L58 Tumor Progression Flashcards
Types of cancer
carcinoma epithelial (90% of mal)
sarcoma: supporting tissue
lymphoma: immune sys
-WBC mass
leukemia blood forming tissue: lymphatic and BM
-large number of malignant loose blood cells
Malignant tumor
breaks through basal lamina and invades tissue ysing MMPs
matrix metalloproteinases
cross talk between tumor cells and supporting stroma
cancer: secretes MMP to remodel
- invasion REQUIRES disruption of ECM
metastasis: most deadly and least understood part of cancer
- decreased amount of cell adhesion molecules (CAM)
- changes in oligosaccharide chains of cell surface glycoproteins through increased activity of N-acyctylglucosamine transferase.
- results in elongated changes and structural reorganization of receptors and other mols
Properties of cancer cells molecularly (blood supply)
sustained angiogenesis
- response to hypoxia
- increased levels of HIF1…induces VEGF
- 02 nutrients to tumors for metastasis
- disorganized leaky vessels
inactivation of apoptosis
normal: chrom condensation, cell shrinkage, blebbing, phag cell
proteolytic enzymes: procaspases-caspases
- cut off contact with surrounding cells, shut down cell metabolism, inducing cels to display signal for phagocytosis-disintegrate
- has extrinsic and intrinsic path, we will focus on intrinsic with the mitochondria
- exposure to ROS (initiation) or DNA damage
- pores form in OMM
- cytochrome C released to cytoplasm
- CytoC interacts with APAF1 to form apoptosome
- activates procaspases to caspases
BCL2 typically controls release of cyto C and other protiens by opening these channels: can block (anti apoptotic) or enhance
-controlled by balance of apoptotic an anti protiens
CANCER: different phosphorylation state of BCL2 can inhibit the apoptotic process, by not allowing BCL2 to block the membrane
OR
Mutation in P53 can inhibit apoptotic path
cancer cells accumulate mutations
accumulate over time
three stage model
- initiation
- cell receives potential for abnormal proliferation - promotion: initiated cell stimulatied to grow by external factors (GF’s or inflammation)
- mutation OR epigenetic - progression sustained enough mutations that it is no longer dependant of expternal factors to proliferate -invasive
with age more likely…not sporadic
metabolic changes with cancer
weight loss
- losss of TAG in adipose tissue
- loss of protein in muscle: energy for tumors
- hypermetabolisim - increased energy expenditure due to increased rate of tumor cells
most deaths from infection dut to
- immuse system imparement by metabolic disturbances
- marked weight loss varies
Aerobic Glycolysis????
even with high oxygen cancer cells shift glucose metabolism to glycolysis to produce lactic acid (Warburg effect, aka aerobic glycolysis)
convert glucose to lactate regardless of o2 presence
-mito remain functional
-faster route for energy immediately
-hypoxic tumor microenvironment
growth advantage in this environment. HIF1 not only supprts angiogenesis but increases expression of metabolic enzymes in glycolytic [athway as well as down regs genes involved in ox phos
tumors have different isoenzyme of PK1-PK2
-less production of ATP
Fat
hydrolysis of TAG in adipose tissue increased due to loss of body weight
- yet the flasma FFA level is not increased, suggesting liver is uptaking more
- ATP from BOx used for lactate glycolysis
esterification of FA in liver, VLDL hydrolyzed with some FA released in blood
increased E expenditure, and hypermetabolism ??
SLIDE 23
Protein breakdown in tumors
degredatin of muscle protein contrinutes to weight loss and wasteing in patients
-supplied AA for protein syn in tumors
BCAA: metabolism, transfer N to glutamate to glutamine
Methionine: methy group donation for DNA synth
degredation of AA: in liver produces NH for synthesis of NEAA and conditionally EAA
GLutamine in cancer
Phagocytosis of tumor cells in first defense in metastasis
-tumor cells have high rate glutamine consumption (depletes the level in the blood and impairs function of immune system)
many cancer patients die of infection and pneumonia
lung relies on macrophagtes
supplement diet with glutamine but you are also assisting cancer
Targetted therapies antibodies
antibodies
Herception: 25% cancers overexpress HER2 gene
- cell surface receptor for HER2 binds growth factor that stimulates proliferation of breast cancer cells
- ab inhibits this
Rituxan- binds to a cell surface protein that is present on malignant B cells
-binding of the Ab inhibits cell growth and induces apoptosis
non hodgkind B cell treatment
targeted therapy inhibiting activity of cancer proteins
ABL/BCR fusion created that allows for constitutively active tyrosine kinase
-BCR ABL can be bound by GLEEVEC when its inactive preventing it from activatin and phsphorylating other kinases
Targeted therapy againt angiogenesis
and note
avastin: inhibitor of VEGF receptor, blocks signal for angiogenesis
NOTE: multidrug treatement should be done AT THE SAME TIME.
one after the other results in adaptation to both and supercancer
used with standard chemotherapy for colorectal
