Chapter 20- Cancer

Question 1

2 heritable properties that define cancer cells

Answer 1

1. Reproduce in defiance of normal growth restraints- can grow forever
2. Invade & colonize territories reserved for other cells- encroach on other cells’ niches

Question 2

Neoplasm

Answer 2

“New growth”- otherwise known as a tumor, or mass of cells. This is due to the uncontrolled growth and proliferation observed in cancer cells

Question 3

Benign tumor

Answer 3

Not yet invasive- removal usually results in cure

Question 4

Malignant tumor

Answer 4

Cells have become invasive, resulting in true cancer. Invasiveness is essential for cancer- cells break loose, enter the blood or lymphatics, and form secondary tumors (metastases). These are usually what kill the patient

Question 5

Carcinomas

Answer 5

Cancers that arise from epithelial cells- these account for 80% of all human cancers. This is because the epithelia are subject to constant renewal in adults and comes into contact with most forms of physical and chemical damage

Question 6

Sarcomas

Answer 6

Cancers that arise from connective tissue or muscle cells

Question 7

Leukemias and lymphomas

Answer 7

Cancers derived from white blood cells and hematopoietic precursors

Question 8

How does cancer originate?

Answer 8

Metastasized cancer can usually be traced back to single primary tumor. The developed cancer is derived from a single cell with a heritable change, and additional changes occur in descendent cells. These changes allow tumor cells to outgrow, out-divide, & outlive the normal neighboring cells

Question 9

Genetic mutations causing the development of cancer

Answer 9

5-10% are germline mutations (inherited from an individual’s parents). The rest are somatic mutations (mutations that occur throughout your life due to environmental factors). Genetic abnormalities (a set of mutations) will develop in cancer cells that distinguish them from normal cells. These mutations are heritable and will therefore be passed to progeny cells. Cancer incidence increases with age- this is because we have progressive, random accumulation of a set of mutations as we age

Question 10

How do somatic mutations originate?

Answer 10

Carcinogens are liked in mutagenesis in somatic cells. Carcinogens can be chemical, which typically cause local changes in nucleotide sequences. Radiation (X-Ray, UV) can also be a carcinogen. It causes bulkier lesions which lead to mutations

Question 11

Cancer-causing mutations

Answer 11

Cancer starts from one mutation in one cell, but successive mutations occur throughout generations. As mutations accumulate, cancer cells will exhibit a selective advantage over normal cells and will be able to grow better and better. The cells become more fit to thrive in the environment over normal cells, and the cells evolve into cancer cells as uncontrolled growth occurs

Question 12

Transformation (mutation) of cancer cells

Answer 12

Cancer cells grow forever and do not have any signals to inhibit growth. In normal culture, cells may require attachment to grow and will form a monolayer of cells (100% confluency). In these normal cells, they will receive signals to inhibit growth. However, cancer cells do not rely on attachment-dependent proliferation. They will continue growing beyond confluence, growing on top of other cells

Question 13

Properties of cancer cells (5)

Answer 13

1. Transformation (mutations)
2. Warburg effect
3. Can overcome the end replication problem
4. Tumor microenvironment (stroma)
5. Cancer cells can metastasize using lymphatic and blood vessels

Question 14

Warburg effect

Answer 14

The rapid consumption of glucose by cancer cells. Cancer cells can import glucose from the blood at a rate 100X higher than normal cells. Despite that increased glucose uptake, the same amount of glucose is used for oxidative phosphorylation as in normal cells. Cancer cells undergo glycolysis and pyruvate like normal, but most of the pyruvate is used for lactate fermentation rather than the production of mass ATP through oxidative phosphorylation. The extra imported glucose is devoted to lactate fermentation, for use in building organic cellular material. In a normal cell, very little glucose goes toward lactate fermentation

Question 15

Lactate fermentation

Answer 15

This is when pyruvate is taken from glycolysis, and 2 hydrogens are donated from NADH to the pyruvate molecules. This process creates 2 molecules of lactate. In normal cells, lactate fermentation helps to power glycolysis in low oxygen situations

Question 16

Which non-cancerous cells undergo the Warburg effect?

Answer 16

In addition to cancer cells, embryonic cells are hyperproliferative. They are the only non-cancerous cells that undergo the Warburg effect

Question 17

What is the end replication problem?

