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BIOCHEMISTRY > EXAM2_L25_Biochemistry_of_Tumor_Progression > Flashcards

EXAM2_L25_Biochemistry_of_Tumor_Progression Flashcards

1
Q

6 Properties of cancer at the cellular level

A
  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
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2
Q

What causes cancer cells to be immortal? limitless growth?

A

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

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3
Q

Microscopic appearance of cancer cells:

A
  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
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4
Q

Loss of contact inhibition

A

Normal cells stop when contact other cells

Cancer cells continue to form on each other (tumor)

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5
Q

Genetic instability

A

Cell cycle Checkpoints Disabled

  • (mutations in cyclins, CDK, RAS, MYC, RB, P53)
  • No DNA REPAIR
  • Aneuploidy
  • Apoptosis not stimulated (b/c deranged chromosomes)
  • No differentiation
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6
Q

(MMPs) Matrix Metalloproteinases

A

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

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7
Q 
Decreased CAMs (cell adhesion molecules)
Oligosaccharide glycosylation
A

low CAMS allows cancer cells to detach/migrate

Oligosaccharide changes cause Receptor structural re-organization

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8
Q

Benign vs Malignant tumors:

A

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)

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9
Q

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?

A

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

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10
Q

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

What characteristics of Vessels in tumors?

A

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
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11
Q

Progression of metastasis

A
  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
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12
Q

TWO apoptotic pathways:

A
  1. Extrinsic (death receptors)

2. Intrinsic (mitochondria)

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13
Q

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

A

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.

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14
Q

INTRINSIC PATHWAY for Apoptosis
How is apoptotic cascade activated?

What binds?

What is formed?

What controls release into cytosol?

A

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

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15
Q

Apoptosis and P53

A

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

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16
Q

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

A
  • 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

17
Q

Evidence of monoclonality of tumors: CML

A

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

18
Q

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 ?

A

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)

19
Q

What is the growth advantage to the Warburg Effect?

A

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

20
Q

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

What does hypoxia activate?
What does that factor stimulate?

A

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

21
Q 
Low Oxygen Levels
What organ senses Low O2?
What does it secrete?
 What does that stimulate and where?
What is expression controlled by?
A

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

expression of EPO controlled by PTM of HIF-1

22
Q

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

A

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

OXYGEN DEPENDENT:

  1. Proline Hydroxylation of HIF-1a
  2. Ubiquitination by E3 marks HIF-1a for degradation
23
Q

Hydroxylation/Ubiquitination of HIF-1a in low oxygen

A

– 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

BIOCHEMISTRY (33 decks)

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