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Medicine Year 1 Semester 1 > FUN Cancer > Flashcards

FUN Cancer Flashcards

1
Q

What are the 3 types of extracellular signals that regulate cell proliferation/cell death?

And

What are the 3 stimulation factors? Define each

A
  1. Endocrine signaling: Hormones
  2. Autocrine: Targets sites on the same cell
  3. Paracrine signaling: signaling from adjacent cells

Mitogens: Stimulate cell division by relieving intracellular negative controls that block the cell cycle progress

Growth factors: Stimulate cell growth by promoting synthesis of proteins/macromolecules and by inhibiting their degradation

Survival factors: Promote cell survival by suppressing apoptosis

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2
Q

What are the 4 types of cyclins? What do each do?

A

G1 cyclins: help promote passage through the restriction point in late G1

G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication

S-cyclins: bind Cdks during S phase and are required for the initiation of DNA replication

M-cyclins: promote the events of mitosis

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3
Q

What are cyclins? State their role

A

cyclins are regulatory subunits that increase and decrease during the cell cycle. They act as a substrate for CDK enzymes switching on kinase activity

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4
Q

True or false:

CDK activity requires substrate binding to function

A

True

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5
Q

What is the substrate for CDKs and when bound, what are they called?

A

Cyclins are the substrate

When bound they are known as the cyclin dependent kinase complex or CDKC

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6
Q

Briefly state how the levels of CDK and cyclin change during the cell cycle

A

Levels of CDK are at a steady state

Levels of cyclin proteins fluctuate during the cell cycle

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7
Q

How are cyclins degraded?

A

Cyclins are degraded through ubiquitylation as it is more target-specific

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8
Q

Discuss and explain the processes that occur in the mid-G1 Cyclin/CDK checkpoint. Give an example of a cancer that can result from compromising the checkpoint’s integrity.

A

Cyclin D1 is responsible for this checkpoint
In a non-proliferating cell, p16 inhibits the formation of an active CDK4/Cyclin D1 complex.
Active RBC protein inhibits the entry into the cell-division cycle. Active RBC is bound to E2F which is a transcription factor. When bound, it halts cell division machinery.

When p16 is inactive or absent, kinase activity phosphorylates RB leading to its inactivation. This encourages cell division.

Over-activity of Cdk4 or cyclin D1 encourages unregulated cell division. An example of this is Mantle Cell Lymphoma:

Expression of cyclin D1 is placed under the control of the IgH promoter. As a result of chromosomal translocation, the upregulation of cyclin D1 is induced. When bound, it activates the transcription factor E2F, releasing it from negative regulation by the tumor suppressor Rb.

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9
Q

Discuss p53 as a key regulator of cell proliferation

A

P53 is a transcription factor that is activated by DNA damage. It stops cell replication. It’s mutation is the main cause in many cancers.

DNA damage sensors launch a cascade of signaling events which induce the phosphorylation and activation of p53. p53 is a tumor suppressor that, when induced, causes cell cycle arrest.

P53 induces p21 which inhibits the activity of the cyclin-CDK complex such that Rb is not phosphorylated, remaining bound to E2F. This leads to the S phase genes turned off.

If DNA is repaired p53 levels drop, p21 decreases, and the process continues normally. If not, then p53 remains high and the cell undergoes programmed cell death.

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10
Q

Briefly differentiate between apoptosis and necrosis

A

Apoptosis is the programmed process of cell death which protects the organism from damaged cells. Necrosis is cell death through an external force such as poison and injury which leads to the random degradation of DNA

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11
Q

Briefly describe the 2 mechanisms of apoptosis

A

External signals activate the cell membranous death receptors

Internal signals trigger the release of cytochrome c from the mitochondrion

Both pathways converge with the activation of caspases 3,6, and 7 which ultimately leads to apoptosis

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12
Q

Which apoptotic mechanism leads to changes in mitochondrial function?

