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Extensive notes for Oncology exam 2 (Lectures and Book WITHOUT KW SEMINARS) - Molecular Biology of Cancer Auteur: Pecorino, Lauren | ISBN: 9780198833024$6.89
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Extensive notes for Oncology exam 2 (Lectures and Book WITHOUT KW SEMINARS) - Molecular Biology of Cancer Auteur: Pecorino, Lauren | ISBN: 9780198833024
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Course
Oncology (AB_1184)
Institution
Vrije Universiteit Amsterdam (VU)
Book
Molecular Biology of Cancer
This document contains extensive notes of the lectures that belong to the second exam of oncology WITHOUT KW SEMINARS. Many pictures are included with an explanations and also things that were mentioned in the book but not during the lexctures are included. It is in it English because the exam will...
Oncogenic mutations sites in relevant proto and oncogenes
Leerstof Oncology Ch7/14
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Vrije Universiteit Amsterdam (VU)
Gezondheid En Leven
Oncology (AB_1184)
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Lectures Oncology Exam II
Index
Lecture 1 – Chapter 7: Apoptosis ............................................................................................................ 2
Lecture 2 – Chapter 8: Stem cells and differentiation. ......................................................................... 16
Lecture 3 – Chapter 9: Metastasis. ........................................................................................................ 26
Lecture 4 – Chapter 14: Technology and drug and diagnostics development ...................................... 36
Lecture 5 – Chapter 10: Angiogenesis ................................................................................................... 45
Lecture 6 – Chapter 11: Nutrients, hormones and gene interactions. ................................................. 54
Lecture 7 – Chapter 12: Tumor immunology and immunotherapy and part of chapter 13:
Inflammation ......................................................................................................................................... 65
Lecture 8 – Chapter 13: Infectious agents and inflammation ............................................................... 86
In lecture 7 and 8 the teacher said which information was especially important for the exam which I
marked with (important for exam).
,Lecture 1 – Chapter 7: Apoptosis
Part I: General Introduction
Definition of apoptosis
- Apoptosis is a form of cell death.
- Apoptosis is a regulated and orderly destruction of a cell through a genetically encoded
process also known as programmed cell death (PCD).
- Apoptosis is a type of ‘cell suicide’ that is intrinsic to the cell.
- Apoptosis is a crucial tumor suppression mechanism within the body, because it gets rid of
cells that have extensive DNA damage and the potential to lead to cancer.
Apoptotic process.
- Apoptosis is organized neat, and tidy, leaving behind little evidence of the preexisting cell.
- The cell undergoing apoptosis is swept clean during phagocytosis by macrophages or other
neighboring cells that recognize molecular flags (phosphatidyl serine).
o When a cell committed suicide it is taken up by another cell that recognize
phosphatidyl serine on the outside of the apoptotic cell membrane.
o Phosphatidyl serine is normally on the inside of the cell but when a cell is dying then
it flipflops to the outside of the membrane.
Function of apoptosis.
- Active ATP dependent process that physiological is already present in many organs:
o Developmental morphogenesis → The developmental process by which tissues
and organs acquire the shape that is critical to their function.
▪ Example → By the apoptotic process fingers and toes are formed during
embryogenesis.
o Controls cell numbers → A lot of cells are dividing but also a lot of cells are
dying → Balance between dividing and apoptosis.
o Removal of damaged cells → When cells are too much damaged then the cell will
die through apoptosis.
o Negative and positive selection of lymphocytes → When lymphocytes bind to self
antigen they will get a signal to induce apoptosis.
o Cytotoxic effect of radio- and chemotherapy → In treatment of cancer we try to kill
the cancer cells by triggering apoptosis.
Apoptosis in humans
- Estimation of apoptosis in human → 25 x 10^6 apoptosis per second.
o 2,2 kg cells per day.
- 25 x 10^6 mitosis per second.
o So cell number is consistent.
