Lecture 8: tumor microenvironment Flashcards
what are the factors that influence survival rates
-genetivs
-epigenetivs
-phenotypes
-microenvironment
-clinical response
which type of cancer accounbds for 90% all cancers and arise from epithelial cells
carcinomas
which type of cancer arise from supporting tissues like bone, cartilage, fat and muscle
sarcomas
what are the 3 main characteristics of cancer
-loss of growth control
-local invasion
-altered tissue organozation
what are the 3 corollaries of smt (somatic mutation theory)
-mutations are necessary for cancer to arise
-mutations make founder cell unable to control its proliferation= tumor formation
-cancer is irrevercible
-this implies that cancer is a cellular disease
are mutations sufficient for cancer devlopment
maybe not
true or false: epithelial tissues are typically highly proliferative
true
true or false: epithelial tissues are often maintained by stem and progenitor pops
true
carcinboma frequently devlop fronm what
pre malignat stages
tumor incidence is determined by what
life long generative capacity of mutated cells
tissues subject ti what generally exhibit high cancer incidence
chronic inflammation
hepatocellular cancer is the leading cause of what
death in patients with liver cirrhosis
which type of cancer is associated with IBS
colorectal cancer
stromal cells accumulate and become activated, creating….
pro tumorigenic niche
true or false, systematic inflammation is always pro cancer
false it can also fuck uop some cancers
predicted cancer incidence of lung, gastrointestinal, reproductive and skin cancers is higher in ….
immunosupressed organ transplant recipients
which cancer has a reduced incidence in transplant recipients
breast cancer
Possible mechanisms for spontaneous regression
- Silencing oncogenes/activating tumour suppressors
- Epigenetic mechanisms
- Tumor inhibition by growth factors and/or cytokines
- Induction of differentiation
- Hormonal mediation
- Elimination of a carcinogen
- Tumor necrosis or apoptosis
- Angiogenesis inhibition
- Immune mediation
what are the 3 corollaries of TOFT are
- Mutations lead to cancer by disrupting morphostats.
- Mutations that induce proliferation are not needed for
carcinogenesis; - Genetic instability is a byproduct of carcinogenesis
true or false: according to toft, carcinogenesis is not reversible
false, it is
what is edac
-epithelial defense against cancer
-intrinsic ability of normal epithelial cells to supress or eliminate adjacent tumor cells
-ex: apoptosis, senescence, cell competition against more and less fit cells, apical extrusion
what is apical extrusion
-cells know the mechanical difference between normal and cancer cells, apical extrusion is when the cells go to die in the lumen
systemic signaling can modify what
the tumor microenvironment
systemic signaling in obese tissues
-aligned collagen
-increased stiffness
-hypoxic
-pro-inflammatory state
systemic signaling in lean tissue
-less aligned ecm
-lower stiffness
-normotoxic
competition results in ….
senescence of damages cells
cell competition that selects for the least damaged cells,is controlled by what?
-competition is controlled by p53
-distinct from the classical p53 mediated dna damage response
-depends on the relative rather than absolute level of p53 in competing cells
the cell competition is mediated by what
-by non cell autonomous induction of growth arrest and senescence related gene expression in outcompeted cells with higher p53 activity
in which breast cancer stage does myoepithelial cells breakdown
stage 0
which type of cells dynamically prevent dissemination
myoepithelial cells
true or false: many of the hallmarks of cancer events are non cell autonomous
true
they depend on the interactions with the microenvironment
true or false: camcer is a tissue level disease
true
stromal phenotype can predict what
patient outcome
reciprocal; interactions between tumor and associated immune and stromal cell types evolve as……
the tumor grows, thus allowing for modulation of both tumor cell intrinsic and extrinsic processes
true or false: the stroma and the tumor develop together
true
true or false: many stromal cells are initially repressive, and become trained by the tumor to be supportive
true
The inconsistency of CAF
markers/gene signatures, which
represents the heterogeneity of the
stromal compartment and the ample
reservoir for their cell of origin,
suggest ……
that the tumor and its
microenvironment exhibit a
considerable degree of plasticity
CAFs’ should be defined as …….
the
dynamic state of fibroblast-like cells
found in the vicinity of the tumor
that promote its progression – for
brevity a ‘CAF state’.
fibbrpblast directly associate with and lead what ?
cancer cells during invasion
non cellular components of the stroma influence what?
epithelial cancer cell behaviors
hypoxia influence what
tumor progression
-tumor vascularization
-chemo abd radio resistance
-emt
-metastasis
dual role of macrophages in cancer
-m1: killing tumot cells and antihumor immunity
-tissue remodelling and angiogenesis and tumor progression
macrophage polarization
-activated at a given point in space and time
-macrophages intergrate multiple signals from microenvironment to control polarization
what do tams to in ovarian cancer
they promote metastasis
EGF secreted by TAMs activates……..
EGF secreted by TAMs activates
EGFR on tumor cells, which in turn
upregulate VEGF/VEGFR signaling
in surrounding tumor cells to
support tumor cell proliferation
and migration.
