Table of Contents
Course 1: cancer is a systemic disease and metastasis is an early event .............................. 2
Course 2: communication in tumor ecosystems .................................................................. 7
Course 3: metastasis-associated cellular activities ............................................................ 10
Course 4: models in cancer research ................................................................................. 18
Course 5: life in transit and premetastatic niche ............................................................... 23
Course 6: Dormancy ......................................................................................................... 34
Course 7 & 8: Angiogenesis and lymphangiogenesis ......................................................... 39
Course 9: Cancer Associated Fibroblasts (CAFs) ................................................................. 47
Course 10: use of ecosystem concepts in cancer treatment ............................................... 54
The immunology of cancer PART 1 – Karim Vermaelen ..................................................... 56
The immunology of cancer PART 2 – Karim Vermaelen ..................................................... 60
EMT: invasion and metastasis – Geert Berx ...................................................................... 65
1
,Course 1: cancer is a systemic disease and metastasis
is an early event
1. What are the hallmarks of cancer? Which hallmark determines patient outcome?
The 14 hallmarks of cancer include:
• sustained proliferation,
• evasion of growth suppressors,
• resistance to cell death,
• replicative immortality,
• angiogenesis,
• activation of invasion and metastasis,
• immune evasion, metabolic reprogramming, inflammation, genomic instability,
phenotypic plasticity, epigenetic reprogramming, polymorphic microbiomes,
senescent cells.
The hallmark that best explains differences in patient outcome is activating invasion and
metastasis.
=> Tumors of similar size may have very different prognoses depending on their ability to
invade surrounding tissues and form metastases, making metastasis the most important
determinant of cancer-related death.
2. True or false: cancer is a local disease.
Cancer is not a local disease, but a systemic disease!!
• In the early stages, cancer can be a local disease, meaning it is confined to its site of
origin.
• However, malignant tumors have the ability to invade surrounding
tissues and metastasize through the blood or lymphatic system to distant organs.
• Once metastases are present, cancer becomes a systemic disease.
This distinction is important because:
• Local treatments (surgery, radiotherapy) are most effective for localized disease.
• Systemic treatments (chemotherapy, immunotherapy, targeted therapy, hormone
therapy) are needed when cancer has spread beyond the primary tumor.
3. What are critical determinants of metastatic disease?
The critical determinants of metastatic disease are adaptation and cellular plasticity.
These properties enable cancer cells to change phenotype, survive under different
conditions, colonize distant organs, and develop therapy resistance. Targeting the
mechanisms that drive plasticity may therefore limit metastatic progression.
4. Do all cancer cells metastasise?
No, not all tumor cells metastasize. Metastasis is a highly inefficient process in which
approximately 99% of disseminated cancer cells die.
To form a metastasis, a cancer cell must invade, enter the circulation, survive immune
attack and physical stress, extravasate into a distant organ, adapt to the new
microenvironment, and proliferate.
Only a small subset of highly adaptable cells, called metastasis-initiating cells (MICs), can
successfully complete this process and form overt metastases.
2
,5. Drag and drop the metastasis related keywords to the correct place in the figure:
1. Local invasion
The process starts when cancer cells leave the primary tumor and invade the surrounding
tissue. To do this, they must overcome physical barriers such as the basement membrane
and extracellular matrix. This often requires increased motility and cellular plasticity.
2. Intravasation
After invasion, cancer cells enter blood vessels or lymphatic vessels. Once inside the
circulation, the cells become circulating tumor cells (CTCs). They can travel individually or as
clusters.
3. Survival in the circulation
This is a major bottleneck because the bloodstream is a hostile environment.
Cancer cells face:
• Mechanical stress due to blood flow.
• Loss of attachment to their normal environment.
• Attacks by immune cells such as NK cells.
Many cells die during this phase. To survive, cancer cells can bind platelets, which act as a
camouflage and help them evade immune recognition. Cancer cells may also travel in
clusters, where different cells cooperate to enhance survival.
4. Extravasation
The surviving cancer cells leave the circulation and cross the vessel wall to enter a distant
organ. The difficulty of this step depends on the organ. For example, entering the brain is
more difficult because of the blood-brain barrier.
5. Dissemination and seeding
After entering the distant tissue, cancer cells settle in the new organ. This is known
as seeding. However, most disseminated cells still fail to establish a metastasis. They need a
supportive microenvironment or niche to survive.
3
, 6. Cryptic metastasis (micrometastasis/dormancy)
Many disseminated cancer cells enter a dormant state and form micrometastases or cryptic
metastases. At this stage:
• The cells survive but do not actively proliferate.
• They are clinically undetectable because only a few 100 cells may be present.
• Imaging techniques such as CT, MRI, or PET cannot detect them.
