Week 10 Flashcards
Metastatic cascade: step 1
3 points
Cell detachment
Decrease in cell-cell interaction
E-Cadherin is lost
Metastasis cascade: step 1 - Normal role of e-cadherin
To attach normal cells
“Molecular glue”
Metastasis cascade: step 1 - what else happens?
B - catenin translocates into the nucleus and acts as a TF
Metastasis cascade: step 1 - what else happens? Pt. 2
Increase in pro-tumor molecules via b - cat
Metastasis cascade: step 2 - basement membrane detachment
Explain what happens here
3 points
Decrease in normal cell-BM (basement membrane) interactions
Increase in protease production that degrade BM leading to loss of laminin
Upreg of integrins (AvB3 + AvB5)
Step 2/3 - integrin signaling
Outside-in
Inside-out
Integrin binds to ECM, initiates intracellular signaling, causes cell proliferation + cytoskeletal changes
Intracellular signals on the inside leads to reduced integrin-ECM binding
Step 3: MATRIX DEGRADATION + CELL MIGRATION
3 points
Cancer cells outside blood vessels in ECM
MATRIX degraded via increase in MMPs + uPAs
cancer cells can go through the lining
Step 3: MATRIX DEGRADATION + CELL MIGRATION
What increases?
MMPs + uPAs (proteases)
What’s MMP? Where is it upregulated?
Matrix Metalloproteinase
upregulated in CAFs, TAMs, tumor cells
What is uPAs?
what converts into what
urokinase plasminogen activator
when bound to its receptor, it converts plasminogen to plasmin
which degrades matrix
Step 4 : INTRAVASATION
3 points
Entry into circulatory system
EMC has been degraded
Endothelial cell lining is degraded which was connected by VE- cadherin
What happens when the VE-cadherin degraded?
Endothelial cells separate in a way where cancer cells go get through
How is VE-cadherin degraded? How are endothelial cells separated?
4 points
1) MMPs bind to PAR (protease activated receptor) on EC
2) Notch receptor on cancer cell binds to Notch ligand on EC
3) Activation if ADAM12
4) EC retraction by TNF-a (from TAMs) and TGF-b (from cancer cells)
What’s TMEM?
3 points
TMEM: tumor microenvironment of metastasis
combination of tumor cells, endothelial cells, and macrophages
negatively correlated with survival
Degrades VE-cadherin and separates endothelial cells
Step 5: TRANSPORT/SURVIVAL in blood steam
3 points
ATP, cancer cells gphave entered the bloodstream
To survive, Cancer cells surround themselves in platelets to form emboli for mechanical and immune protection
Can metastasis
Step 6: capillary bed arrest
What are the 2 ways in which cancer cells will adhere to capillary bed?
Way 1) Homing/receptor-mediated arrest = cells bind to receptors to attach themselves to capillary bed
Way 2) Mechanical/physical arrest = cells get trapped in the capillary bed because they’re too big to fit through
Step 7: EXTRAVASATION - getting out of the bloodstream
5 points
Cancer cells must make it out of the
bloodstream to the underlying tissue to proliferate and metastasis
Process: cancer cells attach to endothelial lining via platelets already attached to cancer cells
Attachment results in increase of inflammatory response + attract macrophages
Results in changes of endothelial cell receptors which increases VEGF
VEGF triggers endothelial cellular connection + retraction
Step 8: creating a suitable environment in order for secondary growth to occur
Cancer cannot grow w/o correct environment
Way 1 for cancer to grow suitable environment
Optimal tumor environment already exists
Seed and soil theory vs mechanical theory
Seed and soil theory
seed = cancer cells w/ correct receptors
Soil = the matrix w/ the correct GF present at the secondary site
Theory argues that seed can be planted anywhere but it will not grow unless it has the right soil
Mechanical theory
Cancer cells metastasis to where they do based on distance given CC are bigger so they get stuck in an earlier capillary bed
way 2 for cancer to grow sutible environment
Environmental change to optimize environment - systemic signals that will change the makeup of the soil
Injury, inflammation, infection, long term exposure to carcinogens, removal of primary tumors
What are micromets?
Cancer cells that have broken away from primary tumor
Are dormant until systematic signals. Secondary tumor grows
way 3 for cancer to grow sutible environment
CANCER CELLS CREATE
SUITABLE ENVIRONMENT AFTER
ARRIVING by….
(1) THE CANCER CELLS DIRECT NORMAL CELLS WITHIN THE NEW ENVIRONMENT TO PRODUCE GROWTH FACTORS
(2) rELEASE GROWTH FACTORS NTO THE EXTR2ACELLULAr MATRIX
OSTEOLYTIC CASCADE
In breast tissue
Cancer cells in og tumor Release PTHRP
Activate osteoclasts which breaks down the bone
TGFbeta is released
Helps cancer growth
OSTEOBLAST CASCADE
In prostrate tissue
Cancer cells in og tumor stimulated osteoblasts which increase bone production
BMP is released
GF are released
Helps cancer grow
OSTEOLYTIC CASCADE VS. OSTEOBLAST CASCADE
Both help cancer bc of INCREASE in GF
Way 4 for cancer to grow sutible environment
CANCER CELLS SEND OUT SIGNALS TO
CREATE THE PERFECT ENVIRONMENT &
ARRIVE LATER
Emphasizing way 4 of cancer making its perfect environment
Remodel kitchen before you arrive
Primary tumor @ first site can send signals to secondary site to release tumor derived factors (TD) + exosomes
——> also sends signals to the bone marrow which sends signals to secondary site ???
Tumor derived factors are able to modify + activate secondary site
Modified stroma can recruit bone marrow cells to further activate and prepare tissue
Cancer cells arrive @ optimal environment
What are exsosomes
Micro vessicles containing RNA + proteins
animal models: Syngeneic
Inject mouse tumor cells under skin
animal models: Orthotopic
Inject cells in tissue of origin (i.e. breast)
animal models: Immunocompromised mice
Allows human cancer cell growth in
mouse model
types of immunodeficient mice
Non-Obese Diabetic (NOD)/SCID
Lack B and T cells and depleted NK
NOG/NSG: these also lack dendritic
cells/cytokines and lack NK cells
what doe nude mice lack?
T cells
humanized BLT mice
generates a human-like immune system
better at mirroring human cancer + immune response
GEMM is good for…
long term studies given TET operon promoter
Patient-specific humanized mice
Tumor biopsy transplanted into mouse creating similar tumor microenvironment