MACROPHAGES STIMULATE WHAT
invasion and metastasis
immunoediting 3 stages
-elimination
-equilibrium
-escape
elimination
Elimination
* Tumour cells that are vulnerable to attack by the immune system are cleared
* cells that have or acquire a capacity to circumvent surveillance can survive and
propagate a new tumor that is primed to evade the immune system
equioibrium
driven by a strong selective pressure from the adaptive arm of the immune system, including T cells
escape
-establishing a global immunosuppressive state by secreting a plethora of anti-
inflammatory cytokines
* recruiting immunosuppressive cell types (Treg cells and MDSCs), which further
contribute to the anti-inflammatory cytokine milieu
Directing the immunoediting process to remain in the equilibrium phase
could ……
synergize with standard-of-care therapy to manage incurable disease and maximize the remission period for patients
T cell activity can be modulated by
several factors
- T cell exhaustion, a state in which T cells become less responsive to antigens and are ineffective at providing T cell help or eliminating appropriate targets
- Immune checkpoint (suppression by cancer and stromal cells)
- Many cells have suppressive functions in the
tumour microenvironment (for example,
neutrophils and Treg cells);
hot and cold tumors
Immunologically Hot Tumors:
Definition: Immunologically hot tumors are characterized by a high level of immune activity within the tumor microenvironment.
Features:
High levels of pro-inflammatory cytokines.
Generally associated with a better response to immunotherapies, such as immune checkpoint inhibitors.
-pd1 and pdl1 receptors
Immunologically Cold Tumors:
Definition: Immunologically cold tumors have a low level of immune activity within the tumor microenvironment.
Features:
Limited infiltration of immune cells into the tumor.
Low expression of immune checkpoint proteins.
Reduced production of pro-inflammatory cytokines.
Generally associated with a poorer response to immunotherapies.
true ort false: stroma is genetically stable compaired to tumor cells
true
-less susceptible to classical mechanisms opf therapeutic resistance
Limited benefit from therapies aiming to deplete stromal cells
Various angiogenesis inhibitors have had limited benefits
possibly because they generally block the anti-tumorigenic effects of the microenvironment
true or false: eliminating sub-populations of stromal cells may have therapeutic benefit
true
….. cancer-associated stromal cells may have
therapeutic benefit
“Re-educating”
immunotherapy
- Improve or induce immunological surveillance recognition and destruction cancer cells
- Modify or stimulate a patient’s immune system to target cancer cells
approaches of immunotherapy
-Adoptive cell transfer
Checkpoint inhibitors
Monoclonal antibodies (recognize cancer cell-specific
antigen and stimulate immune response)
Cancer vaccines
Cytokines (modulate the immune system)
Adoptive cell transfer
Chimeric antigen receptors are generated to target specific antigens. Patients T cells are
engineered to express the chimeric receptor.
n 2017, two CAR T-cell therapies were approved by the FD
-one for the treatment of
children with acute lymphoblastic leukemia (ALL)
- for adults with advanced
lymphomas. Designed to recognize CD19 on B-cella
CTLA-4 (cytotoxic T lymphocyte–associated
protein 4)
- Inhibits T-cell activity by outcompeting
costimulatory CD28 for CD80/CD86 - anti-CTLA-4 - advanced melanoma; other
cancers in clinical trials
PD1 (programmed cell death 1 (PD-1)
receptor) and its ligand PD-L1
- PD-L1 expressed on cells within a tumor
and inhibits T-cell function - Anti-CPDL or anti-PDL1 – melanoma,
NSCLC, RCC, Bladder, head and neck,
other cancers
immune checkpoint blockade inhibitors
-ctla4 and pd1
Target cancer cells with monoclonal
antibodies
- Markers differentially expressed between
normal stem cells and leukemic stem cells
CD44, the cytokine receptor IL3R, and the
immunoglobulin mucin TIM-3 - Treatment with antibodies against these cell
surface molecules dramatically decreased
leukemogenicity and eradicated leukemic
stem cell
Activates immune system to remove targeted
cells
immunotherapy stimulate what
immune destruction of tumors
pancreatic cancer stem cells express what
high levels of EpCAM on the surface
what is mt110
- MT110 – bispecific antibody that recognizes 2
specific antigens
1) CD3, lymphocyte marker
2) EpCAM
immunotherapy redirects what
cutotoxic cd8 T cells to the primary tumors aka xenographs
Tumour-associated macrophages (TAMs) can be reprogrammed pharmacologically to restore their anti- tumour activity
Macrophages depend upon colony stimulating factor (CSF)-1
for differentiation and survival.
TAMs were not depleted in treated mice.
…..BLZ945, a CSF-1R inhibitor was used to target TAMs in a mouse glioblastoma mode
- BLZ945, a CSF-1R inhibitor was used to target TAMs in a
mouse glioblastoma model
* regressed established tumors and patient-derived glioma xenografts
* dramatically increased survival
Activated/M2 macrophage markers decreased in …….
surviving TAMs, consistent with impaired tumor-promoting functions
immunotherapy is working on both immune hot and cold
false only hot tumors, aka nmot on cold like prostate camcer
Challenges for immunotherapy
Some tumors are densely infiltrated by immune cells from the innate
and adaptive immune systems (“immune hot”)
* Some tumors have immune cells restrict immune infiltration (“immune cold
New approaches to turn cold into hot tumors being investigated
Combination with cytotoxic therapeutics induces apoptosis which can stimulate an
immune response
