cancer 3

-Cell transformation – normal to neoplastic
-Growth of transformed cells
-Local invasion by transformed cells
-Distant metastasis
tumor progression
how does tumor spread to distant organs
via lymphatics or veins
implementation of cancer cells into new tissue
metastasis
first step of local invasion
metastasis, then spread to other tissues
if cancer remains localized it is easier to treat meaning it has
better outcomes
-Cell multiplication
-Mechanical pressure
-Decreased cell-cell adhesion
-Increased motility of tumor cells
-RELEASE OF LYTIC ENZYMES
mechanisms important in local invasions
mechanical pressure =
tumor growth
if cells due around the tumor the tumor will
get bigger because there is more room for it to grow
-tumor cells infiltrate adjacent tissues
-through vascular walls – enter circulation “intravasation”
-cells leave circulation pass into vessel walls “extravasation”
motility factors produced by cancer cells
through vasular walls- enter circulation
intravasation
cells leave circulation pass into vessel walls
extravasation
tumors degrade normal cell matrix because tumors produced
lytic enzymes
cancer cells have high levels of hydrolases which is an enzyme that
degrades proteins
normal cells with antiproteases
block breakdown of its cell matrix
tumors with high levels of protease
overwhelm antiproteases, allowing them to breakdown the cells matrix
this is produced by cancer cells allowing them to break down proteins. these are high in epithelial cancers and have a role in angiogenesis- more blood vessels
matrix metalloproteinases (MMPs)
highly agressive tumors are high in
MMP collagenase
Degrade collagen of epithelial/vascular cells, invade and enter blood
High MMP collagenase
inhibiting collagenase reduces
metastases
-Tumor cell attachment to matrix
-degradation (break down) of matrix
-locomotion (invade) into matrix
3 major steps of tumor invasion
on the matrix there are
laminin and fibronectin
tumor cells attatch to
laminin receptors on the matrix
the more aggressive the tumor the more _____ it has
laminin receptors it has
tumor excretes _______ that overwhelms the proteases inhibitors and degrades matrix
proteolytic enzymes
tumor that starts at the liver and starts invading the cells at the liver
direct metastasis
Tissue spaces
Lymph vessels
Blood vessels
Body cavities
Cerebral spinal spaces
potential regions of tumor spread
-Invasion local tissue
-Penetration into lymphatic or blood or body cavity
-Transport to new site (secondary tumor)
-Cells stabilize/proliferate (Seconday site)
-Cell clumps from primary tumor improved survival
-Most common metastasis – lymph
Metastasis by lymphatics and bloodstream
-Penetrate blood vessels – Inside blood system
-Survive immune attack
-Survive mechanical stress blood flow
-Attach and break through vessel walls
-Tumors shed cells during growth
-Millions of cells released
metastasis by blood stream
tumor growth requires
blood supply
blood vessel development
angiogenesis
Vascular Endothelial growth factor (VEGF) (important angiogenic factors that recruit blood vessels to increase tumor growth)
Pro-angiogenic factors identified
Platelet factor- 4
Angiostatin
angiogenesis inhibitors
tissue factor (TF)
angiogenesis tumor factor
normal cells block angiogenesis by producing ______ cancer cells stop producing this so angiogenesis proceeds
Thrombospondin
because tumor cells are farthest from the blood supply they are hypoxic and produces ______ normal cells do not produce this
Hypoxic-inducible factor -1a (HIF-1a)
VEGF cause angiogenic switch which
produces new blood vessels
proliferation/migration endothelial cells triggered by
angiogenic growth factors
takes out active dividing cells, destroying tumor cells
chemo
faster growing, more sensitive to chemo
small tumors
slower growing, mildly sensitive to chemo m
large tumors
2nd gen chemotheraoy agent
disrupts micro tubules by blocking cell division
rapidly diving cells sensitive to chemo drugs
taxotere
taxol analog with albumin nanoparticle
3rd gen
water soluble so less side effects requiring pre medication
abraxane
tumors expressing membrane glycoprotein = “P-170”
transporter moving chem drugs out
multidrug resistance protein
treats rapidly dividing cells
the cells die after appropriate exposure
radiation
blocks the growth of the tumor
monoclonal antibody that binds to HER2 receptor
treatment for some breast cancers
herceptin
receptors can become active without growth factors
activates cell divison and growth
HER2
Herceptin binds to HER2 receptor and blocks activation inhibiting
tumor growth and division
how do tumors invade the immune system?
create an immunosupressive micro enviornment
1)Recruiting myeloid-derived suppressor cells (suppresses immune attack of tumor)
2)Tumor produced immunosuppressive factors (ex. TGF – beta)
2 ways to create and immunosuppressive micro enviornement
bone marrow stem cells produce blood cells
myeloid
Increase extracellular matrix surround tumor (basically walls itself off from matrix)
Blocks chemokines/cytokines = blocks T-cell infiltration of tumor
TGF – Beta
tumors surrounded by barrier block
immune cell infiltration and protects tumor
2 tumors with extensive extracellular matrix
ovarian cancer and colorectal cancer
programmed cell death ligand 1
produced by tumors and noramlly highly active t cells
supress t cell function
induces t cell apoptosis
NEGATIVE FEEDBAK BLOCKS HYPERACTIVATION
PD-L1
what is the reasons t cells can not attack tumors
tumors producing PD-L1 suppress immune attack by T – cells
checkpoint inhibitors result in
longer life with advanced cancers
monoclonal antibodies that bind to PDL1 on tumors, so that t lymphcytes an bind to the tumor and destroy it
checkpoint inhibitors
chemo
surgery
radiation
immunotherapy
steps for treating breast cancer
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