasts with minimal invasiveness. IPS can then be reconverted back to ES like cell and differentiate into any type of human cells (fat cell, neuron, heart muscle cell)
process: (take culture of fibroblasts from skin biopsy, introduce transcription regulators, form IPS cell)
IPS cells offer a solution to IMMUNE REJECTION PROBLEM, and provide material for studying patient-specific disease mechanisms.
67
What is immune rejection?
| What diseases will eventually be curable when stem cell engineering is engineered?
Immune rejection: is when an organ's immunes system rejects a donor organ, as it sees it as foreign and attempts to eliminate or destroy it.
once stem cell engineering achieved: you may cure
-Muscular dystrophy, Parkinson's disease, type 1 diabetes, heart attack, spinal cord injury and neurodegenerative diseases,
68
What cells are used to make Embryonic stem cells? What kind of cells are embryonic stem cells?
Cells of the INNER CELL MASS of BLASTOCYST (early embryo) are used to make EMBRYONIC STEM (ES) .
Embryonic stem cells are PLURIPOTENT, if not TOTIPOTENT and can be cultured Indefinitely.
similar cells can be derived from unused human IVF embryos.
69
How does in vitro differentiation lead to production of different cell types?
In vitro differentiation protocols require knowing and administering specific factors and culture conditions to produce different cell types.
pluripotent stem cells can differentiate and create neurons and glial cells.
70
Where do Human Embryonic stem cells come from? What other ways can ES-like cells be obtained?
Human ES cells come from embryos from in vitro fertilization (IVF).
ES-like cells (with same developmental potential) can be obtained:
- Somatic cell Nuclear transfer (SCNT)- nucleus of patient's cell will be transferred to cytoplasm of an ES or ES-like cell.
-Co-transfection of a cocktail of 3 or 4 master regulatory factors into a differentiated cell to convert it into IPS cell
Factors: Oct3/4, Sox2, Myc, Klf4 or Oct3/4, Sox2, Nanog, Lin28
(when cocktail of three or four factors expressed in fibroblast, few of cells revert to ES-like state becoming IPS cells).
71
What is SCNT? How does this process occur? What it can it be used for?
SCNT- Somatic Cell nuclear transfer- process of cloning.
you are creating a viable embryo from nucleus of body cell fused into empty egg cell to. This is used for reproductive cloning (clone a calf) and personalized ES cells (therapeutic cloning)
This SCNT technique is highly variable and many attempts are needed for one success.
EXTENSIVE EPIGENETIC REPROGRAMMING of differentiated cells is required (a process that is inefficient and inexact)
72
Describe the reason of why cancer cells arise and how it affects multicellular organisms. What kind of disease is cancer?
Cancer cells break the most basic rules of cell behavior that multicellular organisms are built and maintained upon.
Cancer- GENETIC disease, where tumors eventually develop through process that resembles evolution and natural selection.
73
How do cancer cells misbehave?
Cancer cells escape normal growth controls on somatic cells, compete with neighbors for blood supply and space, and move away from their origins and grow elsewhere in body.
74
List the the different forms of cancer, in terms of tumor type.
What kind of medical tests are used to visualize mestatases>
Neoplasm- tumor, a growing mass of abnormal cells
BENIGN tumor- a tumor that remains a single mass, and me be possible to remove by SURGERY
MALIGNANT- tumor that can invade tissues (what makes cancer named "CANCEROUS"
MESTATASES- secondary tumor that are the result of the [spreading of primary tumor, not possible to remove by surgery alone, must use Chemotherapy, radiation or combination of all three.
Medical tests like CT and PET scans with radioactive FDG are used to view metastases.
75
How many different types of cancer are there? how many organs can develop cancer?
There are more than 200 different types of cancer; more than 60 organs that can develop cancer.
Each organ is made up of multiple tissue types.
76
How are tumors classified? what are the common types of tumors that can be malignant?
Tumors are classified by their tissue of origin
Types of tumors that can be malignant:
1. CARCINOMAS- cancers arising from EPITHELIAL cells, about 90% of all tumors
2. SARCOMAS- cancers arising from muscle cells, fat cells, bone, blood vessels or connective tissue.
3. LEUKEMIAS- Cancers arising form hematopoietic (blood ) cells
4. Tumors of nervous system.
77
Why are most of the human cancers epithelial in origin?
