LT19-21
55 important questions on LT19-21
What is seed and soil?
Where tumors metastasize, infinity between tumor types and where they develop metastasis.
Number of cells in the primary tumor, those cells have an affinity to some specialized tissue.
Number of cells in the primary tumor, those cells have an affinity to some specialized tissue.
What is thrombosis an indication for?
Someone has developed cancer and you have tumor cells in the circulation and get stuck somewhere
What does EMT mean? What are the characteristics?
Epithelial cells become mesenchyaml.
Epithelial cell:
- cell polarity
- cell adhesion (to each otehr and to ECM)
- stationary
- high level of E-cadherin
- low level of N-cadherin
Mesenchymal
- no cell polarity
- loss of cell adhesion
- ability to migrate and invade
- low level of E-cadherin
- high level of N-cadherin
Epithelial cell:
- cell polarity
- cell adhesion (to each otehr and to ECM)
- stationary
- high level of E-cadherin
- low level of N-cadherin
Mesenchymal
- no cell polarity
- loss of cell adhesion
- ability to migrate and invade
- low level of E-cadherin
- high level of N-cadherin
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How can tumors invade?
Tumor cells can express enzymes which are defined as matrix metallo proteinases.
They have the capacity to digest the components of the ECM, that is how tumor cells go through the basement membrane.
They have the capacity to digest the components of the ECM, that is how tumor cells go through the basement membrane.
What is matrix metallo proteinase?
MMP1.
Collagenease, molecules like fibornectin as well.
Enzymes can destroy the components of the ECM, and tumor can gain the capacity to express such enzymes. This can be classified as one of the hallmarks of cancer.
Collagenease, molecules like fibornectin as well.
Enzymes can destroy the components of the ECM, and tumor can gain the capacity to express such enzymes. This can be classified as one of the hallmarks of cancer.
How is the activation of metastatic programs in tumor cells?
TGF beta pathway.
If you have TGF beta expressed in surrounding tissue that will bind to the receptor.
Activation of such pathways promotes the invasion and metastatic capcity of tumor cells by repressing the expression of genes like E-cadherin, but activating the expression of genes like MMP.
Tumor cells that gain the ability to destroy the surrounding tissue.
Inflammatory respones -> IL, cells can produce TGF beta, strong immune suppressor
If you have TGF beta expressed in surrounding tissue that will bind to the receptor.
Activation of such pathways promotes the invasion and metastatic capcity of tumor cells by repressing the expression of genes like E-cadherin, but activating the expression of genes like MMP.
Tumor cells that gain the ability to destroy the surrounding tissue.
Inflammatory respones -> IL, cells can produce TGF beta, strong immune suppressor
Which role do fibroblasts play in cancer?
Tumor cells acquire some properties that allow them to manipulate fibroblasts that are constituence of the stroma.
They transform a normal fibroblast to cancer associated fibroblast.
It got properties that provide tumor development and tumor growth.
They start producing molecules pro-tumors and attract immune cells, which would cause immune suppression.
Stimulation of VEGF
They transform a normal fibroblast to cancer associated fibroblast.
It got properties that provide tumor development and tumor growth.
They start producing molecules pro-tumors and attract immune cells, which would cause immune suppression.
Stimulation of VEGF
What is the role of platelets in cancer?
Function as a physical barrier.
Platelets migh have some molecules on them eg growth factors that keep the tumor cells happy while they're circulating.
Platelets migh have some molecules on them eg growth factors that keep the tumor cells happy while they're circulating.
What is the role of angiogenesis in tumors?
Suppresion of growth factors can activate endothelial cells in pre-existing vessels.
These will grow and form new vessels which will irrigate the tumors
You activate this if you don't have enough oxygen in tissues (normal physiological person). If you have hypoxia, there is a signal to activate the formation for new vessels, so the tissue can get more oxygen and nutrients to surpass the stage of hypoxia
These will grow and form new vessels which will irrigate the tumors
You activate this if you don't have enough oxygen in tissues (normal physiological person). If you have hypoxia, there is a signal to activate the formation for new vessels, so the tissue can get more oxygen and nutrients to surpass the stage of hypoxia
What are the routes of metastasis?
