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EXMD 504 > Lecture 8: tumor microenvironment > Flashcards

Lecture 8: tumor microenvironment Flashcards

1
Q

what are the factors that influence survival rates

A

-genetivs
-epigenetivs
-phenotypes
-microenvironment
-clinical response

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2
Q

which type of cancer accounbds for 90% all cancers and arise from epithelial cells

A

carcinomas

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3
Q

which type of cancer arise from supporting tissues like bone, cartilage, fat and muscle

A

sarcomas

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4
Q

what are the 3 main characteristics of cancer

A

-loss of growth control
-local invasion
-altered tissue organozation

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5
Q

what are the 3 corollaries of smt (somatic mutation theory)

A

-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

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6
Q

are mutations sufficient for cancer devlopment

A

maybe not

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7
Q

true or false: epithelial tissues are typically highly proliferative

A

true

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8
Q

true or false: epithelial tissues are often maintained by stem and progenitor pops

A

true

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9
Q

carcinboma frequently devlop fronm what

A

pre malignat stages

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10
Q

tumor incidence is determined by what

A

life long generative capacity of mutated cells

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11
Q

tissues subject ti what generally exhibit high cancer incidence

A

chronic inflammation

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12
Q

hepatocellular cancer is the leading cause of what

A

death in patients with liver cirrhosis

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13
Q

which type of cancer is associated with IBS

A

colorectal cancer

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14
Q

stromal cells accumulate and become activated, creating….

A

pro tumorigenic niche

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15
Q

true or false, systematic inflammation is always pro cancer

A

false it can also fuck uop some cancers

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16
Q

predicted cancer incidence of lung, gastrointestinal, reproductive and skin cancers is higher in ….

A

immunosupressed organ transplant recipients

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17
Q

which cancer has a reduced incidence in transplant recipients

A

breast cancer

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18
Q

Possible mechanisms for spontaneous regression

A
  • 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
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19
Q

what are the 3 corollaries of TOFT are

A
  1. Mutations lead to cancer by disrupting morphostats.
  2. Mutations that induce proliferation are not needed for
    carcinogenesis;
  3. Genetic instability is a byproduct of carcinogenesis
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20
Q

true or false: according to toft, carcinogenesis is not reversible

A

false, it is

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21
Q

what is edac

A

-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

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22
Q

what is apical extrusion

A

-cells know the mechanical difference between normal and cancer cells, apical extrusion is when the cells go to die in the lumen

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23
Q

systemic signaling can modify what

A

the tumor microenvironment

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24
Q

systemic signaling in obese tissues

A

-aligned collagen
-increased stiffness
-hypoxic
-pro-inflammatory state

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25
systemic signaling in lean tissue
-less aligned ecm -lower stiffness -normotoxic
26
competition results in ....
senescence of damages cells
27
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
28
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
29
in which breast cancer stage does myoepithelial cells breakdown
stage 0
30
which type of cells dynamically prevent dissemination
myoepithelial cells
31
true or false: many of the hallmarks of cancer events are non cell autonomous
true they depend on the interactions with the microenvironment
32
true or false: camcer is a tissue level disease
true
33
stromal phenotype can predict what
patient outcome
34
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
35
true or false: the stroma and the tumor develop together
true
36
true or false: many stromal cells are initially repressive, and become trained by the tumor to be supportive
true
37
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
38
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’.
39
fibbrpblast directly associate with and lead what ?
cancer cells during invasion
40
non cellular components of the stroma influence what?
epithelial cancer cell behaviors
41
hypoxia influence what
tumor progression -tumor vascularization -chemo abd radio resistance -emt -metastasis
42
dual role of macrophages in cancer
-m1: killing tumot cells and antihumor immunity -tissue remodelling and angiogenesis and tumor progression
43
macrophage polarization
-activated at a given point in space and time -macrophages intergrate multiple signals from microenvironment to control polarization
44
what do tams to in ovarian cancer
they promote metastasis
45
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.
46
MACROPHAGES STIMULATE WHAT
invasion and metastasis
47
immunoediting 3 stages
-elimination -equilibrium -escape
48
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
49
equioibrium
driven by a strong selective pressure from the adaptive arm of the immune system, including T cells
50
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
51
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
52
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);
53
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.
54
true ort false: stroma is genetically stable compaired to tumor cells
true -less susceptible to classical mechanisms opf therapeutic resistance
55
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
56
true or false: eliminating sub-populations of stromal cells may have therapeutic benefit
true
57
..... cancer-associated stromal cells may have therapeutic benefit
“Re-educating”
58
immunotherapy
* Improve or induce immunological surveillance recognition and destruction cancer cells * Modify or stimulate a patient’s immune system to target cancer cells
59
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)
60
Adoptive cell transfer
Chimeric antigen receptors are generated to target specific antigens. Patients T cells are engineered to express the chimeric receptor.
61
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
62
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
63
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
64
immune checkpoint blockade inhibitors
-ctla4 and pd1
65
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
66
immunotherapy stimulate what
immune destruction of tumors
67
pancreatic cancer stem cells express what
high levels of EpCAM on the surface
68
what is mt110
* MT110 – bispecific antibody that recognizes 2 specific antigens  1) CD3, lymphocyte marker  2) EpCAM
69
immunotherapy redirects what
cutotoxic cd8 T cells to the primary tumors aka xenographs
70
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.
71
 .....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
72
Activated/M2 macrophage markers decreased in .......
surviving TAMs, consistent with impaired tumor-promoting functions
73
immunotherapy is working on both immune hot and cold
false only hot tumors, aka nmot on cold like prostate camcer
74
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
75
New approaches to turn cold into hot tumors being investigated
Combination with cytotoxic therapeutics induces apoptosis which can stimulate an immune response
76

EXMD 504 (12 decks)

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