Most cancers are epithelial by origin because the epithelial cells are more abundantly found in the body, covering skin and lining organs.
Epithelial cells are also constantly exposed to environmental insults like chemicals and solar radiation
adenoma- benign; adenocarcinoma- malignant
78
what kind of genes affect DNA repair and other chromosomal components?
What happens if there is a mutation in this gene? provide and example of this kind of gene.
DNA MAINTENANCE GENES affect DNA repair, fidelity of replication, chromosome alignment during mitosis and chromosome stability.
cells that have mutations in DNA maintenance genes will develop cancers.
BRCA1/2 are DNA maintenance genes.
some cancer cells have a mutation rate 10-20 times mutation rate of normal cells.
79
What are the examples of genetic instability in cancers? What are the factors that contribute to genetic instability?
forms of Genetic instability in cancers:
-point mutations, small insertions and deletions (indels), chromosomal rearrangements, chromosomal translocations, duplications or deletions of whole chromosomes (Aneuploidy).
Factors contributing to genetic instability:
-defects in DNA replication, DNA repair, defect in cell-cycle checkpoints and errors mitosis.
80
What leads to progression of cancer cells? How do theses mutations occur? What can increase the chances of developing a tumor?
For cancers cells to progress, the cells must accumulate somatic cells.
mutations occur due to inherent error rate of copying DNA as cells divide. Mutations that predispose to cancer may run in families.
Increased exposure to agents will cause mutations to increase chancers of tumor developing.
81
provide examples of how cancer may not appear till after long exposure to causative agent.
Occupational exposure to asbestos for 30-50 years: mesothelioma (affects lungs)
Heavy smoking for 10-20 years: lung cancer
Atomic bombs at Hiroshima and Nagasaki for 5 years of exposure: leukemias
82
How many mutations required to cause cancer? What is cancer incidence? Describe the delayed onset of cancer when exposed to carcinogen
Single mutations is NOT enough to cause cancer. Cancers require multiple genetic changes to be malignant (10 or more changes)
Cancer incidence increases with age (proving, that more than one mutation required to turn normal cell into cancerous cell).
The longer you are exposed to causative agent, the more likely you are to have cancerous cells.
83
Where must mutations occur for cancer to form? How many cell divisions does an individual have in life?
What is the spontaneous mutation rate per cell division?
Mutations must occur in proliferating cells for cancer to form.
terminally differentiated cells are not at all likely to form tumors.
estimate of cell division in individual's life: 10^16
average spontaneous mutation rate: 10^-6 per cell division (rate without environmental causes)
every single gene is likely to have acquired a mutation on more than 10^9 separate occasions in one cell or another.
84
what determines the characteristics of particular cancers?
| Where do melanocytes develop from?
The characteristics of particular cancers reflect cells of its origin.
Melanocytes develop from migrating neural crest cells.
melanomas easily form metastases.
metastases of melanomas can be pigmented like \melanocytes .
85
Describe what a karyotype of cancer cells would look like and include its characteristics.
What is spectral karyotyping?
Karyotype of cancer- would have multiple chromosomal abnormalities visualized as a combination of colors mixed together or different colors representing the chromosomes in patient with cancer.
Spectral Karyotyping- "Chromosomal painting" is a way of analyzing chromosomes with abnormalities such as those seen in cancer cells. Cancer cells are GENETICALLY UNSTABLE
A cancer cell has aneuploidy- incomplete set of chromosomes.
86
Describe the kind of karyotype and chromosomes in cancer cell vs normal cell
A cancer cell has aneuploidy- incomplete set of chromosomes.
A normal cell has euploid- has complete set of chromosomes.
87
What contributes to the progression of tumors?
Tumor progression involves successive rounds of mutation and selection.
one mutation will give cell advantage, for cancer cell to survive and proliferate; second mutation increases advantage again, third mutation increases advantage for further survival and proliferation and makes the cell invasive.
88
How any mutations or alterations in genes are needed to drive tumor progression?
as many as alterations in 20 genes are needed to drive tumor progression.
subset of genes are found to be repeatedly mutated in particular type of cancer.
