Neoplasia 3-4

Question 1

why does obesity increase risk for breast/prostate cancer?

Answer 1

o High level inflammation in adipose, which tends to spread.
o Insulin resistance, so more in circulation and increases risk since is a growth promoter.
o Release a lot of adipokines, which are somewhat different and plays a role in cancer.

Question 2

epidemiology of breast cancer?

Answer 2

o Risk is age-related – 1/8 is only for women over 85 years old.
o High survival rate (91%) – as long as there is no metastasis at detection.
o Continual decrease in mortality in Canada.

Question 3

risk factors of breast cancer

Answer 3

o High dietary fat intake – obesity.
o Lack of regular exercise.
o Alcohol and cigarettes.

Question 4

causes of breast cancer

Answer 4

o Genetic: BRCA1 and 2: defective DNA repair.
o Environmental is the biggest factor:
 No evidence that oral contraceptives increase risk of breast cancer but decreases risk of ovarian cancer.
 Hormone replacement therapy decreases risk of heart disease, colon, cancer, Alzheimer’s disease, and osteoporosis, and very small increased risk of breast cancer (but no real convincing evidence to show this increase risk in breast cancer)
 Weight gain, lack of regular exercise, smoking, and alcohol are the biggest risk factors.

Question 5

symptoms of breast cancer seen in men

Answer 5

lumps, nipple discharge, reddening, inversion of the nipple, skin dimple.

Question 6

what are the main types of breast cancer? how do they compare?

Answer 6

• Ductal origin: originates in the ducts of mammary glands.
  o Most common
• Lobular origin: originates in the lobules of mammary gland.
  o Pathology:
   Discohesive: tumor cells infiltrating as single file strands in a concentric manner around normal breast ducts.
   Histological variants:
• Solid, alveolar, tubular-lobular, pleomorphic.
   Lose contact inhibition, no cadherin expression.

Question 7

how are breast cancers diagnosed?

Answer 7

• Many benign lesions can occur in the breast, so most lumps are not malignant.
  o Many patients say they feel lumps, palpable mass, pain, or nipple discharge but only very small fraction is cancer – can ben an abscess, a cyst, or a benign tumor/lesion.
• Mammography: x-ray of the breast.
• Cancer not distributed equally in the breast, most common in upper outer side of the breast.
• Fine needle aspiration cytology: insert in needle, remove some cells, and look at the cells.
  o Idea is to diagnose as benign or malignant.

Question 8

what is the prognosis of each stage?

Answer 8

• Stage 1 and 2: almost everyone survives (5-year survival)
• Stage 3 has a good 5-year survival.
• Stage 4: about 1/3 survive at least 5 years.

Question 9

prognosis factors of breast cancer

Answer 9

• HER2 status: worst prognosis but have better drugs to target this now.
  o Is an epidermal growth factor receptor.
• ER status: better prognosis – less undifferentiated and respond to hormone manipulation.
• Vascular invasion: more invasions indicate poorer prognosis.
• Histological grade: G1 to G4 – from most to least differentiated.
  o Higher grade = worst prognosis.
• Type: some different types have better or worse prognosis.
• Size: larger = worse prognosis.
• Lymph node invasion: more lymph node invasion = poorer prognosis.
• Proliferation index (Ki67)
• DNA ploidy.

Question 10

therapy for breast cancer

Answer 10

• Surgery
  o evolution of conservative strategies: radical mastectomy, total mastectomy, partial, lumpectomy.
  o Limited surgery with radiation has a better survival than extensive surgery.
• Detection and relevance of the sentinel lymph node: the major lymph node draining the tumor.
  o Now inject a tracer into the region close to the tumor, then detect where it went to find the sentinel node (and other nodes), which is removed along with the tumor.
• Radiation and Chemotherapy: eliminate anything that wasn’t removed with surgery (radiation for local and chemotherapy for rest of body)
• Antiestrogens (hormone therapy): if ER+, block the receptor since the tumor needs it to survive.
  o Block the receptor or the synthesis of estrogen.
• Monoclonal antibodies: use in the case that there is an overexpression of a receptor, e.g. HER2, that will target and slow tumor progression.

Question 11

what is benign prostatic hyperplasia? what is the treatment?

Answer 11

o Consequences: enlarged prostate, compressing the urethra, causing difficulty urination.
 Since urine is retained, there are changes in the urinary wall (thickening – hyperplasia)
 Not a risk factor for cancer but can cause a lot of trouble (can cause secondary infections)
o Treatment:
 take out the prostate through the urethra.

