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Cancer Biology > Chapter 8 > Flashcards

Chapter 8 Flashcards

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1
Q

What aspect of tumor suppressors are we focusing on in chapter 8?

A

Tumor suppressors ability to promote differentiation.

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2
Q

What aspect of the processes that contribute to net cell number are we focusing on for this chapter?

A

Cells that become differentiated often enter G0 and do not undergo mitosis.

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3
Q

What does the word ontogeny mean?

A

It is the creation of a being - development of an individual.

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4
Q

Where do embryonic stem cells come from?

A

They are derived from the inner cell mass.

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5
Q

What do the hematopoietic stem cells give rise to?

A

They give rise to all the different blood cell types.

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6
Q

What does the term totipotent mean?

A

Totipotent is a type of stem cell that can become any single cell within the growing organism.

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7
Q

What does the term pluripotent mean?

A

This also refers to a stem cell’s ability to differentiate into any cell in the body with the exception of the extraembryonic cells that make up the placenta and the amniotic sac.

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8
Q

What is a progenitor cell?

A

Progenitor is another term that refers to the variety of cells that a stem cell can differentiate into. Here, it refers to a much more narrow ability of differentiation than the previously mentioned cells.

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9
Q

What is a precursor cell?

A

A precursor cell is the final term that refers to a stem cell’s ability to differentiate into other cell types. This is the most specific type in which these cells have a relatively certain fate.

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10
Q

Define differentiation.

A

Differentiation is the functional specialization of a cell as a result of the expression of a specific set of genes.

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11
Q

What does the term enucleation mean?

A

It refers to the characteristic of RBC’s not having a nucleus.

They also do not have a mitochondria!

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12
Q

All of the cells in the body contain the full complement of the human genome with two exceptions.

What are the exceptions?

How is this possible?

A

The exceptions are RBCs and germline cells.

This is made possible by different expressions among these cells.

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13
Q

How are stem cells important in adult life?

Give one example.

A

They are important for regeneration of tissues during life.

Example is hematopoietic stem cells that are continuously active to replace cells as they mature and die off.

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14
Q

HSCs show some differentiation plasticity.

What does this mean?

A

They can differentiate into cells that are not typical to their lineage under certain circumstances.

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15
Q

Even mammary cells can be reprogrammed to direct the development of a new individual - think dolly the cloned sheep.

What importance does this fact play?

A

The pattern of gene expression of a differentiated cell is not permanently fixed.

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16
Q

What are the two defining features of stem cells?

A
  1. They have the ability to self-renew
  • the daughter cell maintains the characteristics of a stem cell
  1. They have the ability to give rise to committed progenitors of differentiated cell types - cells that typically withdraw from the cell cycle.
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17
Q

What are cancer stem cells (CSCs) ?

A

They are the cells within a tumor that have the ability to self-renew and to give rise to phenotypically diverse cancer cells.

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18
Q

Are cancer stem cells particularly common?

A

No, only a small percentage are cancer stem cells - the rest are differentiated.

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19
Q

What would happen if cancer stem cells were transplanted into a host animal?

A

They have the ability to initiate new tumors when transplanted - think about that one tumor that guy discovered putting cancer cells into chickens.

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20
Q

How can markers of stem cells be useful?

A

They are things that are expressed on the surface of the cell and are characteristic of the stem cell that is normally present in the tissue.

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21
Q

For normal HSCs, the markers CD34 and CD38 should be?

A

+ for CD 34
- for CD 38

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22
Q

The proportion of CSCs present often correlates with the prognosis of the cancer.

What does this mean?

A

This means that when there are fewer cancer stem cells, there is a better prognosis and when there are more cancer stem cells there is a worse prognosis.

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23
Q

What is the cancer stem cell model?

A

The model proposes that there are subpopulations of cells within the tumor that have stem cell properties that can initiate and maintain the cancer phenotype.

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24
Q

How was the cancer stem cell model demonstrated?

A

There have been experiments that demonstrate small populations within tumors that drive tumorigenesis.

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25
Q

How are cancer stem cells relevant to carcinogenesis?

A
  1. Their ability to self-renew provides increased opportunities for carcinogenic changes.
  2. If the system that normally regulates self-renewal gets disrupted, these cells can grow uncontrollably and cause cancer.
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26
Q

What normally happens to differentiated cells?

A

They will eventually die within days or months - they exit the cell cycle and eventually undergo apoptosis.