In breast and colorectal cancers, cancer cells have accumulated enough mutations to cause aa change in proteins of 100 genes.
89
How do cancer critical mutations affect the characteristics of cancer cells?
they may cause increase rate of division, disable programmed cell death (apoptosis or autophagy), decrease propensity for differentiation, prevent senescence due to stress and damage, or affect any of the other characteristics of cancer cells.
90
What are the major characteristics of cancer cells?
Characteristics of cancer cells:
1. Reduced dependence on signals from other cells for survival (mutations)
2. Increased tolerance for stress and internal derangement (defective apoptosis)
3. Indefinite proliferation (normal cells have limitations on number of divisions they undergo) (cell senescence due to telomere shortening)
4. Genetic instability (once DNA repair mechanisms are damaged, mutations more frequent)
5. Increased invasiveness- loss of cadherins and adherence molecules, signals they generate (allow movement)
6. High need for nutrients (cancer cells use glycolysis for ATP, less efficient)
7. Survival and proliferation in abnormal locations (independence on extracellular signals and lack of apoptosis remove barriers from growth out of place)
8. ability to modify surrounding tissues (cancers can remodel tissues and cause non-tumor cells to support tumor growth)
9. Escape from immune surveillance- immune system requires certain markers to recognize and destroy aberrant cells (tumor cells suppress or eliminate markers)
91
What are three main things that cancerous growth depend on?
Cancerous growth depends on defective control of cell death, cell differentiation or both.
increased cell division and decreased apoptosis lead to tumors.
92
define critical cancer genes, oncogenes, protooncogenes, and tumor suppressor genes.
Cancer critical genes- not necessarily cancer causing; they regulate cell proliferation, cell growth, DNA repair, cell death and survival, apoptosis and gene expression.
oncogenes- genes that actively cause cancer, usually mutant form and genetically dominant
Protooncogenes- genes that when mutated can become oncogenes.
Tumor suppressor genes- genes whose absence causes cancer, they normally prevent formation of cancer; genetically recessive
93
what are the two types of mutated cancer genes? differentiate between oncogenes and tumor suppressor genes?
Two types of mutated cancer genes:
1. Oncogenes- Dominant mutation (Gain of function)- excessive activity required (not normally have in normal cells). You activate mutation in proto-oncogene to turn it into oncogene and stimulate cell survival/proliferation
2. Tumor suppressor genes- recessive mutation (loss of function)
-You inactivate on BOTH copies of tumor suppressor gene (ABSENCE of gene) promote cell survival and proliferation.
beware, that inactivating one copy of TS gene has no effect on cell.
94
What are different ways of activating an oncogene?
Ways of activating a proto-oncogene to become an oncogene:
1. Mutation in Coding sequence- leading to hyperactivity of protein
2. Gene amplification leading to normal protein overproduction
3. Chromosome rearrangement where either a nearby regulatory DNA sequence causes normal protein to be overproduced or fusion to actively transcribed gene produces hyperactive fusion protein
ex: Philadelphia chromosome.
95
How does APC affect Wnt signaling?
APC is a tumor suppressor that prevents cells from growing in uncontrollable way (like how it occurs in cancer)
When APC is active, the B-catenin will be degraded and Wnt responsive Genes are OFF leading to no proliferation of stem cells.
When APC inactive (wnt signal bound to receptor), B- catenin released and activate TCF complex leading to TRANSCRIPTION of Wnt responsive genes PROLIFERATION of cells
APC inhibits Wnt signaling pathway.
96
What are the possible ways of inactivating both copies of tumor suppressor genes
ways of inactivating both copies:
1. who paternal chromosome lost- NONDISJUNCTION
2. Region containing normal gene DELETED
3. Loss of function mutation in paternal gene (normal before)
4. Gene activity SILENCED
you can also eliminate normal gene through mitotic recombination, point mutation gene conversion or chromosome loss then duplication.
Normally you have heterozygosity (loss of function mutation in TS gene of maternal chromosome and normal TS gene in paternal chromosome).