• They are often resistant to chemotherapy because most anticancer drugs target
proliferating cells.
This phase can last months, years, or even decades.
7. Colonization and metastatic outgrowth
If conditions become favorable, dormant cancer cells reactivate and start proliferating. They
adapt to the new organ environment and eventually form a visible metastasis. This step is
called colonization and is considered one of the most difficult steps in the metastatic
cascade.
8. Overt metastasis (macrometastasis)
Once sufficient growth has occurred, the metastatic lesion becomes clinically detectable. This
is referred to as an overt metastasis or macrometastasis. At this stage, the secondary tumor
can continue to grow and contribute significantly to patient morbidity and mortality.
6. Give 6 characteristics demonstrating that cancer is a systemic disease.
1. Metastasis – Malignant cells from the primary tumor disseminate into the
circulation, colonize distant tissues, and expand in vital organs such as the lungs
and brain. (A&B)
2. Cancer-associated cachexia – Tumor-secreted factors such as TNF-α and IFN-γ
can disrupt normal metabolic functions, leading to cachexia, which is a
progressive wasting of adipose tissue and skeletal muscle mass. It’s a multi-organ
syndrome. (C)
3. Impaired immune response – During cancer progression, myeloid-derived
suppressor cells (MDSCs) accumulate in the spleen, causing splenomegaly (=
vergrote milt) and suppression of anti-tumor immune responses, resulting in
increased susceptibility to infections, because the immune system becomes less
effective at eliminating cancer cells. (D)
4. Bone marrow mobilization – Tumors mobilize bone marrow-derived cells,
including mesenchymal stem cells and circulating endothelial progenitor cells.
These cells support tumor progression by promoting angiogenesis, invasion, and
metastasis. (E)
5. Coagulation abnormalities (Trousseau’s syndrome) – Primary tumors can
activate procoagulatory factors and inhibit fibrinolytic factors, resulting in
thrombosis formation. Cancer-associated thrombosis is a major complication of
advanced cancer. (F)
6. Paraneoplastic syndromes – A set of signs and symptoms, which develop at
distant sites from a tumor/cancer. This syndrome occurs as a result of cancer in
the body. In some patients, symptoms of paraneoplastic syndrome can be seen
before the diagnosis of cancer.
o Triggered by hormone secretion = common in lung cancer
o Triggered by an altered immune system
4
Course 1: cancer is a systemic disease and metastasis is an early event .............................. 2
Course 2: communication in tumor ecosystems .................................................................. 7
Course 3: metastasis-associated cellular activities ............................................................ 10
Course 4: models in cancer research ................................................................................. 18
Course 5: life in transit and premetastatic niche ............................................................... 23
Course 6: Dormancy ......................................................................................................... 34
Course 7 & 8: Angiogenesis and lymphangiogenesis ......................................................... 39
Course 9: Cancer Associated Fibroblasts (CAFs) ................................................................. 47
Course 10: use of ecosystem concepts in cancer treatment ............................................... 54
The immunology of cancer PART 1 – Karim Vermaelen ..................................................... 56
The immunology of cancer PART 2 – Karim Vermaelen ..................................................... 60
EMT: invasion and metastasis – Geert Berx ...................................................................... 65
1
,Course 1: cancer is a systemic disease and metastasis
is an early event
1. What are the hallmarks of cancer? Which hallmark determines patient outcome?
The 14 hallmarks of cancer include:
• sustained proliferation,
• evasion of growth suppressors,
• resistance to cell death,
• replicative immortality,
• angiogenesis,
• activation of invasion and metastasis,
• immune evasion, metabolic reprogramming, inflammation, genomic instability,
phenotypic plasticity, epigenetic reprogramming, polymorphic microbiomes,
senescent cells.
The hallmark that best explains differences in patient outcome is activating invasion and
metastasis.
=> Tumors of similar size may have very different prognoses depending on their ability to
invade surrounding tissues and form metastases, making metastasis the most important
determinant of cancer-related death.
2. True or false: cancer is a local disease.
Cancer is not a local disease, but a systemic disease!!
• In the early stages, cancer can be a local disease, meaning it is confined to its site of
origin.
• However, malignant tumors have the ability to invade surrounding
tissues and metastasize through the blood or lymphatic system to distant organs.
• Once metastases are present, cancer becomes a systemic disease.
This distinction is important because:
• Local treatments (surgery, radiotherapy) are most effective for localized disease.
• Systemic treatments (chemotherapy, immunotherapy, targeted therapy, hormone
therapy) are needed when cancer has spread beyond the primary tumor.
3. What are critical determinants of metastatic disease?
The critical determinants of metastatic disease are adaptation and cellular plasticity.
