Stromal-epithelial interactions and tumor immunology Flashcards
Accordingly to the somatic mutation theory…
a) Genetic instability is a byproduct of carcinogenesis
b) Cancer is reversible
c) Cancer is a tissue/organismal disease
d) Cancer is not reversible
e) The default sate of cells is proliferation
d) cancer is not reversible
The first approved immunotherapies are base on :
a) Cancer vaccines
b) Immune checkpoint blockade
c) A chimeric antigen receptor that recognizes CD19
d) There are not any approved immunotherapies yet, they are all in clinical trials
e) CSF-1R inhibitors targeting tumor-associated macrophages
c) A chimeric antigen receptor that recognizes CD19
Which of the following statements on epithelial cells is true?
a) Can be derived from adipocytes, tissue-resident fibroblasts, and mesenchymal stem cells
b) Can eliminate cancer cells by apical extrusion
c) Can eliminate cancer cells following stimulation by antigen presenting cells
d) Give rise to carcinomas which account for 50% of all cancers
e) Can prevent dissemination by capturing invasive cancer cells
b) Can eliminate cancer cells by apical extrusion
Why is there so much variability in survival rates of cancer between different tumor types
Location of the tumor and screening
How do tumors arise? Whats the main driver for initiating tumors?
Mutations, they occur in the DNA and give rise to growth advantages
Whats the somatic Mutation theory (SMT)
(3 conclusions)
- Mutations are necessary for cancer to arise
- Mutation make a founder cell unable to control proliferation : resulting in tumour formation and assumes that the default state of a cell is quiscence
- Cancer is irreversible
Why do we get these mutations? What causes somatic mutations?
Error, normally there a good mechanism for the cells to repair those error
Sometimes those errore are important genes
Whats the somatic mutation theory of tumor progression?
cancer develops through the accumulation of genetic mutations in cells, leading to uncontrolled growth and the formation of tumoWrs.
True or false: Cancer is a single disease
False its not
Cancer may be considered a collection of rare diseases: What are the different features ?
Genetic, epigenetic, phenotypic, microenvironment, Clinical responses (treatment, side effects, survival)
Whats carcinoma: Account for 90% of all cancer and arise from…that covers…
Epithelial cell that covers internal and external body
Sarcoma: arise from … like ….
Arise from the cells of supporting tissues like bone, fat, cartilage, connective tissue, muscle
Lymphomas and leukemias: arise from… and …origin. The term leukemia is used in cancer in which the malignant cells … mainly in the…rather than growing as a solid tumor
arise from cells of blood and lymphatic origin. The term leukemia is used in cancer in which the malignant cells proliferate mainly in th blood stream rather than growing as a solid tumor
Brain cancers: arise from…
cells in brain tissue
What are the 3 characteristics of cancer
- loss of growth control (number of cells and differentiation.)
- Local invasion - may metastasize to distant site
- Altered tissue organization
True or false: The outer cells (peripheral) interact with the stromal microenvironment (other cell types and extracellular matrix)
true
True or false: Cancer cells dont interact with the microenvironment, even when you switch from normal tissue to pre-malignant tissue
False, they do interact with the microenvironment when they switch from normal tissue to pre-malignant
Complete sentence: Epithelial tissues are typically highly….
They have a high turnover to eliminate damaged cells
Often maintained by stem and progenitor populations
Proliferative
Complete sentence: … frequently develop from pre-malignant stages
Carcinoma
True or false: carcinoma may take year or decades to develop
true
Are mutations sufficient for cancer development in any cell?
No, if stem cells are mutated you have chance of cancer, but if you add mutated stem cells to more differentiated celle that didnt have upper limited capacity, nothing happens.
true or false: not all cells are equally susceptible and cells that already have a generative capacity are more susceptible to tumors
True
True or false: Some factors are coming in and sensitizing these tissues to be able to form a tumor (the microenvironment is really relevant for that)
True
Is inflammation associated with increased cancer incidence?
Yes, tissues subject to chronic inflammation generally exhibit high cancer incidence
Which cance is the leading cause of death in patients with liver cirrhosis?