A

Intrinsic pathway

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13
Q

List the steps involved in the extrinsic signaling pathway leading to apoptosis

A
  1. A pro-apoptotic ligand binds to transmembrane death receptors
  2. Trimerisation of receptor
  3. Activation of pro-caspase 8
  4. Activates caspases 3,6, and 7 leading to apoptosis with death fragmentation
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14
Q

List the steps involved in the intrinsic signaling pathway leading to apoptosis

A

Cytoplasmic p53 responds to cell damage and induces mitochondrial outer-membrane permeabilization

This leads to cytochrome c leakage from mitochondria into cytoplasm

Cytochrome c binds to Apaf1 (apoptotic protease activating factor)

Cytochrome c-Apaf1 complex binds to initiator caspase 9 and activates it forming the apoptosome

Apoptosome activates other caspases ultimately leading to apoptosis

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15
Q

Explain the common stage between intrinsic and extrinsic pathways.

A

Initiator caspases such as caspase 8 and 9 are cleaved in response to activation signals from other proteins. They then activate the executioner (effector) caspases.

This leads to DNA fragmentation by endonuclease activity, loss of cell shape, and organelle breakdown.

Apoptotic bodies are then phagocytosed by macrophages

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16
Q

How can a cancer cell bypass apoptosis? Explain using the 2 mechanisms

A
  1. Over-ride intrinsic pathway: An example of which is p53 mutations. In this case, DNA is not repaired and mutagenic lesions accumulate.

Another example is the upregulation of anti-apoptotic proteins which lead to the overexpression of BCL2 in numerous forms of leukemia

  1. Do not respond to extrinsic signals. This is done through decoy receptors which bind the death ligands but do not transduce the signal.
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17
Q

What are the two types of neoplasms? Define each

A

Benign: localized growth. They grow by expansion, compression, or displacing surrounding normal tissue. They often have a capsule

Malignant: Capable of invasion and/or metastasis. They grow by local infiltration, destroying the tissue through which they invade

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18
Q

What are the types of cancers classified according to their origin? Which one contains the majority of cancers

A

Carcinomas: Epithelial cells (majority)
Sarcomas: Mesodermal origin
Lymphoma/Leukemia: Circulating cells of blood and lymph

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19
Q

Briefly describe the two models for tumor propagation. Are these two models mutually exclusive?

A
  1. Clinal evolution model: mutant tumor cells with a growth advantage are selected and expanded. => first mutation is the growth advantage and second mutation is the resistance to apoptosis. Natural selection
  2. Cancer Stem Cell Model: Refers to a rare subset of Tumor cells that have the ability to self-renew and generate diverse tumor cells. A hier by exists where there is:

Self renewing stem cells that are essential for initiation and long-term maintenance of tumor

Transit-amplifying cells: Responsible for expansion of the tumor but are incapable of long term maintenance

Population: May or may not be capable of proliferation. Incapable of maintaining the tumor. May be differentiated

No they are not mutually exclusive

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20
Q

What are the three classes of genes that can cause cancer? Briefly explain each with their normal function

A

Proto oncogenes: Normal activity is to promote cell proliferation. The mutant form is the oncogene. Gain of function mutations create forms that are excessively active

Tumor suppressor genes: Normal activity is to inhibit cell proliferation or promote apoptosis. Includes genes that prevent inappropriate cell cycle progression and promote apoptosis of damaged cells

Caretaker genes: Ensure accurate replication, repair, and segregation of DNA. Mutations of these genes leads to genomic instability

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21
Q

What are the 6 hallmarks of cancer?

A

No need for extra details
1. Growth signal autonomy: Cancer cells are not dependent on normal growth factor signaling.

  1. Evasion of growth inhibitory signals
  2. Evasion of apoptosis
  3. Unlimited replication potential: Maintain the length of telomeres
  4. Angiogenesis: Altered balance between angiogenic inducers and inhibitors can activate the angiogenic switch
  5. Invasion and metastasis: Mutations alter the activity of enzymes involved in invasion and alter molecules involved in cell-cell and cellular-extracellular adhesion.
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22
Q

What are the 4 ways that tumor suppressor genes can be inactivated?