Blood vessels
Lymphatic vessels
Body cavities
Lymphatic vessels
Body cavities
What role play lymphatics in tumor cells?
Tumor cells can use lymph nodes to metastasize at distance.
Immune cells constantly produce growth factors.
Inflammation is pro-tumor genic.
Tumor cells are using other cells around them to sustain growth and ehance the tumor potential
Immune cells constantly produce growth factors.
Inflammation is pro-tumor genic.
Tumor cells are using other cells around them to sustain growth and ehance the tumor potential
LSVI and breast cancer.
Pathologic analysis of lymph nodes is not 100% reliable.
There might be restricted to a small part of the lymph node.
The lymph node staging is not always fool proof.
There might be restricted to a small part of the lymph node.
The lymph node staging is not always fool proof.
LSVI and endometrial cancer
Invasion in lymphatic vessels, the chance of metastaizing is higher.
Lymph node and distant metastasis
Alterations that in majority of cases, distant metastaes and lymph node metastases originated from independent subclones within the primary tumor.
For example the micro-environment int he liver is different from the lymph node.
Tumor cells need different properties tometastasize in different organs.
For example the micro-environment int he liver is different from the lymph node.
Tumor cells need different properties tometastasize in different organs.
What is vascular metastasis?
spread through capillaries and veins to various organs.
common sites are the lung, liver, bone and brain
common sites are the lung, liver, bone and brain
What is lung metastasis?
Can occur within a wide range of malignant neoplasms.
sarcomas -> osteosarcomas
Carcinomas -. breast, stomach, large intestine
kidney
malignant teratoma
sarcomas -> osteosarcomas
Carcinomas -. breast, stomach, large intestine
kidney
malignant teratoma
What is liver metastasis?
Common site for colorectal cancer (in the portal vein)
Bronchial carcinoma
Breast carcinoma
Menaome
Pancreatic cancer
Bronchial carcinoma
Breast carcinoma
Menaome
Pancreatic cancer
What is bone metastasis?
Can cause destruction of bone (pathological fractures)
Bronchial carcinoma
Breast carcinoma
Thyroid carcinoma
Renal carcinoma
prostate
Bronchial carcinoma
Breast carcinoma
Thyroid carcinoma
Renal carcinoma
prostate
What is brain metastasis
You can get a melanoma, bronchil carcinoma (NSCLC< SCLC)
often late in disease progression
tumors often don't metastasize to the brain, because of the blood brain barrier. It is a very selective obstacle that tumor cells have to surpass.
Tumor in brain has a bad prognosis
often late in disease progression
tumors often don't metastasize to the brain, because of the blood brain barrier. It is a very selective obstacle that tumor cells have to surpass.
Tumor in brain has a bad prognosis
What is a mechanism of organ tropissm?
Relationship etween metastasis in liver, lung and colon.
Tumor cells express adhesion molecules whose ligands preferentially are expessed on endohtelial cells of specific organs. They need the presenece of specific chemokine receptrs on cancer cells.
Target issue is a non-permessive environmental skeletal muscle and spleen (seldom involved)
If you have a high affinity between receptors and ligands, tumor cell will end up in this organ.
Tumor cells express adhesion molecules whose ligands preferentially are expessed on endohtelial cells of specific organs. They need the presenece of specific chemokine receptrs on cancer cells.
Target issue is a non-permessive environmental skeletal muscle and spleen (seldom involved)
If you have a high affinity between receptors and ligands, tumor cell will end up in this organ.
Where does lung cancer spread to?
Lungs, brains, liver, bone
Short latency, agressive disease course
multi-organ metastassi
Short latency, agressive disease course
multi-organ metastassi
Where does breast cancer spread to?
liver -> lung
Sequential metastasis
Sequential metastasis
Why do tuor cells don't end up in particular tissue?
Skeletal muscle and spleen are bad sites for tumors. not a friendly environment, not the right receptors.