Hepatocellular cancer (liver cancer)
What creates a pro-tumorigenic niche?
Stromal cells accumulating and becoming active
True or false: the systemic inflammatory state of an individual can affect the character of the microenvironment in premalignancies, thus leading to elimination or supporting progression to advanced disease
true
True or false: Predicted cancer incidence of lung, gastrointestinal, reproductive and skin cancers is higher in immunosuppressed organ transplant recipient
True
Is breast cancer incidence reduced in transplan recipients?
Yes
Is cancer reversible?
it could be.. but its rare
What are some possible mechanisms for spontaneous regression?
Silencing oncogenes, activating tumor suppressors, Epigenetic mechanisms, Tumor inhibition by growth factors, induction of differentiation, hormonal mediation, elimination of carcinogen, tumor necrosis or apoptosis, angiogenesis inhibition, immune mediation
What is the Tissue organization Fiel theory (TOFT) name the 3 corollaries:
- mutations lead to cancer by disrupting morphogens
- Mutations that induce proliferation are not needed for carcinogenesis
3.Genetic instability is a by product of carcinogenesis
What does TOFT state:
that carcinogenesis takes place at the tissue level, as does morphogenesis
TOFT states that the default state of cells is…
proliferation… changes in the whole environment and tissue make this amenable
According top TOFT, carcinogenesis is reversible or irreversible?
Reversible
What are morphostats
Theyre genes that are involved in regulating the homeostasis of a tissue
What happens when theres disruption of the homoestasis
It can have an effect on growth …
Argues that mutations that induce proliferations are not needed
Epithelial Defense against cancer (EDAC) .. explain the concept
Its an intrisinc ability of normal epithelial cells to suppress or eliminate adjacent tumour cells
What are some features of EDAC
-Cell competition between more and less fit cells
-Non-cell autonomous functions
-Apical extrusion
-Apoptosis
-Senescence
What happens to mutated cells surrounded by normal cells
gets eliminated
In which organ can we see apical extrusion (popped-out of the tissue) of Ras-transformed cells
Lung, pancrea, intestine
What happens to active non-cell autonomous elimination of cells by apical extrusion (cell competition)
contest among cells where weaker or damaged ones get pushed out by healthier ones, keeping tissues healthy and balanced..
Whats basal extrusion
damaged cells get .. from the …, keeping the tissue strong by getting rid of unhealthy cells.
damaged cells get pushed out from the bottom of the tissue layer, keeping the tissue strong by getting rid of unhealthy cells.
What happens to cells when theyre in the lumen
They die. They cant survive if theyre not in contact with neighboring cells or the basement membrane, so they go into the lumen and die
What happens to cells when they go basally
After basal extrusion, the cells leaving the epithelial layer would encounter the ECM, which can influence their fate. The interaction between these extruded cells and the ECM may trigger signaling pathways that could contribute to their clearance, degradation, or potentially affect surrounding cells and tissues.
How is cell competition regulated?
by the microenvironment
They did experiment on systemic signalling that can modify the tumor microenvironment.. what was the experiment
they showed that obese mice didnt have the ability to extrude the cells apically, leading to retention of these cells within the epithelium
Obese tissue (fat) VS lean tissue (no fat)
Obese tissue : aligned collagen, increased stiffness, hypoxic, Pro-iniflammatory state
Lean tissue : Less aligned ECM, Lower stiffness, Normoxic
True or false: cell competition results in senescence of damaged cells
True
True or false: competition is controlled by P53
True
Is cell competition the same as the classical p53-mediated DNA damage response?
No, theyre distinct concepts
The competition mediated by a non-cell autonomous induction growth arrest and senescence-related gene expresion in outcompeted cells with higher P53 activity… what does that mean?
Less competitive cells show increased activity in genes related to stopping growth and entering a non-dividing state (senescence).
These changes are connected to higher activity levels of the P53 protein, which regulates cell growth and responds to cellular stress.
What is the DCI stage in breast cancer?