,Apoptosis versus Necrosis
- Apoptosis:
o Cell shrinkage.
o Membrane blebbing → Bulges of cell membrane → Zeiosis.
o Organelles stay intact.
o Apoptotic bodies.
o Chromatin condensation and fragmentation.
o No inflammation.
- Necrosis:
o Cell swelling.
o Leaky membranes because of holes forming in the membrane because of the
swelling.
o Organelles are damaged.
o Cell lysis → Cell content released into the environment.
o Chromatin damaged.
o Inflammation → Because cell content is released into the surrounding it leads to
attraction of cytokines and chemokines.
Apoptosis morphology in a lymphocyte.
- A lymphocyte can be recognized by it’s big nucleus and it’s small rim of cytoplasm.
- First you see shrinkage of the cell.
- Then you see blebbing of the outside membrane.
- Then you see condensation of the chromatin.
- Then the nucleus will fall into little fragments → Spheres.
- The spheres will later on result in the apoptotic bodies.
- The apoptotic bodies will be recognized by the macrophages
and phagocytosed.
Apoptosis: Electron microscopy
- On the left you see a necrotic cell.
o The cell is larger than a normal cell and you see holes in the membrane
and leakage of the cell content.
o On the outside of the cell you can see the holes (left bottom picture).
- On the right side you see one normal cell (N) and one cell with a collapsed
nucleus undergoing apoptosis (A).
o On the outside of the cell you see the blebbing of the membrane.
Induction of apoptosis
- On the picture you see T cell leukemia cell line that is
incubated with chemotherapeutic drugs.
- MGG stain → Staining the nucleus purple and the cytoplasm
blue.
o You see that with the drugs the cell nucleus became
smaller → Condensated spheres.
- Dapi (fluorescent microscope) → The more fluorescent you
see, the more cells are undergoing apoptosis.
, Apoptosis signaling
- Induction of apoptosis:
o Programmed → During embryogenesis.
o Loss of growth factors, or adhesion → When cells lack adhesion or growth factor
signaling the cells will die through apoptosis.
o Death receptors of the TNFR family → Stimulating the death receptor will lead to
apoptosis.
o T- and B cell antigen receptors → When stimulated the cell can die.
o Cytotoxic T lymphocytes can induce apoptosis.
o DNA damage → Can be caused by radiation, chemotherapy.
o Stress conditions.
- What happens:
o The induction of apoptosis leads to mitochondrial changes.
o This leads to activation of the caspase family.
o The caspases (proteases) will cleave structural and functional proteins by proteolytic
cleavage.
o Loss of function of the proteins leads to induction of apoptosis morphology.
Caspases
- Caspases are cysteine-proteases synthesized as zymogens → Inactivated form.
o They first have to be cleaved to become an activated form.
- Requirement for an aspartatic acid at the P1 position.
o The caspases contain an amino acid sequence of 4 amino acids that is specific for the
different caspases and this amino acid sequence is important for recognition and
cleavage of the caspase by another caspase.
- 14 family members cloned.
- Caspases 2, 3, 6, 7, 8, 9 and 10 are involved in apoptosis.
- Caspases can be divided into:
o Initiators → 2, 8, 9, and 10.
▪ Upstream in apoptotic pathway.
o Effectors → 3, 6, and 7.
▪ Activated by the initiator caspases and then they will cleave the structural
and functional proteins.
o Inflammatory → 1, 4, and 5.
▪ These caspases are especially involved in neurodegenerative diseases.
Caspase activation
- Caspase domain of an unprocessed caspase contains:
o A pro-domain.
o A large subunit domain.
o A specific amino acid sequence of 4 amino acids.
o A spacer that connects the large subunit domain
with the small subunit domain.
o A small subunit domain.
- In order to activate the caspase 2 cleavages has to occur:
o The spacer is removed and the large subunit domain is bound to the small subunit
domain → Partially processed.
o The pro-domain is removed → Fully processed and active caspase.
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