These properties enable cancer cells to change phenotype, survive under different
conditions, colonize distant organs, and develop therapy resistance. Targeting the
mechanisms that drive plasticity may therefore limit metastatic progression.
4. Do all cancer cells metastasise?
No, not all tumor cells metastasize. Metastasis is a highly inefficient process in which
approximately 99% of disseminated cancer cells die.
To form a metastasis, a cancer cell must invade, enter the circulation, survive immune
attack and physical stress, extravasate into a distant organ, adapt to the new
microenvironment, and proliferate.
Only a small subset of highly adaptable cells, called metastasis-initiating cells (MICs), can
successfully complete this process and form overt metastases.
2
,5. Drag and drop the metastasis related keywords to the correct place in the figure:
1. Local invasion
The process starts when cancer cells leave the primary tumor and invade the surrounding
tissue. To do this, they must overcome physical barriers such as the basement membrane
and extracellular matrix. This often requires increased motility and cellular plasticity.
2. Intravasation
After invasion, cancer cells enter blood vessels or lymphatic vessels. Once inside the
circulation, the cells become circulating tumor cells (CTCs). They can travel individually or as
clusters.
3. Survival in the circulation
This is a major bottleneck because the bloodstream is a hostile environment.
Cancer cells face:
• Mechanical stress due to blood flow.
• Loss of attachment to their normal environment.
• Attacks by immune cells such as NK cells.
Many cells die during this phase. To survive, cancer cells can bind platelets, which act as a
camouflage and help them evade immune recognition. Cancer cells may also travel in
clusters, where different cells cooperate to enhance survival.
4. Extravasation
The surviving cancer cells leave the circulation and cross the vessel wall to enter a distant
organ. The difficulty of this step depends on the organ. For example, entering the brain is
more difficult because of the blood-brain barrier.
5. Dissemination and seeding
After entering the distant tissue, cancer cells settle in the new organ. This is known
as seeding. However, most disseminated cells still fail to establish a metastasis. They need a
supportive microenvironment or niche to survive.
3
, 6. Cryptic metastasis (micrometastasis/dormancy)
Many disseminated cancer cells enter a dormant state and form micrometastases or cryptic
metastases. At this stage:
• The cells survive but do not actively proliferate.
• They are clinically undetectable because only a few 100 cells may be present.
• Imaging techniques such as CT, MRI, or PET cannot detect them.
• They are often resistant to chemotherapy because most anticancer drugs target
proliferating cells.
This phase can last months, years, or even decades.
7. Colonization and metastatic outgrowth
If conditions become favorable, dormant cancer cells reactivate and start proliferating. They
adapt to the new organ environment and eventually form a visible metastasis. This step is
called colonization and is considered one of the most difficult steps in the metastatic
cascade.
8. Overt metastasis (macrometastasis)
Once sufficient growth has occurred, the metastatic lesion becomes clinically detectable. This
is referred to as an overt metastasis or macrometastasis. At this stage, the secondary tumor
can continue to grow and contribute significantly to patient morbidity and mortality.
6. Give 6 characteristics demonstrating that cancer is a systemic disease.
1. Metastasis – Malignant cells from the primary tumor disseminate into the
circulation, colonize distant tissues, and expand in vital organs such as the lungs
and brain. (A&B)
2. Cancer-associated cachexia – Tumor-secreted factors such as TNF-α and IFN-γ
can disrupt normal metabolic functions, leading to cachexia, which is a
progressive wasting of adipose tissue and skeletal muscle mass. It’s a multi-organ
syndrome. (C)
3. Impaired immune response – During cancer progression, myeloid-derived
suppressor cells (MDSCs) accumulate in the spleen, causing splenomegaly (=
vergrote milt) and suppression of anti-tumor immune responses, resulting in
increased susceptibility to infections, because the immune system becomes less
effective at eliminating cancer cells. (D)
4. Bone marrow mobilization – Tumors mobilize bone marrow-derived cells,
including mesenchymal stem cells and circulating endothelial progenitor cells.
These cells support tumor progression by promoting angiogenesis, invasion, and
metastasis. (E)
5. Coagulation abnormalities (Trousseau’s syndrome) – Primary tumors can
activate procoagulatory factors and inhibit fibrinolytic factors, resulting in
thrombosis formation. Cancer-associated thrombosis is a major complication of
advanced cancer. (F)
6. Paraneoplastic syndromes – A set of signs and symptoms, which develop at
distant sites from a tumor/cancer. This syndrome occurs as a result of cancer in
the body. In some patients, symptoms of paraneoplastic syndrome can be seen
before the diagnosis of cancer.
o Triggered by hormone secretion = common in lung cancer
o Triggered by an altered immune system
4