DCIS stands for Ductal Carcinoma In Situ, which is a non-invasive or pre-invasive form of breast cancer. It’s often referred to as stage 0 breast cancer
myoepithelial cells dynamically prevent dissemination… by…
What kind of phenotype is it?
pulling tumor cells back in
Its an invasive suppressant phenotype
What are the different cell types in the microenvironment? (name 5)
- malignant cancer cells
- immune cells
- fibroblasts
- adipocytes
- vasculature
What does a tumor microenvironment implie?
that tumours are heterogeneous ecosyste of cells that can have pro- and anti-tumorigeni properties…. implies that cancer is a tissue-level disease
Can the normal (stromal phenotype) microenvironment predict the patients outcomes
Yes
Whats the communication between tumor epithelium and stroma? (co-evolution process)
We have differences in … and differences in …between these departments but we get cooperation between them
We have differences in oxygen accessibility and differences in metabolism between these departments but we get cooperation between them
As the tumor evolves… the microenvironment …
evolves and develops
True or false: tumors are diverse in the nature of the composition proportion, and activation state of the stroma
True
True or false: Bidirectional communication between tumour and stroma is key because theres a co-development of these two systems
True
True or false: Different activation states at different times of tumor progression. Many stromal cells are initially repressive, and become educated by the tumor to be supportive for tumor growth and progression
True
What are cancer associated fibroblasts (CAFs)
Theyre the most abundant cell type within the microenvironment
What are the features of cancer associated fibroblasts
Resisting cell death, evading growth suppressors, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation
CAFs can have different origins… what are they?
epithelial, fibrocytes, mesenchymal stem cells, endothelial cells, adipocytes, etc..
What is the consequence of CAFs within the microenvironment?
Invasion and metastasis
Name a fibroblast marker ,,,
FSP1
true or false: Fibroblasts directly associate with and lead cancer cells during invasion
True , they can remodel the extracellular matric
Whats the dynamic adhesions between fibroblasts and cancer cells?
Their adhesion molecules interact, and the interaction is so strong it allows the fibroblast to drag the cells
True or fasle: Tumor microenvironment is uniforme
False, its not uniform
What is the main product/role of CAFs?
Secretion of collagen, which is an extracellular matrix protein, and tumors tend to be stiffer than normal tissue, thats why we feel lumps and masses
True or false: the stiffness of the tumor can impact its stiffness
true
As the tumor progresses, it increases the… to modulate growth properties
stiffness
True or false: non-cellular components of the stroma also influence epithelial cancer cell behaviors
True
Whats hypoxia? whats the link to tumor?
Shortage of oxygen reaching the tissues and cells and induces activation of different transcriptional programs.
Hypoxia affects :
tumor vascularization, sensitivity to therapeutics, EMT, metastasis
Whats the dual role of macrophages in cancer
Tumor Promotion(M2): Some macrophages aid tumor growth by promoting inflammation, supporting blood vessel formation (angiogenesis), and suppressing the immune response against the tumor.
Tumor Suppression (M1): Conversely, other macrophages can work to attack and destroy tumor cells, activating the immune response to eliminate cancerous cells.
M1 is ….M2 is…
M1 is anti-tumor and kills tumor cells, M2 is pro-tumor and tissue remodelling, angiogenesis and tumor progression
What are TAMS, and whats their role?
Tumor associated macrophages that promote metastasis in ovarian cancer
CCL2 is one of the primary cytokines that recruits… and macrophages secrete…that is a pro-proliferative factor for many epithelial cell type
- machrophages
- Wnt1
the macrophages that recruit, can… the extracellular matrix and create tracks that epithelial tumor cells will follow
remodel
Whats the combination effect between macrophages and epithelial cells?
collaboration between macrophages and epithelial cells can either promote tumor growth or aid in immune responses against infections and tissue damage, depending on the circumstances.
