EXAM2_L25_Biochemistry_of_Tumor_Progression Flashcards Preview

BIOCHEMISTRY > EXAM2_L25_Biochemistry_of_Tumor_Progression > Flashcards

Flashcards in EXAM2_L25_Biochemistry_of_Tumor_Progression Deck (23)

6 Properties of cancer at the cellular level

1. Proliferation w/o growth signals (some can auto stimulate)
2. lost contact inhibition & Limitless growth (immortal)-telomerase active
3. Genetic instability
4. tissue invasion/metastasis
5. sustained angiogenesis
6. Evades Apoptosis


What causes cancer cells to be immortal? limitless growth?

TELOMERASE shortens w/ each round of replication
normal cells erode and stop, Cancer cells telomerase remains active

Cancer de-represses genes encoding telomerase to remain immortalized


Microscopic appearance of cancer cells:

1. Large irregular shaped nuclei and cells
2. Many cells displaying Cell Division--
3. Disorganized arrangement
4. Variation in size and shape
5. loss of normal features/ poor defined boundary


Loss of contact inhibition

Normal cells stop when contact other cells
Cancer cells continue to form on each other (tumor)


Genetic instability

Cell cycle Checkpoints Disabled
- (mutations in cyclins, CDK, RAS, MYC, RB, P53)
-Apoptosis not stimulated (b/c deranged chromosomes)
-No differentiation


(MMPs) Matrix Metalloproteinases

proteases that remodel ECM
-stimulates cancer cell growth
-Gives ability to invade/spread METASTASIZE
--> (malignant tumors break through of BL)

*Metastatic tumor is the same type of cancer as the primary tumor


Decreased CAMs (cell adhesion molecules)
Oligosaccharide glycosylation

low CAMS allows cancer cells to detach/migrate

Oligosaccharide changes cause Receptor structural re-organization


Benign vs Malignant tumors:

Benign: tumor not broken through basal lamina

Malignant: broken through basal lamina and invaded underlying tissue (USE MMPs)

Normal cells don't migrate b/c tight adhesions to each other and basal lamina (barrier and membrane)


Where are tumor cells most commonly carried to?
tumor cells from most locations to go?
Tumor cells from GI tract?

What types of cancer has a common site in the liver?

Which cancer is not according to blood flow and metastasize to the microenvironments of the bone?

Most locations tumor cells carried to capillary beds of the lungs via the heart

-cells from GI carried to first capillary bed of the liver
-Stomach & Colon

Breast, Prostate--> Bone


How is angiogenesis stimulated?
HIF1 - (hypoxia inducible factor-1)
VEGF- (vascular endothelial growth factor)

What characteristics of Vessels in tumors?

Hypoxia elevates HIF-1, increases VEGF

Tumors get so big, get hypoxic, then stimulates HIF1/VEGF

Angiogenesis can also provide metastatic access to circulatory system

- not normal vessels, disorganized, leak, irregular flow


Progression of metastasis

1. somatic mutation w/ growth/survival advantages
2. GF's support expansion of mutation bearing clones
3. invasion & migration
4. new mutations/autocrine GF loops/ resistant clones
5. angiogenesis
6. metastasis


TWO apoptotic pathways:

1. Extrinsic (death receptors)
2. Intrinsic (mitochondria)


What is the signal cascade for apoptosis?
3 Steps:
What is released into cytosol?

Procaspases cleaved into Caspases
1. -Cut contact w/ surrounding cells
2. -shut down cellular metabolism
3. -trigger signals for phagocytosis
-- releases mitochondrial proteins and Cytochrome C into cytosol.

cytochrome C (located intermembrane space of mito.) involved in ETC.


How is apoptotic cascade activated?

What binds?

What is formed?

What controls release into cytosol?

dna damage> pro-apoptotic proteins act on mito membrane:

- BCL-2 controls cytochrome C release into cytosol

- Cytochrome C binds APAF-1 to form apoptosome

-Apoptosome cleaves procaspases> CASPASES



Apoptosis and P53

Normal cells:
DNA damage> p53 activation> apoptosis initiation proteins transcribed> cytochromeC released> APAF1> Apoptosome>Caspase> APOPTOSIS/DEATH

Cancer- Mutated cells continue through w/o apoptosis


Cancer Development-
What is Clonal expansion?
How does normal cell progress to cancer?

-Cancer originates from single cells undergoing multiple mutations

- Clonal expansion: Single cell gives rise to subpopulation of genetically identical cells "monoclonality"

Over time: cells acquire multiple mutations to progress into malignant phenotype

Initiating mutation> 1st clonal expansion
2nd mutation>2nd clonal expansion
3rd mutation>3rd clonal expansion
Progressively worse


Evidence of monoclonality of tumors: CML

Chronic Myelogenous Leukemia (CML)
-Philadelphia chromosome (BCR-ABL FUSION gene)

A Unique accident occurring in a single cell-

Translocated DNA cloned/sequenced are identical in all leukemic cells in any given patient

*Single mutation not enough to change a normal cell into a cancer cell


Altered Sugar Metabolism found in Cancer:
What is the "effect" name?
What is found?
What products of metabolism for cancer?

What is normal cell metabolism in high & low oxygen ?

Warburg Effect-
- Cancer converts glucose to lactate
(regardless of oxygen availability)

Cancer has high rate of AEROBIC GLYCOLYSIS

- ENERGY, Building blocks, NADPH

Normal cells:
O2 available:
glucose>pyruvate>oxphos to CO2. (O2 final e- acceptor so req for ETC)
O2 limiting:
glucose>pyruvate>lactate (minimal ATP made)


What is the growth advantage to the Warburg Effect?

Tumor cells use fermentation to get precursors for biomolecules (DNA, proteins, lipids) required for fast growth /division

OxPhos completely oxidizes to CO2 and wouldn't work for fast tumor growth


How does using a less efficient glycolysis lead to a growth advantage for a tumor?

What does hypoxia activate?
What does that factor stimulate?

Growth advantage by reprogramming gene expression

- Hypoxia activates HIF-1a (hypoxia inducible factor) to stimulate erythropoietin & angiogenesis

-HIF-1a increases metabolic enzymes in glycolysis pathway
-HIF-1a down-regulates genes for OxPhos

Warburg effect not cause of cancer but is an effect of cancer causing mutations


Low Oxygen Levels
What organ senses Low O2?
What does it secrete?
What does that stimulate and where?
What is expression controlled by?

Kidney secretes Erythropoietin (EPO)
-EPO stimulates RBC production in bone marrow

expression of EPO controlled by PTM of HIF-1


Hydroxylation, Ubiquitination and HIF1a
How does kidney sense oxygen levels?
What two steps?

Kidney's ability to sense Oxygen levels is due to:

1. Proline Hydroxylation of HIF-1a
2. Ubiquitination by E3 marks HIF-1a for degradation


Hydroxylation/Ubiquitination of HIF-1a in low oxygen

-- Low O2: HIF-1a not degraded

-- HIF-1a translocated into nucleus w/ HIF-1b & stimulates EPO> increased RBC production

Low Oxygen: hydroxyproline can't function. HIF-1a not recognized by E3 and HIF-1a not degraded