Answer 17

This is part of the reason why cancer cells can grow forever. As normal cells continue to grow and divide, the telomeres get shorter and shorter, giving the cells a finite dividing capacity. Normal cells have low activity of the telomerase enzyme, which is used to create telomeres. However, cancer cells have high telomerase activity and don’t succumb to this problem. In situations where telomerase is compromised, there is an alternate enzyme called alternative lengthening of telomeres (ALT) that can contribute to the creation of telomeres

Question 18

Telomerase

Answer 18

An enzyme that recognizes telomere repeats (GGGTTA) at the tip of chromosomes on parental DNA strand. Uses its associated RNA template to reverse transcribe DNA at 3’ end, resulting in a protruding 3’ end (an overhang). This helps to replenish the telomere on the parental strand, while normal DNA polymerase replenishes the telomere on the lagging strand. The protruding 3’ overhang tucks into the dsDNA of telomeric repeats, creating a t-loop

Question 19

Telomerase mechanism

Answer 19

Telomerase has an RNA template and reverse transcriptase activity (in its enzymatic portion) to extend the 3’ end of the parental strand, creating a full telomere. The enzymatic portion of telomerase recognizes enzymatic repeats at the 3’ end of DNA. Telomerase uses its associated RNA template to extend the 3’ end, making an overhand. DNA polymerase can synthesize the rest of the lagging strand telomere (complementary to the overhang sequence)

Question 20

Full telomere structure

Answer 20

Contains a T-loop structure that is formed by tucking in the 3’ overhang. The protection of telomeres 1 protein (POT1) binds to the guanine-rich 3’ overhang and therefore stabilizes the T-loop. In addition, POT1 suppresses DNA repair enzymes- they might falsely recognize the T-loop as a damaged portion of DNA

Question 21

Tumor microenvironment (stroma)

Answer 21

Cells that are present in the stroma can be non-cancerous in nature. However, cancer cells induce changes in this environment and cause changes in stromal cell behavior. They also modify the ECM proteases. Cancer cells modify stromal cells to secrete proteins that stimulate cancer cell growth and modify the ECM to make room for the increased growth of cancer cells. Tumor cells and the normal cells of the stroma evolve together

Question 22

Tumor development and metastasis

Answer 22

As cancer cells invade tissue, the cells can also enter capillaries and travel through the bloodstream. Fewer than 1 in 1000 cells will survive to form metastases. More commonly, cancer cells can enter the lymphatic vessels. Lymphatic vessels empty into the bloodstream, so this facilitates spread of the cancer. Tumor cells may also become trapped in the lymphatics, causing lymph node metastasis

Question 23

Cancer critical genes (3)

Answer 23

1. Proto-oncogenes
2. Tumor suppressor genes
3. Genome maintenance genes

Question 24

Proto-oncogenes

Answer 24

Mutations that induce over activation in these genes are called oncogenes. These are usually gain-of-function mutations

Question 25

Tumor suppressor genes

Answer 25

Mutations induce under-activation, these are usually loss of function mutations. Tumor suppressor genes normally express tumor suppressor proteins that suppress the formation of tumors

Question 26

Genome maintenance genes

Answer 26

Genes whose mutations result in genomic instability- hastens the production of cancer-causing mutations

Question 27

Ras

Answer 27

The first oncogene identified- discovered in the early 1980s. It is mutated in around 30% of all human cancers. Ras produces a monomeric GTPase protein that transmits intracellular signals stimulating cell proliferation. Ras is considered a proto-oncogene

Question 28

Ras mechanism (4)

Answer 28

1. Signaling begins with a receptor tyrosine kinase that is embedded in the membrane
2. Leads to the activation of the adaptor protein Drk
3. Ultimately, there is activation of a Ras guanine nucleotide exchange factor (GEF) called Sos
4. Ras is bound to GDP when inactive, but Sos activates Ras with GTP. Once it is associated with GTP, it can send downstream signals that lead to hyperproliferation of the cell

Question 29

What happens to Ras in cancer?

Answer 29

Ras is mutated so it is constitutively active- it undergoes a gain of function mutation. The most common mutations are Gly-12, Gln-61. Glycine 12 is in the phosphate binding domain of Ras and improves its binding to GTP. Glutamine 61 is in the catalytic domain, so it is the domain that transmits the signal- mutations overactivate the signaling portions of Ras. Sometimes, proteins that are upstream of Ras are mutated rather than Ras itself. One mutation is in NF1 (a Ras GTP activating protein). The mutation constitutively activates NF1 which makes Ras hyperactive. Several anticancer drugs inhibit Ras signaling at multiple steps

Question 30

Retinoblastoma protein (pRB)

Answer 30

A tumor suppressor protein that promotes proper DNA replication and accurate chromosome segregation. An individual would need mutations in both alleles to lead to cancer- these mutations would lead to underactivation of pRB

Question 31

p53

Answer 31

A beta-barrel tumor suppressor protein- only need a mutation in one allele to lead to cancer. The most common mutation is in the DNA binding domain. Arginine 248 helps p53 to bind to DNA, and mutations in this domain are commonly found in tumor cells.

Question 32

p53 functions (4)

Answer 32

1. Activates DNA repair pathways
2. Arrests cell growth at the G1/S regulation point- it does this to activate DNA repair
3. Initiates apoptosis, which also controls the growth of cells
4. Essential for senescence response to short telomeres- initiates apoptosis if the telomeres become too short

Question 33

How do p53 mutations lead to cancer?