Immune surveillance in tumors is a mechanism in which the immune system can… and modulate ..
recognize tumor cells and modulate growth problems
Tumors tend to have an extracellular matrix thats organized parallel to the edge of the tumor. it allows the cells to….
migrate through, along the ECM path and macrophages can come and remodel the ECM path
True or false, antigen present tumor cells to T cells, and would induce apoptosis or cytoxic effect between tumor cells, eliminating them
true
Whats the escape phase? theres a balance…
between the immune system and the tumor system, so no advancement of the tumor but its not regressing
What are the 3 stages of immunoediting (3 E’s)
- Elimination - tumor cells are cleared by immune system
- Equilibrium - driven by stron selective pressure from adaptive ar of the immune system, including T cells
- Escape - establishing a global immunosuppressive state
T cells can be modulated by several factors (3)…
- T cell exhaustion
- Immune checkpoint
- Many cells have suppressive function
Whats T cell exhaustion
A state in which T cells become … to antigens and are … at providing T cell help or eliminating appropriate target
A state in which T cells become less responsive to antigens and are ineffective at providing T cell help or eliminating appropriate target
What immune checkpoint
Receptor-ligand interaction that suppresses the activity of T cells
Whats the difference between cold and hot tumors
In “cold” tumors, there aren’t many … fighting the cancer, so treatments like … don’t work as well.
In “hot” tumors, there are more … fighting, so …can be more effective.
In “cold” tumors, there aren’t many immune cells fighting the cancer, so treatments like immunotherapy don’t work as well.
In “hot” tumors, there are more immune cells fighting, so immunotherapy can be more effective.
Why would we want to target microenvironment instead of the cells? or in addition to the epithelial cells?
enhance immune responses, overcome treatment resistance, and hinder cancer spread by disrupting the supportive environment that helps cancer cells thrive
Immunotherapy :
Improved or induces….
immunological surveillance recognition and destruction of cancer cells
modify or stimulate a patients immune system
What are the different approached of immunotherapy
Adoptive cell transfer (ACT - uses patients own immune cells to fight cancer)
Checkpoint inhibitors
Monoclonal antibodies
Cancer vaccine
Cytokines
Whats adoptive cell transfer
T cells are … to recognize specific markers, known as …, found on the surface of cancer cells. These … are often presented by … molecule. The engineered T cells are designed to better recognize these antigens when presented by MHC on the surface of cancer cells. This recognition allows the T cells to target and attack the cancer cells more effectively, enhancing the immune response against the cancer
T cells are engineered to recognize specific markers, known ast antigen, found on the surface of cancer cells. These antigens are often presented by MHC molecule. The engineered T cells are designed to better recognize these antigens when presented by MHC on the surface of cancer cells. This recognition allows the T cells to target and attack the cancer cells more effectively, enhancing the immune response against the cancer
What the 2 immune checkpoint blockade inhibitors
CTLA-4 and PD1
What does CTLA4 do? and anti-CTLA-4?
Inhibits T-cell activity by outcompeting costimulatory CD28 for CD80/86
Anti-CTLA-4, helps the immune system recognize and attack cancer cells
What PD1 and anti-CPDL or anti-PDL1
PD1 (programme cell death 1) is a protein that regulate the immune reponse…
Anti-PD1 or anti-PDL1 block the PD1, helping the immune system attack cancer cells
How do monoclonal antibodies work in cancer
markers differentially expressed between normal stem cells and leukemic stem cells
One way to increase association between tumor cell and T cell
to use bispecific antibodies
true or false: pancreatic cancer stem cells expresses low levels of EpCAM on the surface
False, HIGH levels
MT110 is a bispecific antibody that recognized CD3 and EpCam and acts as…
a bridge to bring the T cell in direct contact with the tumor epithelial cell.
Cancer cell vaccines are made by
taking tumor cell lysates with a variety of molecules, to stimulate the immune system against the cancer cells.
Therapeutic potential of re-educating the stroma… works by
instead of eliminating the macrophages, we reprogram into an anti-tumorigenic.. resulting in a decrease in the tumor promoting functions
What are some challenges for immunotherapy
immunotherapy is not effective on immune cold tumors like prostate, but theres new approaches to turn the cold into hot tumors
What happens when you add cytotoxic drugs
Increase of apoptosis, so machrophages in the microenvironment are activated, and are going to consume the dead cells.