Question 12

what is the epidemiology of prostate cancer?

Answer 12

o Most common in Canadien men, mostly in older individuals.
o Death rate has been declining, good survival unless metastasis.
o Study found that early-stage diagnosis has better survival than control since they changed their lifestyle.

Question 13

risk factors of prostate cancer?

Answer 13

alcohol, obesity, high fat diet

Question 14

does taking selenium and vitamin E supplements help with prostate cancer?

Answer 14

no, it is a misconception

Question 15

how is prostate diagnosed?

Answer 15

• Lump detection during routine exam – located just underneath the bladder.
• Screening:
  o Blood test for PSA, less useful for diagnosis, mostly for monitoring.
• During TURP (transurethral resection of the prostate) – can occur simultaneously with BPH
• urinary obstruction

Question 16

where does prostate cancer metastasize?

Answer 16

o in bone (e.g. vertebrae) is big problem (can go in through lymph node) – causes a lot of pain.

Question 17

what is the prostate specific antigen? what is it useful for?

Answer 17

• Origin: androgens regulate the release of PSA, and it goes into the lumen of the gland and in the bloodstream – when there is a tumor, there is an interrupted barrier, so much more PSA in the blood.
• Value in screening and monitoring therapy:
  o Can monitor the tumor growth: can see how effective therapy is and see if the tumor develops resistance – so allows to detect tumor recurrence very early, so that you can start a new therapy.
• A lot of controversy about using it, since when it is borderline, it triggers a lot of new unneeded stress and tests.

Question 18

how is prostate cancer staged?

Answer 18

• TNM system
• Can easily get into the surrounding lymph nodes.
• relevance of histological grade – Gleason score
  o 1 is best and 5 (most undifferentiated) is the worse

Question 19

therapy for prostate cancer

Answer 19

• Later: surgery, radiation, hormone block.
• Early: watchful waiting (will most likely not cause any trouble) or individualized therapy.
• Brachytherapy: used sometimes.
  o Inserting tiny radioactive capsules around prostate, so you radiate tumor without the other side effects – works for some tumors.
• Antiandrogens: block release (interfere with signalling in brain for testes) or the action of testosterone (block receptor)
  o As tumors develop, they can develop independence from androgens: can make their own, over express receptors, recognize other ligands, or activate without androgens.
  o So now have many drugs that block the androgen pathway at different places depending on what resistance has developed.
• Monoclonal antibodies
• Chemotherapy and radiotherapy.

Question 20

challenges of therapy for prostate cancer?

Answer 20

o Patient variability, tumor variability, cellular/genetic/epigenetic variability

Question 21

age of occurrence for tentacular cancer

Answer 21

peak is late teens and early twenties.

Question 22

survival rate for testicular cancer?

Answer 22

• Survival rates are very high – is curable but need to detect it as early as possible.
  o The 10-year survival rate is very high.

Question 23

how is immune surveillance changed in cancer?

Answer 23

• Normal defenses: does detect abnormal antigens or an abnormal number of antigens at the surface of malignant cells.
• In cancer, the immune system has failed (by definition) – can keep it under control for a certain amount of time, but eventually they escape.
• Mechanisms of tumor escape:
  o Tumors escape recognition, and block antibodies + T-cells.

Question 24

Sequence of molecular changes in tumor formation: colorectal cancer

Answer 24

o Normal epithelium: APC mutation
o Hyperproliferative epithelium: loss of DNA methylation
o Early adenoma: RAS gene mutation
o Intermediate adenoma: loss of tumor suppressor
o Late adenoma: loss of p53 gene
o Carcinoma
o metastasis

Question 25

What makes cancer very hard to deal with?

Answer 25

the fact that tumors are heterogeneous, meaning different cells have different combinations of mutations.

Question 26

features of cancer cells

Answer 26

o Tumor promoting inflammation.
o Activating invasion and metastasis
o Genomic instability
o Resisting cell death
o Inducing angiogenesis
o Deregulating cellular energetics
o Sustaining proliferative signaling
o Avoid immune destruction
o Evade growth suppressors
o Enable replicative immortality

Question 27

what are oncogenes?