A

Deletion
Point mutation
Methylation of promoter (transcriptional silencing)
MiRNAs-post-transcriptional silencing

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23
Q

What are the functions of proto-oncogenes?

A

Growth factors
Cell surface receptors
Intracellular signal transduction molecules
DNA binding proteins including transcription factors
Cell cycle proteins (cyclins, cdks, kinase inhibitors)

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24
Q

How can Proto-oncogenes be activated? Explain each briefly and give an example

A
  1. Point mutation or deletion:
    Example: RAS oncogene controls intracellular signaling networks resulting in transcription of genes promoting cell division and inhibition of apoptosis.

Ras in the off state is bound to GDP
Ras in the on state is bound to GTP
Mutated Ras prevents GTP hydrolysis to GDP => it is continuously active

  1. Gene amplification: Normal protein produced in a much higher amount
    Example: MYCN in neuroblastoma
    MYCN is an oncogenic transcription factor that alters expression of 100s of genes. MYCN amplification is a marker of poor prognosis which is important in determining optimal therapy
  2. Chromosome rearrangement (to create a new gene through fusion or placement of strong enhancer nearby causing overproduction of normal protein):
    Example: Chronic myeloid leukemia (CML)
    Translocation creating Philadelphia chromosome which has a hybrid gene made up of 2 genes. Bar-Abl fusion protein has constitutively active tyrosine kinase
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25
Q

Genomic instability is an almost universal feature of tumor cells. What are the two forms of this instability?

A

Micro-satellite instability: DNA level instability

Chromosomal instability (CIN): Abnormal karyotypes => chromosomal level instability

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26
Q

Define metastasis

A

Metastasis is the spread of tumor cells from a primary site and their establishment at distant secondary locations

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27
Q

Give 3 ways that tumor cells can spread through

A

Blood
Lymph
Within body cavities

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28
Q

True or false

Metastasis is a complex multi-step process. Failure to complete any of the steps prevents metastasis formation

A

True

29
Q

True or False

Only a small % of tumor cells leaving the primary tumor complete all steps to successfully form metastasis

A

True

30
Q

True or false

It only takes once successful cell to complete metastasis

A

True

31
Q

True or False

Larger tumors have a higher chance of metastasis

A

True

32
Q

With every primary tumor site given, give one site of metastasis (secondary tumor)

Breast
Prostate
Stomach
Colon
Melanoma
A 
Bone, brain
Bone
Liver, ovary
Liver, lungs
Brain, liver, and bowel
33
Q

Describe the Seed and Soil Theory

A

Cells (as seeds) are dispersed randomly but only grow in organs which provide the correct factors necessary for growth of that particular tumor (fertile soil)

34
Q

Describe the steps involved in metastasis

A
  1. Disruption of cell-cell and cell-matrix interactions and degradation of ECM
  2. Invasion and migration through stroma
  3. Intravasation into blood or lymph vessel
  4. Survival in circulation
  5. Extravasation out of blood or lymph vessel and migration into new tissue
  6. Survival in new tissue
  7. Once tumor reaches certain size, development of new blood vessels occur (Angiogenesis)
35
Q

Define Intravastation

A

Invasion do cancer cells through the membrane into a blood or lymphatic vessels

36
Q

State the 3 major steps of invasion in metastasis giving the molecules that allow invasion to take place

A
  1. Attachement: cell adhesion molecules - integrins
  2. Proteolysis: Enzymes MMP
  3. Migration: motility factors
37
Q

What are the 2 steps in metastasis that are often targeted by scientists?