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27
Q

Why do stem cells inherently have a higher chance of mutation?

A

Because they are longer lived.

28
Q

Normal stem cells maintain a balance between self-renewal and differentiation.

What is different about CSCs?

A

They will likely have uncontrolled self regulation as well as differentiation that is altered in some way.

29
Q

What are some targets for transformation?

A

Normal stem cells

Progenitor cells

Terminally differentiated cells

30
Q

How can the stage of differentiation of a mutated cell affect the malignant potential and severity of cancer?

A

Poorly differentiated cells will have higher malignant potential.

Cancers that arise from cells like these will oftentimes have worse a prognosis.

31
Q

Flashback to chapter two: nuns have a higher risk of having breast cancer.

Explain why this happens.

A

An early first, full-term pregnancy protects women from breast cancer because of a burst of differentiation during the term for creation of milk producing cells.

What may be happening: there are fewer breast stem cells following pregnancy

Result: lower risk of breast cancer.

32
Q

Regarding the Wnt signalling pathway, what will occur when Wnt is not present?

A

When Wnt is not present, beta-catenin will be marked for degradation and will NOT make it to the nucleus to act as a transcriptional activator for wnt target genes that are involved in cell proliferation.

33
Q

Explain in detail the pathway that happens when Wnt is not present.

A

When Wnt is not present, it will not bind to frizzled protein.

Because of this frizzled protein will NOT work with another protein to phosphorylate another protein (responsible for breaking up the cluster that contains APC).

Because of this the cluster of proteins will work to phosphorylate Beta-catenin and the activator will get tagged with a ubiquitin.

This will cause its degradation by proteasome action, and it will not be able to act as an activator for Wnt targeted genes, because there will not be enough of it in the cytoplasm to get to the nucleus.

34
Q

Regarding the Wnt signalling pathway, what happens when Wnt is present?

A

When Wnt is present, β-catenin is stabilized and accumulates in the cytoplasm, allowing it to translocate to the nucleus where it acts as a transcriptional activator for Wnt target genes involved in cell proliferation.

35
Q

Explain in detail the pathway that happens when Wnt is present.

A

When Wnt is present, it binds to frizzled protein (on the cell’s cytoplasm) which influences another protein that is attached to phosphorylate a protein that exists on the APC complex.

Because of this added phosphate, the complex dissociates and protein kinase X is unable to phosphorylate Beta catenin.

Because of this, Beta catenin does not get degraded to a high degree and makes it to the nucleus, where it WILL act as an activator for genes c-myc and cycling D1.

The activation of these genes rests on the formation of a complex between Beta catenin and transcription factors TCF and LEF.

36
Q

Would Wnt be considered a tumor suppressor or a proto-oncogene?

A

It would be considered a proto-oncogene.

37
Q

Constitutive activation of the Wnt pathway is seen in multiple types of cancer.

What does this mean?

A

This means that the pathway is constantly firing and transcribing genes responsible for proliferation.

38
Q

What percent of colorectal cancers are caused by Wnt pathway constitutive activation?

A

90%

39
Q

There are two types of colorectal cancer.

What are the two types?

A
  1. Familial
  2. Sporadic
40
Q

What is the germline mutation that causes familial colorectal cancer?

What does the mutation entail?

A

It is called FAP

aka familial adenomatous polyposis coli (FAP)

The mutation is carried within one of the alleles for APC

41
Q

Would APC be considered a proto-oncogene or a tumor suppressor?

A

It is a tumor suppressor because it is responsible for helping to ubiquidate Beta catenin

42
Q

What do FAP patients develop in early adulthood?

A

They develop polyps (called polyposis

43
Q

How does intestinal tissue regenerate generally?

A

Within the lining, there exists progenitor cells (transit-amplifying cells) that reside in crypts that will give rise to more differentiated cells that migrate up along the villi - eventually undergoing apoptosis.

44
Q

What is required to maintain these crypt cells?

A

We need Wnt signalling to maintain these cells

45
Q

describe the sequence of progression of colorectal cancer.

A
  1. benign polyps
  2. adenomas
  3. carcinoma in situ
  4. invasive carcinoma
46
Q

What does the term “in situ” mean?

A

It means from where it originated from

47
Q

It has been discovered that restoring APC can revert colorectal cancer cells to normal cells in vivo, even when other tumorigenic mutations are present.

What does this draw similarity to?