Answer 33

In cancer, p53 is inactivated. It has less control over cell cycle arrest, and there is no initiation of apoptosis or entry into senescence. This results in uncontrolled cell growth

Question 34

Angiogenesis

Answer 34

The development of new blood vessels in order to supply the tumor with glucose, oxygen, and other nutrients. This process begins in capillaries with the formation of an endothelial tip cell. This tip cell is distinct from the other endothelial cells as it doesn’t grow or proliferate- it forms the leading edge of the blood vessel that will grow in angiogenesis. Pseudopods extend from the tip cell, and help to direct the growth of the trailing endothelial cells. This stimulates the growth of new blood vessels, which brings increased blood supply and nutrients to cancer cells

Question 35

What stimulates angiogenesis?

Answer 35

During angiogenesis, endothelial cells respond to signals produced by the tissues they invade- this can be a complex array of signaling molecules. One of the key signaling molecules is vascular endothelial growth factor (VEGF), which helps to stimulate blood vessel growth. Hypoxia also serves as a main activator here. There is a lack of oxygen as the tumor grows and the existing blood vessels can no longer support the tumor. Causes an increase in hypoxia-inducible factor 1α (HIF1α) – gene regulatory protein. HIF1α stimulates transcription of vegf in the nucleus. VEGF is secreted, diffuses through tissue to tell the blood vessels to continue to grow

Question 36

VEGF effects

Answer 36

Stimulates nearby endothelial cells to proliferate. Production of proteases to digest basal lamina (to form sprouts). Tip cells of sprout detect & move toward VEGF source. New vessels supply O2 to the tumors, HIF1α decreases due to increase in oxygen, VEGF production shut, angiogenesis ceases

Question 37

VEGF and angiogenesis

Answer 37

In situations of high oxygen, there is low HIF1α and no VEGF is secreted. In situations of low oxygen, there is a high amount of HIF1α and VEGF is transcribed. This stimulates the growth of blood vessels

Question 38

Cervical cancer

Answer 38

Caused by human papilloma virus (HPV), which is an STI. The virus has two cycles – lytic & lysogenic. Lysogenic infection is what can lead to cancer. Cervical cancer is the most common, but HPV can also cause cancers of the anus, vagina/vulva, penis, mouth, and throat

Question 39

HPV lytic cycle

Answer 39

Active infectious cycle

Question 40

HPV lysogenic cycle

Answer 40

When the virus goes into dormancy and can be reactivated to cause infection years later. There is 2 types of dormancy- proviral and episomal

Question 41

Lytic cycle mechanism (2)

Answer 41

1. The virus infects the host cell, inject their DNA, and hijack the host cellular machinery to replicate their DNA and produce their protein components
2. Viruses replicate to a degree that they overwhelm the cell, causing cell lysis
   The lytic cycle is active viral infection

Question 42

Lysogenic (latent) mechanism

Answer 42

1. Episomal latency- circular viral DNA remains in the cells. Stress can later re-activate that and cause a lytic infection
2. Proviral latency- the viral DNA is integrated into the host DNA. HPV is in this latency stage and can cause mutations in the host DNA

Question 43

Cellular entry & viral infection (HPV) (8)

Answer 43

1. The virus enters the body through microabrasions in the epithelium
2. HPV binds to heparin sulfate proteoglycans (HSPGs) on epithelial cells in the dermis
3. This causes a conformational change in the protein coating of the viruses (the capsid)
4. HPV binds alpha 6 integrin on the epithelial cells. The capsid undergoes a second conformational change
5. HPV binds to receptor A2T and triggers endocytosis of HPV into the cell
6. HPV is released into the cytoplasm and the capsid uncoats
7. Viral DNA is released, enters the nucleus, and hijacks the host cellular machinery, and replicates its DNA
8. Result is the production of more HPV

Question 44

Papilloma formation

Answer 44

HPV infects the basal epithelial cells of the dermis. Then, the basal epithelial cells will proliferate. The increased growth results in the formation of a papilloma. In normal HPV, the proliferation is limited. However, if HPV goes into latency, it can result in uncontrolled cell growth and cancer.

Question 45

HPV genome and cancer

Answer 45

The HPV genome contains 2 late expressed (L) & 6 early (E) expressed genes: L1 & L2; E1, E2, E4, E5, E6, E7. E6 and E7 are oncogenes, and E2 regulates the expression of E6/E7. In low risk HPVs, E2 controls the levels of E6/E7. In high risk HPVs, HPV DNA integrates into the host genome, and E2 is disrupted. E6/E7 are not repressed – leads to tumor production

Question 46

E6/E7 in HPV infection

Answer 46

1. E6 causes the degradation of p53
2. E7 represses retinoblastoma protein- this means that 2 important tumor suppressors are underactivated
3. When E2 is produced, it helps to regulate the production of E6 and E7- this controls the rate at which p53 and pRB are destroyed
4. When HPV integrates into host DNA, the E2 gene is disrupted and no longer forms a functional protein
5. E6 and E7 are no longer inhibited, and they will go on to destroy p53 and pRB, leading to the production of cancer