A

Invasion

Angiogenesis

38
Q

Define angiogenesis

A

Angiogenesis is the formation of new blood vessels from pre-existing vasculature

39
Q

True or False

Blood vessels formed by tumors are often unregulated and poorly built

A

True

40
Q

True or False

Vessels formed by tumors can also facilitate metastasis

A

True

41
Q

Give 2 methods of blood vessel formation by tumors

A

Angiogenesis

Vasculogenesis

42
Q

Define vasculogenesis

A

Vessel synthesis from endothelial progenitor cells (similar to first vessels in embryo)

43
Q

Describe the steps involved in Angiogenesis

A
  1. Secretion of angiogenic factors by tumor cells: VEGF
  2. Release of pro teases from activated endothelial cells
  3. Permeabilization of blood vessel wall and release of vascular endothelial cells
  4. Migration of endothelial cells into the interstitial space and into the tumor
  5. Endothelial cell proliferation
  6. Lumen formation
  7. Fusion of newly formed vessels
  8. Initiation of blood flow
44
Q

Give 4 factors that stimulate angiogenesis

A

Cytokines and growth factors: VEGF
Hypoxia
Oncogene activation
Loss of tumor suppressor genes (p53)

45
Q

Can tumor cells recruit healthy cells?

A

Yes

46
Q

Why is angiogenesis stimulated by Hypoxia?

A

Hypoxia stimulates angiogenesis due to the fact that it has poor blood supply and hence drug delivery is impaired. In addition to that, hypoxic cells are not actively proliferating and hence they are resistant to chemotherapy which targets dividing cells.

47
Q

Give an example of 2 angiogenesis inhibitors

A

Angiostatin

Endostatin

48
Q

Describe the regulation of angiogenesis through the Angiogenic switch hypothesis

A

It is the balance between pro and anti-angiogenic factors.
Usually inhibitors are high and activators are low. When switched to pro-angiogenic, inhibitors are low and activators are high hence allowing for frequency cell division and proliferation

49
Q

Describe the different vessel structure between normal and tumor blood vessels

A

Normal: Regularly patterned and functioning vasculature is formed with a normal vessel wall and endothelium

Tumor: Vasculature, endothelium, and vessel wall exhibit structural and functional abnormalities, leading to regions of severe hypoxia

50
Q

What are the 3 main approaches to eliminating cancer?

A

Surgical excision (local)
Radiotherapy (local/regional)
Chemotherapy (systemic/targeted)

51
Q

Define Adjuvant therapy

A

Systemic therapy used in patients with primary tumor removed but who are at high risk of metastatic disease.

52
Q

Define Neoadjuvant therapy

A

Treatment given prior to local therapy (shrinking the tumor before surgery)

53
Q

What is the role of cytotoxic drugs? What are their limitations?

A

Cytotoxic drugs inhibit proliferation of dividing cells but kill normal, rapidly proliferating cells as well such a s bone marrow and GI mucosa

54
Q

What are the 3 stages of tumor growth? Which is the most dangerous?

A

Stage A = dividing
Stage B = resting, but capable of division (dangerous and associated with recurrence)
Stage C: No longer capable of cell division

55
Q

What are the 4 classes of cytotoxic drugs?

A

Antimetabolites
Alkylating agents
Cytotoxic antibiotics
Plant alkaloids/microtubule inhibitors

56
Q

Outline the steps of Folate metabolism

A

Folates —> FH2 —> FH4 (THF) —> CH2THF —> CH3THF —. Purine biosynthesis

57
Q

How do antimetabolites act?

A

They are structurally similar to endogenous compounds involved in DNA and RNA synthesis. They act by competition or block and subvert metabolic pathways in the biosynthesis of DNA/RNA.

58
Q

What are the 2 types of antimetabolites?

A

Folate antagonists

Nuclei acid synthesis inhibitors

59
Q

Discuss Folate antagonists giving a drug as an example

A

Folates are essential for the synthesis of purine nucleotides as well as thymidylate. These are essential for DNA synthesis and cell division.

The drug Methotrexate (MTX) acts by inhibiting the metabolism of folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR) which converts folates to tetrahydrofolate.

Affinity for DHFR is about 1000x that of folate for DHFR. Maximal effects are S-phase specific when they are most active

60
Q

What enzyme is responsible for the reaction that forms THF from DHF?