97
Describe the type of pathologies found regarding issues with colons, including the mutation and the specific gene.
some people can have an inherited predisposition for colon cancer through disease called Familial adenomatous polyposis coli (FAP).
This disease is caused by a defect in the APC gene (adenomatous polyposis coli).
98
What is the development process of colorectal cancers?
Colorectal cancers can evolve slowly through succession of visible changes.
Initially, you may see an adenomatous Polyp of colon that is non-cancerous.
Later on, the colon can develop into a carcinoma, where colon cancer cells now invade surrounding tissue.
99
What main cancer critical genes are common to large fraction of colorectal cancers?
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Main cancer critical genes are :
Oncogenes:
1. K-ras - affect receptor kinase signaling
2. B-Catenin that affects Wnt signaling
Tumor suppressors:
3. APC- wnt signaling
4. p53- respond to stress and DNA damage
also TGFB receptor II and SMad4
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100
Describe the steps of tumor progression and highlight the specific cancer critical genes involved.
Steps of tumor progression:
1. initially begin with normal epithelium, before tumor suppression gene APC is lost
2. Now have excessive epithelial proliferation and oncogene RAS is activated creating small tumor.
3. Small tumor becomes larger tumor since another Tumor suppressor has been lost.
4. Large tumor now becomes invasive after losing third TS p53.
5. Losing p53 will make tumor become invasive (carcinoma) lead to accumulation of other mutations, forming metastasis
101
What is each case of cancer characterized by? What kind of defects (that can be seen in karyotype) do colorectal cancers have?
Each case of cancer characterized by its own array of genetic lesions (tumors also have own set of genetic lesions)
Colorectal cancers have defects in DNA mismatch repair that can be seen in karyotype (with chromosome abnormalities)
102
who discovered the Philadelphia chromosome? which of the 23 chromosomes is this Philadelphia chromosome and what kind of mutation is it?
Scientists Nowell and Hungerford discovered Philadelphia chromosome in 1961.
This Philadelphia chromosome is abnormality seen on chromosome and 22 and chromosome 9 (translocation part of 9 on 22)
103
Describe the importance of the drug Gleevec in cancerous cells. How does Gleevec treat different tumors?
Gleevec is a molecule that can be used to treat several tumors (leukemia, sarcoma, melanoma). This molecule can inhibit specific oncogene proteins.
Gleevec will inhibit or block the oncogenic kinase, and prevent phosphorylation of target protein that signals for proliferation and survival of cell, causing leukemia.
if ocongenic kinase active, protein phosphorylated and signal of proliferation.
Gleevec affects action of Bcr-Abl and other kinases like platelet-derived growth factor receptor (PDGFR) and Kit
104
What provides evidence that tumors arise from single cells? provide an example for this evidence.
evidence for tumors arising from single cells is due to having UNUSUAL mutations.
if all cancer cells shared the same unusual mutations, they are very likely to be a clone.
Philadelphia chromosome translocation seen in patient with Chronic myelogenous Leukemia (CML is an unusual mutation)
most causal genetic changes in cancers: more subtle, clonal origin.
105
what is the result of translocation of Philadelphia chromosome? Describe the formation of BCR-Ab1 fusion protein.
Result of translocation of Philadelphia chromosome: generation of BCR=Ab1 gene.
106
what is the result of translocation of Philadelphia chromosome? Describe the formation of BCR-Ab1 fusion protein and highlight the part of gene that causes cancer.
Result of translocation of Philadelphia chromosome: generation of BCR-Ab1 fusion protein.
The BCR-Ab1 resembles the individual Abl and Src (50% identical)
The primary cancer causing feature of protein is that is its UNREGULATED EXPRESSION (fusion protein causes cell division to be sped up uncontrollably leading to leukemia)
107
Explain how immunotherapies can cure incurable cancers.
Immunotherapies that target inhibitory regulation of T-cells such as anti-PDI antibodies, can cure incurable cancers.
Having anti-immune antibodies that disinhibit (prevent inhibition) cytotoxic T cells that recognize novel parts of proteins on cancer cells (help reduce and eliminate tumor through binding antibody to T cell)
ex: antibody ipilimumab bind to T cell CTLA- resulted in elimination of tumor in patient.