Answer 27

Normal genes (proto-oncogene) that have been modified/altered, leading to enhanced cell growth, limit apoptosis, and block immune recognition

Question 28

ways in which proto-oncogenes can become oncogenes

Answer 28

• Point mutation:
  o Within a control element leads to normal growth-stimulating protein in excess.
  o Within the gene leads to hyperactive or degradation resistant protein (abnormal protein)
  o Ras mutation: the mutation interferes with Ras inactivation, leading to continuous cell proliferation – it is usually very rapidly inactivated.
• Gene amplification: normal growth-stimulating protein in excess.
• Gene translocation: a promoter is added in front of the gene, leading to increase activity of the protein.
  o This is what happens with chronic myeloid leukemia – Bcr-Abl (Philadelphia chromosome), leading to abnormal tyrosine kinase and therefore activation of growth factor signalling pathways.
  o We can study chromosome translocation through chromosome painting.

Question 29

oncogenes can have an effect in which steps of cell proloferation?

Answer 29

o Growth factors
o Growth factor receptors
o Singal transduction factors
o Transcription factors (increased or abnormal)
o Apoptosis
o Cell Cycle

Question 30

Cancer involves something going wrong with the ______ regulation

Answer 30

cell cycle

Question 31

what can go wrong in the cell cycle regulation in cancer?

Answer 31

o Overexpression of cyclin/CDKs, leading to continual proliferation.
 CDK1 controls G2 to M phase.
o Inactivation of CDK inhibitors/RB leads to the inability to stop the cell cycle.
 RB controls G1 to S phase.

Question 32

what happens to bcl-2 in cancer? what is this effect?

Answer 32

increased expression, leading to decrease apoptosis

Question 33

what are tumor suppressor genes?

Answer 33

o Normally, act as a break to stop cell growth.
o In cancer, these don’t work (e.g. are inactivated), leading to excessive proliferation.

Question 34

what are some common tumor suppressor genes?

Answer 34

• retinoblastoma
• p53
• APC

Question 35

role of retinoblastoma (normal and in cancer)

Answer 35

o It controls the G1 to S transition of the cell cycle.
o It attaches to transcription factor E2F, which binds DNA, leading to the blocking of the cell cycle.
o When abnormal: it is overly phosphorylated, leading to release of transcription factor and continual cycling of the cell.

Question 36

role of p53 (normal and in cancer)

Answer 36

o Is a sensor of multiple forms of stress – activated with multiple types of injuries (including those leading to cancer) of the cell.
o If cell injured beyond repair, will lead to apoptosis.
o If not (low level of damage) will put the cell in cell cycle arrest to allow for DNA repair to occur.
o Most commonly mutated gene in human cancers.
o Normally, there is continual turnover of the p53 protein, when DNA damage occurs, kinases protect the protein (phosphorylate it), so p53 accumulates and then binds DNA, where it can stop cell cycle or trigger apoptosis.
o When mutated, leads to continual accumulation of mutations since cannot stop cell cycle to allow DNA repair.
o Genetic defect: born with only 1 p53, leading to an almost inevitable cancer growth.

Question 37

role of APC (normal and in cancer)

Answer 37

o Regulates level of B-catenin, which is a stimulator of cell growth.
o When lost, there is increase transcription, leading to continuous cell cycles.
o Familial polyposis: born with one defective APC, so it is a matter of time they lose the second, leading to cancer formation.

Question 38

role of BRCA in cancer

Answer 38

o DNA repair is defective, so as the person gets older, there are more chances to develop breast cancer.

Question 39

epigenetic changes in cancer

Answer 39

• DNA methylation leads to transcriptional silencing.
  o Hypomethylation: overexpression of growth factors or oncogenes, alteration in DNA repair enzymes
  o Hypermethylation: silence tumor suppressor genes.

Question 40

what are microRNAs and what can it affect?

Answer 40

• microRNAs can alter transcription of a protein, by binding to mRNA and block production of a protein.
• Alteration of microRNA can affect:
  o Cell motility (related to metastasis)
  o Angiogenesis
  o Cell proliferation
  o Evasion of apoptosis

Question 41

how do microRNA affect cancer?

Answer 41

• Depending on the person’s microRNA expression, it can affect their cancer prognosis since can affect their response to therapy.

Question 42

what are exosomes and its effect with cancer?

Answer 42

• Exosomes: extracellular vesicles from cancer cells which alter surrounding cells.
  o Contain proteins, DNA, mRNA, miRNA.
  o Can control activities of cells surrounding the cancer cells.