How is the primary sites and metastatic sites?
tumor cells prepare the soil where they are going to via exosome secretion.
Exosomes contain a number of molecules proteins, growth factors, RNA or DNA.
Those exosomes are released by the tumor cells and eter the circulation.
Once they get to a place where they can extravasate, they can release all the stuff and prepare the organ where they'll end up.
For example, angiogenesis, suppress the immune system, invasion/metastasis, anchorage indeendent growth, prliferation
Exosomes contain a number of molecules proteins, growth factors, RNA or DNA.
Those exosomes are released by the tumor cells and eter the circulation.
Once they get to a place where they can extravasate, they can release all the stuff and prepare the organ where they'll end up.
For example, angiogenesis, suppress the immune system, invasion/metastasis, anchorage indeendent growth, prliferation
What is direct seeding?
Tumor spread through coelemic spaces. Tumors can go through organ and invade surruounding tissues.
If they travel through the fluids of the body cavities, they can spread to other organs.
Often for tumors of the abdomen
If they travel through the fluids of the body cavities, they can spread to other organs.
Often for tumors of the abdomen
What is a Sister Mary Josephs nodule?
Tumor cells, which are from a tissue that is different from the original tissue.
What is Krukenberg tumor?
Ovary, characteristic, you have tumor cells producing a lot of mucus. They have ring differentiation of cells. Ring shaped tumor cells.
Adenoma carciomas come from the stomach or colorectal
Adenoma carciomas come from the stomach or colorectal
What is Virchow's lymph node?
GPs often diagnose metastatic disease in supraclavicular lymph nodes, particularly on the left side, because there is the lyphatic duct and tumor cells get stuck there.
Backflow of lymph from the thoracic duct can pass into the supraclavicular nodes.
In tumors of the bronchus and some abdominal eg stomach
supraclavicular lymph nodes particularly on the left side may enlarge indicating spread.
Backflow of lymph from the thoracic duct can pass into the supraclavicular nodes.
In tumors of the bronchus and some abdominal eg stomach
supraclavicular lymph nodes particularly on the left side may enlarge indicating spread.
What metastatic sites and types of carcinomas?
- local invasion and spread (ovarian cancer)
- regional lymph nodes (LVSI)
- supraregional lymph nodes
- haemotogenous spread (lung, liver, bone, brain)
- regional lymph nodes (LVSI)
- supraregional lymph nodes
- haemotogenous spread (lung, liver, bone, brain)
What metastatic sites and types of sarcomas?
- local invasion and destructive growth
- haematogenous spread (lung liver)
- no lyphatic spread
- haematogenous spread (lung liver)
- no lyphatic spread
What role play immune reactions in tumors?
Tumor fields which are surrounded with cytotoxic T cells.
Correlation between degree of infiltration of tumors, patients that have tumors that are highly infiltrated by lymphocytes, have a much better prognosis than people where immune cels don't get to.
Interaction between tumor cells and the immune system.
The immune system can have a positiev effect ont tumor behavior
Correlation between degree of infiltration of tumors, patients that have tumors that are highly infiltrated by lymphocytes, have a much better prognosis than people where immune cels don't get to.
Interaction between tumor cells and the immune system.
The immune system can have a positiev effect ont tumor behavior
How can tumor cells be recognized by the immune system?
DNA damage activates pathways or expression of ligands at the surface of tumor cells that can be recognized by cells of the immune system.
What is the role of dendritic cells?
Tumor cells and there are some bearing antigens.
Cell death always in tumors, and macrophages clean up the mess. Dendritic cells are another type of cells and take up debris.
They are activated and migrate to lymph nodes.
The anti tumor response is initated there.
CD8 and CD4 are preferably both activated and will then migrate back to the tumor tissue, where they will recognize which cells have those antigens on the surface.
APC is essential
Cell death always in tumors, and macrophages clean up the mess. Dendritic cells are another type of cells and take up debris.
They are activated and migrate to lymph nodes.
The anti tumor response is initated there.