A

the idea of oncogene addiction

48
Q

If you disrupted the protein-protein interaction between TCF (TF) and beta catenin (activator) what would this result in?

What about eliminating the cancer stem cells?

A

It would hopefully result in differentiation.

Eliminating the cancer stem cells could result in eradication of the tumor.

These methods have only been tested pre-clinically to date though.

49
Q

What is the hedgehop (Hh) signalling pathway normally important for?

A

It is very important for embryonic development as well as self-renewal.

It is essential for pattern formation in neural tube, skin and gut tissues.

50
Q

The hedge hog signalling pathway uses intercellular molecules that act as ligands to induce signalling through a patched receptor.

How many members of the Hh pathway are there?

What are the target genes?

A

There are 3 members

Target genes include:

Cyclin D
Bcl2
VEGF

51
Q

Give a detailed overview of the pathway in the absence of Hh.

A

When Hh is absent, the patched receptor, located on the cillial membrane, inhibits another protein called smoothened, making it inactive, preventing it from accumulating at the tip of the cilium.

Smoothened in the inactive form, cannot activate Gli (transcription factor) via downstream pathways that will activate the transcription of target genes.

52
Q

Give a detailed overview of the pathway in the presence of Hh.

A

When Hh is present, it binds to the Patched receptor, which causes Patched to move away from the tip of the cilium. This allows Smo to accumulate at the tip of the cilium.

Once at the tip, Smo becomes activated and triggers the activation of Gli transcription factors, preventing their degradation. These activated Gli transcription factors then enter the nucleus, where they promote the expression of target genes

53
Q

What does Cyclin D gene contribute to?

A

It contributes to cell proliferation

54
Q

What does Blc2 gene do?

A

It is anti-apoptotic

55
Q

What does VGEF gene do?

A

it promotes angiogenesis

56
Q

Is Patched a tumor suppressor or a proto-oncogene?

A

It is a tumor suppressor because when Hh pathway signalling is off, it prevents the activation of target genes involved in proliferation, survival and angiogenesis.

57
Q

Is sufy a tumor suppressor or an oncogene?

A

It is a tumor suppressor because when Hh signalling is off, it prevents Gli from being activated.

58
Q

Would smoothened protein be a tumor suppressor or a proto oncogene?

A

It would be an oncogene because it indirectly activates Gli which activates the target genes we have been talking about.

59
Q

Would Hh be considered a tumor suppressor or a proto-oncogene?

A

It would be considered a proto-oncogene.

60
Q

What are three ways to target hedgehog signalling that are being tested pre-clinically?

A
  1. Smoothened inhibitors
  2. Hh binding inhibitors - stuff that fits into the same binding site for Hh, but does not inactive patched.
  3. Inhibitors of Gli - either bind to Gli itself or to the DNA sequence that precludes the transcription of target genes.
61
Q

What are polycomb group of proteins?

A

They are a group of proteins that repress the transcription of genes through epigenetic modifications.

62
Q

How do polycomb proteins acheive this?

A

They inhibit the transcriptional machinery by recruiting methyl transferases, which in turn attract HDACs, allowing for chromatin compaction.

63
Q

Why do we call polycomb group proteins the guardians of stemness?

A

Because they repress the target genes that are involved in development and differentiation.

64
Q

What would de-repression of PcG target genes look like?

What would it acheive?

A

It would likely include the removal of PcG from the promoter regions of the target genes, and reversal of the epigenetic modifications.

Hopefully achieve differentiation.

65
Q

How do PcG proteins contribute to carcinogeneis?

A

They maintain stem cell state as well as silencing tumor suppressor pathways.

66
Q

How is PcG proteins involved in AML?

A

It is involved because most leukemic cells have limited capacity for self renewal, but the tumor gets replenished by leukemic stem cells of which PcG proteins play a role.

67
Q

What did you learn about differentiation therapy during the assignment 4?

A

APL is a subtype of AML that is caused by the translocation of chromosomal components that cause the fusion of the PML gene with retinoic acid receptor. (PML-RARA)

Normally physiological amounts of retinoic acid are needed to bind to to RARA and through a few processes, promote the transcription of genes involved in differentiation.

But in the APL case, we need more than that. Employing ATRA (analog/type of retinoic acid) in supraphysiological levels to promote this differentiation.

ATO arsenic trioxide, degrades PML-RARA moiety, leading to apoptosis.

Cancer Biology (10 decks)

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