Question 43

properties of tumors

Answer 43

• Altered cellular metabolism: increase uptake of glucose and glutamine, allowing then to grow much more readily than surrounding tissue (increase cell synthesis)
• Tumor progression:
  o When heterogeneous, it is more aggressive and more resistant to therapy, since there is a combination of cell types, which can respond differently to therapy.
• Angiogenesis:
  o Tumors release angiogenic factors and pulling in cells from the environment to help the tumor and protect it.
• Motility and Invasion: they can acquire motility, which is the biggest risk for metastasis.
• It also exchanges information with normal surrounding cells, which actually helps them survive and proliferate.

Question 44

external factors leading to carcinogenesis

Answer 44

• chemical
• viruses
• radiation
• chronic inflammation

Question 45

how can chemicals cause carcinogenesis?

Answer 45

can cause DNA damage

Question 46

how can viruses cause carcinogenesis? (with examples)

Answer 46

can also alter/damage our genes.
o HPV: inactivates p53 and RB – leading to inhibition of apoptosis and continual proliferation.
 Causes almost all cases of cervical cancer.
o Hepatitis C (causes liver cancer): causes inflammatory injury in the liver and continual turnover of hepatocytes.
o Epstein-Barr virus: leads to malaria

Question 47

how can radiation cause carcinogenesis?

Answer 47

o Induces tissue injury.
o Women painted material on watches using radium to make it glow in the dark, and since it is very hard, they would put the brush in their mouth the make the tip pointier, but it was carcinogenic.
o There is background radiation all over the planet, but it is mostly under control.
o Chernobyl: lead to many cases of cancers such as leukaemia (showed up first), thyroid (in children mostly, also showed up rapidly), breast, lung, bone.
 There was a minimal latency period.

Question 48

how can chronic inflammation cause carcinogenesis?

Answer 48

because of the cellular damage, cytokines being released, and continual growth of cells, it is a risk factor for cancer – promotes tumor growth.

Question 49

risk factors for cancer?

Answer 49

• Environment by far the biggest factors leading to cancer (not genetics).
• Global variation: environmental factors are different.

Question 50

prevention for cancer

Answer 50

o most would be prevented if we didn’t smoke, we exercised, and have a healthy diet.
o Do not need vitamins if have a good diet (too much vitamin can be just as harmful)
o HPV virus completely prevents cervical cancer and parallel cancers in males.

Question 51

how is radiation used to kill cancer?

Answer 51

use radiation dose that will cause minimal damage to surrounding tissues, and maximal damage to cancer cells (also, cancer cells are usually more vulnerable to radiation than normal cells – repair processes are abnormal).
o Treatment is intermittent to allow normal cells to repair themselves.

Question 52

what therapy can be used for Burkitt’s lymphoma

Answer 52

combination chemotherapy can often cure this problem

Question 53

most common side effects of chemotherapy?

Answer 53

o Hair loss, pain, trouble breathing, nausea/vomiting, weakened immune system, rashes, neuropathy, constipation/diarrhea, bruising/bleeding.

Question 54

what is the GRP78 targeted cancer therapy?

Answer 54

 Changes the balance between cell survival and cell death – tend to allow cancer cells to survive.
 It is normally inactivated (located in the ER), but in response to ER stress (and cancer), it releases ligands, moves to the cell membrane (functions as a receptor), promoting cell survival.
 Blocking it kills head/neck cancer cells (also kills cells resistant to chemotherapy) in cancer cell lines – it initiates apoptosis.

Question 55

how does immunotherapy work in cancer?

Answer 55

o Now fairly common.
o Tumor antigens should be recognized by CD8+ T cells, but many cancers have ways to avoid them.
o With this therapy can free up the T-cells to attack the tumor cells.

Question 56

how are monoclonal antibodies used for cancer?

Answer 56

o Valuable if we can find targets on tumors that are not common on the rest of the body.
o B-cells have a particular target not expressed on other body cells, but present on lymphomas (CD20) – so strategy was to make an antibody to trigger cytotoxicity on only the cancer cells by binding to CD20.
o There are antibodies that can target Bcr-Abl.
o Angiogenesis inhibitors exists, but they are not as effective as we thought they would be, but now looking at is as an option for combination therapy.
 Not as effective since tumors find a way to work around the drug.

Question 57

Targets for cancer therapy

Answer 57

o Tyrosine kinase inhibitors, apoptosis agonist, hormone modulators, angiogenesis inhibitors, immune system activation, matrix degradation.