CD8 and CD4 are preferably both activated and will then migrate back to the tumor tissue, where they will recognize which cells have those antigens on the surface.
APC is essential
Via which mechanism do cytotoxic T cells work?
When T cells become activated, they can express Fas.
Secretion of proteased released by immune cells and those will destroy the cells.
If a tumor cell has a Fas receptor, T cell can induce cell death.
Fas receptor is loosening from the tumor, which gives properties to allow tumor cells to invade the immune system
Secretion of proteased released by immune cells and those will destroy the cells.
If a tumor cell has a Fas receptor, T cell can induce cell death.
Fas receptor is loosening from the tumor, which gives properties to allow tumor cells to invade the immune system
What does TGFb eta?
immunosuppressive effects, generation of regulatory T cells
Tell why it is a problem to target self-proteins.
You also target antigens n the normal tissues.
Antigens that arrive from somatic mutations are real tumor specific antigens, because they're not find anywhere else in the body
Antigens that arrive from somatic mutations are real tumor specific antigens, because they're not find anywhere else in the body
What is immune evasion?
Downregulation of HLA class I expression, ligands are activated by the innate damage response, if you loose the expression of the ligands
Tumor negative for HLA class I expression, surrounded by lymphocytes, but they only accummulate, they don't know where to migrate into the tissue. They're activated by dendritic cells, but since tumors dont express HLA class I, they dont know where the peptides come from.
PD-L1 expressed by tumor cells, give inhibitory signals to T cells
Tumor negative for HLA class I expression, surrounded by lymphocytes, but they only accummulate, they don't know where to migrate into the tissue. They're activated by dendritic cells, but since tumors dont express HLA class I, they dont know where the peptides come from.
PD-L1 expressed by tumor cells, give inhibitory signals to T cells
What is outgrowth of antigen-negative variants?
Clonal selection.
Generation of cloncal diversity/loss of tumor suppressor functions.
Selective pressure exerted by the tumor micro-envinorment.
Clonal slection and outgrowth of fittest tumor clones.
Generation of cloncal diversity/loss of tumor suppressor functions.
Selective pressure exerted by the tumor micro-envinorment.
Clonal slection and outgrowth of fittest tumor clones.
What phases are there in cancer immunoediting?
Phase 1: elimination of tumor cells: immune system is very competent at eliminating tumor cells at some point.
Equilibrium face: steady state where the amount of tumor cells is more or less constant. , ultiamtely you get genetic instability and/or immune selection.
This gives immune exhaustion or inhibition with tumor cell variants.
Escape phase: cancer progression, non-immunogenic tumors
Equilibrium face: steady state where the amount of tumor cells is more or less constant. , ultiamtely you get genetic instability and/or immune selection.
This gives immune exhaustion or inhibition with tumor cell variants.
Escape phase: cancer progression, non-immunogenic tumors
What are the goals of immunotherapy?
Boost cancer immunity and activation mechanisms
Target immunosuppresive pathways
Target immunosuppresive pathways
Immunotherapy, what is the strategy in T cells?
T-cell therapy
antibodies PD-1, PDL1, CTLA4
antibodies PD-1, PDL1, CTLA4
Immunotherapy, what is the strategy in dendritic cells
DC vaccination
Immunotherapy, what is the strategy in NK cells
Injection of activated NK cells
Immunotherapy, what is the strategy in antigen presentation
antigen vaccination
Immunotherapy, what is the strategy in effector cytokines
IL-2, IL-3
What is known about IL-2 therapy?
Limited success in other tumor types
Toxicity: reatment-related death, heaptic and renal dysfunction, capillary leak syndrome. It activates T cells in general.
Even T cells that recognize antigens which are normal in the body. You get abnormal inflammatory responses
Toxicity: reatment-related death, heaptic and renal dysfunction, capillary leak syndrome. It activates T cells in general.
Even T cells that recognize antigens which are normal in the body. You get abnormal inflammatory responses
What is known about T cell therapies?
You isolate T cells from the blood of a patient.
If you have tumor tissue of the patient, you intubate the T cells you isolated with the tumor cells.