A

Dihydrofolate reductase

61
Q

Discuss Nucleic Acid synthesis inhibitors as an antimetabolites drug. Give an example

A

Nucleic acid synthesis inhibitors are analogues (structurally similar) of purines and pyrimidines. They inhibit enzymes directly or by forming a false compound. They form a false RNA or DNA which is unable or slower to replicate due to extra binding groups.

5-Fluorouracil (5-FU) is a drug used for colorectal cancer. 5-FU exerts its anti cancer effects through the inhibition of thymidylate synthase and the incorporation of its metabolites into RNA and DNA.

5-FU is converted to several active metabolites including FdUMP which prevent the formation of DNA. 5-FU is metabolized extensively in the gut and liver and hence 5FU pro drugs are developed for oral administration such as Capecitabine

62
Q

Discuss Alkylating agents as a cytotoxic drug. Give 2 examples

A

Alkylating agents form covalent bonds with DNA inhibiting DNA synthesis during the S phase and interpreting with transcription. They contain reactive alkyl groups that form irreversible bonds on guanine residues on the same or adjacent strands. These bonds can form both intra and inter chain linking. Most effective when some parts of the DNA are unpaired.

Examples include Cyclophosphamide (nitrogen mustard derivative) that forms bifunctional DNA adducts. Another example is Carmustine which causes the alkylation of DNA and form carbamoyl adducts with proteins. This drug is unique as it can pass the blood brain barrier => can be used in the treatment of brain tumors.

63
Q

Discuss Cytotoxic Antibiotics as a Cytotoxic drug giving one example

A

Cytotoxic antibiotics are substances of microbial origin which prevent mammalian cell division. They are flat molecules which interpose themselves between coils of DNA (intercalation) and cause the inhibition of macro molecular biosynthesis.

An example is doxorubicin which is an anthracycline. It interacts with the DNA through intercalation and prevents correct uncoiling and exposure of DNA by stabilizing the DNA-topoisomerase II complex. It is used to treat leukemias, lymphomas, and solid tumors. It does, however, have an adverse effect being cumulative cardiac toxicity.

64
Q

What are the two types of Plant alkaloids?

A

Vinca alkaloids

Taxâmes

65
Q

Discuss Plant alkaloids/microtubule inhibitors as a cytotoxic drug giving an example for each type

A

Plant alkaloids have two types being Vinca alkaloids and taxanes. They act on tubuliflore/microtubule dynamics.

Vinca alkaloids such as vincristine act by binding to tubular and inhibiting its polymerization into microtubules as well as preventing spindle formation causing the arrest at metaphase during mitosis

Taxanes such as paclitaxel or Taxol interferes with mitosis by promoting the formation of intracellular microtubules and preventing disassemble of formed microtubules during anaphase

=> Vinca alkaloids prevent microtubule assembly whereas taxanes prevent microtubule disassembly.

66
Q

What are the two types of resistance to cytotoxic drugs?

A

Primary - present when the drug is first given

Acquired - Developed during treatment with the drug

67
Q

How does acquired drug resistance occur? Give the 5 mechanisms of drug resistance with an example of a drug or a type of drug that is affected with each.

A

Acquired resistance can be either due to the adaptation of tumor cells or to mutation. Selective advantage of some cells can lead to a reappearance of the tumor despite previous successful response.

  1. Decrease in amount of drug taken up by the cell (methotrexate or anti metabolic drugs)
  2. Insufficient activation of drug (5FU)
  3. Increased concentration of target enzyme (methotrexate)
  4. Increased utilization of alternative metabolic pathways (anti-metabolites)
  5. Repair of drug induced lesion (Alkylating agents)
68
Q

Discuss Multidrug Resistance (MDR) in tumor cells

A

It is the simultaneous resistance to many structurally different anticancer drugs. MDR results from elevated expression of drug transporters known as the ATP-binding cassette (ABC) transporter proteins.

P-glycoproteins decrease accumulation of drugs in the cell using energy (ATP) in a non-specific efflux of drugs.

Medicine Year 1 Semester 1 (23 decks)

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