Lectures Oncology Exam II (with KW seminars)
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
Lecture 9 – KW seminar: Health-related quality of life in cancer ......................................................... 97
Lecture 10 – KW seminar: Hematology. .............................................................................................. 102
Lecture 11 – KW seminar: Radiotherapy ............................................................................................. 109
Lecture 12 – KW seminar: Principles of immunotherapy for head and neck cancer. ......................... 116
Lecture 13 – KW seminar: Lung cancer ‘Clinic’.................................................................................... 126
Lecture 14 – KW seminar: Molecular Imaging .................................................................................... 134
In lecture 7, 8, and 12 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.
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
Lecture 9 – KW seminar: Health-related quality of life in cancer ......................................................... 97
Lecture 10 – KW seminar: Hematology. .............................................................................................. 102
Lecture 11 – KW seminar: Radiotherapy ............................................................................................. 109
Lecture 12 – KW seminar: Principles of immunotherapy for head and neck cancer. ......................... 116
Lecture 13 – KW seminar: Lung cancer ‘Clinic’.................................................................................... 126
Lecture 14 – KW seminar: Molecular Imaging .................................................................................... 134
In lecture 7, 8, and 12 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.