Those are genetically engineered T cells.
You put an antibody fused with a T cell receptor and this antibody will recognize something that is in the outside of the cell
If you have tumor tissue of the patient, you intubate the T cells you isolated with the tumor cells.
Those are genetically engineered T cells.
You put an antibody fused with a T cell receptor and this antibody will recognize something that is in the outside of the cell
What is known about antigen therapies? viral antigen therapies
Proteins that are coded by HPV in the cells that is infecting.
Proteins for vaccination.
You hope to stimulate the immune system to recognize the proteins that are expressed in the tumor cells.
It is a specific therapy, because immune respnsoes will be directed to the virus. You dont expect toxicity
Proteins for vaccination.
You hope to stimulate the immune system to recognize the proteins that are expressed in the tumor cells.
It is a specific therapy, because immune respnsoes will be directed to the virus. You dont expect toxicity
What is known about antigen therapies? tumor associated protein
Gp100-glycoprotein enriched in melanocytes.
Not tumor specific limited efficacy.
Why isn't this very successfully? Problem of targeting proteins that are normally expressed in the human body, even if they're higher expressed in tumor cells.
It is difficult to generate immune responess against proteins that are normal part of the organism, because there is tolerance for this peptides
Not tumor specific limited efficacy.
Why isn't this very successfully? Problem of targeting proteins that are normally expressed in the human body, even if they're higher expressed in tumor cells.
It is difficult to generate immune responess against proteins that are normal part of the organism, because there is tolerance for this peptides
What is known about antibody therapies?
They use engineered antibodies.
Rituximab int reatment of B cell lyphomas.
Rituximab targets CD20, which is expressed in nearly all B cells
It is not tumor specific, but you can live without B cells for a while.
B cells are taken up by macrophages or lysed by NK cells, or you can have complement mediated cytotoxicity.
It is lineage specific
Rituximab int reatment of B cell lyphomas.
Rituximab targets CD20, which is expressed in nearly all B cells
It is not tumor specific, but you can live without B cells for a while.
B cells are taken up by macrophages or lysed by NK cells, or you can have complement mediated cytotoxicity.
It is lineage specific
What is known about targeting of co-inhibitory receptors in T cells?
T cell receptor interacts with HLA class I or II and also with CD28 and B7.
PD1 and PDL1 receptor and CTLA4 and B7 give inhibitory signals to T cells.
They balance the activation which is provided for the TCR and MHC molecule.
People need to block the interaction, and this increases the activation of immune cells against tumor cells.
If antigen is presenting to a T cell without the presence of a strong activation signal, the T cell will start expressing whhcih creates tolerance.
PD1 and PDL1 receptor and CTLA4 and B7 give inhibitory signals to T cells.
They balance the activation which is provided for the TCR and MHC molecule.
People need to block the interaction, and this increases the activation of immune cells against tumor cells.
If antigen is presenting to a T cell without the presence of a strong activation signal, the T cell will start expressing whhcih creates tolerance.
What are early co-inhibitory signals?
CTLA on t cell and B7 on APC
What are novel co-inhibitory signals?
CD28, TIM3, VISTA
What are adverse effets of targeting of co-inhibitory receptors in T cells?
autoimmunity
What is the activated T cell response, what is the exhausted T cell respone and what is the effecotr T cell immune respones?
Activated: proliferation, cytokines and cytotoxicty omhoog
Exhausted: proliferation, cytokines and cytotoxicity omlag, door expressie van oa PD-L1 op tumor cellen of APC and PD-1 op T cel
Effector: je geeft een medicijn dat ervoor zrogt dat PD1 niet aan PDL1 kan binden, dit verhoogt prolfieratie, cytokines and cytotoxicyt
Exhausted: proliferation, cytokines and cytotoxicity omlag, door expressie van oa PD-L1 op tumor cellen of APC and PD-1 op T cel
Effector: je geeft een medicijn dat ervoor zrogt dat PD1 niet aan PDL1 kan binden, dit verhoogt prolfieratie, cytokines and cytotoxicyt
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